Trump's HHS, CMS Leadership Choices Underscore Focus on ACA Reform

Regulatory Update Legislation Manufacturing Quality Brexit: EMA Could Lose Up To Half Its US FDA Getting More Money Up Front FDA’s Revised Quality Metrics Program: Staff If It Has To Move, p. 10 Under Cures Bill Revisions, p. 5 Voluntary Now, Mandatory Later, p. 19

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costs, both Tom and Seema will play an in- Trump’s HHS, CMS Leadership Choices tegral role in leading that effort.” Price, a physician and current chairman of the House Budget Committee, has been Underscore Focus On ACA Reform a vocal critic of the ACA. He has sponsored Cathy Kelly [email protected] legislation (HR 2300) that would repeal the law completely and then establish a resident-elect Donald Trump’s choices series of programs designed to broaden to lead HHS and the Centers for Medi- insurance coverage, such as refundable tax Pcare and Medicaid Services demon- credits and high-risk insurance pools. The strate his focus on implementing alterna- legislation would also seek to lower costs tives to the Affordable Care Act – and not through medical liability reforms and fur- just repealing it. ther eliminating fraud and abuse in Medi- The Trump transition team announced care and Medicaid. Nov. 29 that Rep. Tom Price, R-Ga., will be Price’s bill is not generally expected nominated as HHS secretary and a health to serve as the template for a Trump-en- care policy consultant with ties to incom- dorsed attack on the ACA but it shows his ing Vice President Mike Pence, Seema Ver- interest and engagement in developing ma, will be named CMS administrator. alternatives to the law. Given Republican control of the Senate, Tom Price One likely starting point is expected to confirmation of the two appointments be legislation passed by both chambers seems assured. Sen. Orrin Hatch, R-Utah, of Congress through the budget reconcili- head of the Senate Finance Committee, ation process in December 2015. That bill which will hold hearings on the confirma- focuses on repealing key provisions of the tion, announced his support for the nomi- ACA related to the coverage expansion, nees in a Nov. 29 statement. HHS Secretary- such as federal subsidies and the individu- “Congressman Price has been selected al mandate. It would also eliminate the an- for this crucial HHS post because of his designee Price has nual market share fee paid by biopharma experience as a respected physician and manufacturers that was established by the deep understanding of the health law and strongly criticized law, a plus for industry. its flaws,” he said. “Verma’s strong health the CMS Innovation Price’s selection also signals a couple policy background will benefit the reform of other positive developments for drug effort at CMS, a mammoth agency whose Center and its firms. He has strongly criticized some responsibilities ballooned under President of the recent payment demonstration Obama ad his health law. As Republicans Medicare Part B projects developed by the CMS Center chart the course to repeal and replace the drug payment for Medicare and Medicaid Innovation, health law with patient-centered reforms particularly the Medicare Part B drug that increase access to care and reduce demonstration. Continued on page 4

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exclusive online content inside: Cover Trump’s HHS, CMS Leadership Choices Underscore UK To Ratify Unified Patent Court Deal Despite Focus On ACA Reform Uncertainty Over Its Future Participation http://bit.ly/2ghb7BN Legislation The UK government has announced that it will proceed 5 US FDA Getting More Money Up Front Under Cures with preparations for ratifying Europe’s Unified Patent Court Bill Revisions agreement, despite uncertainty over whether the UK will be able 6 Cures Bill Authorizes ‘Intercenter Institutes,’ to remain part of the UPC system once it leaves the EU. But Will US FDA Create Them? 8 21st Century Cures Revisions Tell FDA To Highlight ‘Patient Gottlieb Joins HHS Transition Team; Will Next Stop Be FDA? Experience Data’ http://bit.ly/2gheng9 Former US FDA, CMS official has been among those thought to Regulatory Update be in the running for Trump’s FDA commissioner nomination. 10 Brexit: EMA Could Lose Up To Half Its Staff If It Has To Move 11 EMA’s PRIME to Speed Sage’s Plans For Postpartum Sunscreen Industry Asks FDA For Flexibility Despite Depression Guidances’ Rigidity 12 Japan’s PMDA Hits Markers On Path To Key http://bit.ly/2gOztpK Performance Targets FDA latest sunscreen guidances incorporate little industry 17 ‘Regulatory Risk’: A New Factor In Risk/Benefit Equation input and are met with frustration and hope among industry At US FDA? stakeholders. The PASS Coalition and the Natural Products Association weigh in on future cooperation between FDA and Generic Drugs industry under SIA. 14 FDA’s ANDA Approvals

Amicus Eyes Broad Future Label For Migalastat After Clinical Trials Huge Filing Setback 15 New French Clinical Trial Rules Focus on Phase I http://bit.ly/2g0PEPE 16 Second French Trial Tragedy Verdict: No Danger Signs US FDA recommends company start a new study of oral Fabry In Lower Dose Triallists disease drug, to be designed using the agency’s irritable bowel syndrome guidance for measuring efficacy in diarrhea. Manufacturing Quality 19 FDA’s Revised Quality Metrics Program: Voluntary Now, Podcast: The Price is Right – HHS Transition And Next Mandatory Later FDA Commissioner? http://bit.ly/2gJaSQp Consumer Drugs Listen in for perspectives on the nomination of Tom Price as HHS 22 OTC Monograph Application Reviews Get Deadlines, secretary and other policy developments evolving since the US Not GRASE Flexibility elections. Drug Review Profile 25 Gilead’s Epclusa: FDA Sought To Push Efficacy Bar Higher Podcast: ACA Repeal And The Drug Industry In Hepatitis C http://bit.ly/2fP4oCB 28 Harvoni Approval Led To Narrowing Of Epclusa’s Listen in to this podcast on risk and opportunities for biopharma Breakthrough Status and possible scenarios for repeal of the US health care reform law and development of potential new provisions, once the new Advisory Committees Congress convenes and Donald Trump takes office as president. 30 Harvoni Approval Led To Narrowing Of Epclusa’s Breakthrough Status pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 3 US Election 2016

Continued from cover spent more than 10 years in Congress and experiment. Prospects that the Part B demo is also currently a member of the House would be implemented under his regime Ways and Means Committee and its Sub- now seem non-existent. committee on Health. Price has also spoken out in opposition of the Medicare Independent Payment Advisory CMS Administrator Choice Board, which was established by the ACA to Trump’s choice for Brings Medicaid Expertise develop cost cutting proposals that could be Trump’s choice for CMS administrator, Seema Verma, is president and founder of fast-tracked through Congress. IPAB has long CMS administrator, SVC Consultants, a health care consultancy been in the cross-hairs for biopharma compa- Seema Verma, has based in Indianapolis, Indiana. She brings nies because it has been expected to focus its experience with Medicaid reforms in a cost cutting efforts on drug spending. experience with number of states to her new role, signaling Price’s selection does not follow the re- Medicaid reforms in a the Trump administration’s likely focus as it cent pattern of former state governors approaches entitlement reform. being named to head the department number of states. Verma is considered the architect of but it is not without precedent (see box). the Healthy Indiana Plan, the nation’s first Former President Ronald Reagan named consumer-directed Medicaid program, es- two former members of Congress to head tablished in 2007 under Governor Mitch HHS during his administration – Richard Daniels and extended under Governor Schweiker and Margaret Heckler. Price has Mike Pence. The program requires Med- icaid enrollees to contribute to their own healthcare expenses through a mecha- A History Of HHS Secretaries nism modeled on health savings accounts. She and her company have also devel- • Sylvia Burwell, serving from 2014 to the present under oped Medicaid reform programs in Iowa, President Obama; was previously director of the Office of Ohio and Kentucky and helped design Management and Budget. Tennessee’s Medicaid expansion proposal. Verma also served as the state of Indiana’s • Kathleen Sebelius served from 2009-2014 under President Obama; health reform lead following passage of was previously governor of Kansas. the ACA and worked with public health agencies and state insurers as they pre- • Mike Leavitt served from 2005-2009 under President George W. pared to implement the law. Bush; was previously governor of Utah. Prior to her consulting firm, Verma • Tommy Thompson served from 2001-2005 under president George served as VP of planning for the Health & W. Bush; was previously governor of Wisconsin. Hospital Corporation of Marion County, Ind. And as director with the Association • Donna Shalala served from 1993-2001 under President Bill Clinton; of State and Territorial Health Officials in was previously chancellor of the University of Wisconsin-Madison. Washington, DC. She does not bring a track record in op- • Louis Sullivan served from 1989-1993 under President George Bush; erating large organizations to her role as was previously president of the Morehouse School of Medicine. head of CMS, which manages nearly $1tn in annual benefit outlays. That is unlike • Otis Bowen served from 1985-1989 under President Ronald Reagan; previous administrators, such as Marilyn was previously governor of Indiana. Tavenner, who was secretary of Health and Human Resources in the state of Vir- • Margaret Heckler served from 1983-1985 under President ginia before moving to CMS. Verma will Ronald Reagan; was a member of the US House of Representatives likely focus mainly on the policy side of the 1967-1983. job, working with Congress to design and • Richard Schweiker served from 1981-1983 under President Ronald implement measures to scale back some of the programs and responsibilities insti- Reagan; was a member of the US Senate from 1969-1981 and of the tuted for CMS by the ACA. US House from 1961-1969. Published online November 29, 2016

4 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Legislation

US FDA Getting More Money Up Front Under Cures Bill Revisions

Derrick Gingery [email protected]

DA would begin receiving 21st Century Cures funding sooner Paying It Forward: FDA Funding in under a revised schedule, which should help with implemen- 21st Century Cures Legislation Ftation of some of the bill’s provisions. The agency still will receive $500m in additional revenue as part of the bill, which the House passed overwhelmingly (392-26) on Nov. 30. But in the updated pay-out that was included in a manager’s amendment released Nov. 29, the agency’s first Cures payment would arrive in fiscal year 2017, rather than FY 2018 as was prescribed in the previous draft. The Cures bill is designed in part to help bring innovative treatments to patients faster. The House passed another version of the bill more than a year ago, but it stalled in the Senate. The latest draft is a compromise version that supporters hope reaches the White House before Congress’ lame-duck session ends. The Senate Nov. 29 Manager’s is expected to take up the bill early next week. Year Nov. 25 Draft Amendment FDA would receive $20m in FY 2017 in its “Innovation Account” under the new pay schedule, followed by $60m in FY 2018. That is $10m FY 2017 - $20m less than the agency would have received during the first two years of the previous schedule, but since the payouts begin a year sooner, FY 2018 $30m $60m the agency actually receives $70m more in the first three years from FY 2019 $60m $70m enactment in the manager’s amendment (see table). In return, FDA receives less in the final few years of the overall FY 2020 $60m $75m nine-year period than under the original schedule. But agency officials likely would prefer to receive more money sooner, rather FY 2021 $50m $70m than have to hope for congressional appropriations years down the road when enthusiasm over the bill has faded. FY 2022 $50m $50m Additional funding for FDA as well as NIH had been a sticking point throughout the process. The new total is $50m less than was FY 2023 $50m $50m included in the original House-passed Cures bill. That version also FY 2024 $50m $50m provided the money to FDA over five years. FY 2025 $75m $55m Countermeasures Excluded From Funding… The updated bill also further limits the uses for the additional mon- FY 2026 $75m - ey, which may in fact prove helpful for FDA. Under the manager’s amendment, the innovation account can Total $500m $500m no longer be used for provisions in the bill related to medical coun- Me Is This Shutterstock: termeasures. The section in question would allow FDA to issue workload problem they create. FDA has said it is not convinced the priority review vouchers to sponsors of approved “material threat incentive is working correctly. medical countermeasure” applications. Those include drugs that But industry and patient advocates like the programs, which prevent or treat harm caused by biological, chemical, radiological have been popular in part because vouchers can generate mil- or nuclear agents. The voucher program would sunset after Oct. 1, lions if they are sold. Companies already paid more than $300m for 2023, according to the bill. some vouchers, but they may be dropping in price. It is unclear why the change was made, but given FDA’s opposi- However, in a few cases, they have been redeemed for products tion to priority review vouchers, it may not be surprising that the that either were not approved or not approved within the expe- agency did not want to devote more money to it. dited timeframe. FDA officials oppose the vouchers, which allow a priority review The updated Cures bill also would extend the rare pediatric dis- for any application the holder chooses, in part because of the ease voucher program until 2020.

pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 5 Legislation

… But Drug Development, Patient Data Items improve collection and use of patient experience data. Still Eligible And if the agency decides to set up cross-center groups to im- The funding amendment still allows the new money to be used for prove application review in a specific disease area, the funding drug development provisions in the Cures bill, which include en- would be available. hancements to the biomarker qualification process, increased use That may include FDA’s Oncology Center of Excellence, which now of real world evidence, and guidance for novel trial designs. is being implemented. The idea was part of the federal Cancer Moon- Funding also could be used to establish a limited population shot initiative, which would receive $1.8bn in the Cures bill. antibacterial approval pathway, which would allow the agency to approve antibiotics for small patient groups, as well as changes to Published online November 30, 2016

Cures Bill Authorizes ‘Intercenter Institutes,’ But Will US FDA Create Them? Derrick Gingery [email protected]

A number of Former FDA Commis- sioner Mark McClellan, who stakeholders have favors passage of the bill, has said FDA resources re- embraced the main limited and that some of its areas of expertise are opportunity to potentially limited in size compared to use the legislation to the rest of the agency and may not lend themselves to reorganize FDA around such a reorganization. FDA would receive $500m diseases instead of in additional funds through the Cures bill, spread be- product areas. tween fiscal years 2018 and 2026. Among the uses for DA may wind up only meeting the by the federal Cancer Moonshot initiative, the FDA Innovation Account are creation minimum requirements for establish- which mandated creation of an Oncology of intercenter institutes. Fing intercenter institutes within the Center of Excellence at FDA. agency that are included in the new ver- But the Cures language is interesting Patients Can Be A Focus sion of the 21st Century Cures bill. because it states that FDA “shall establish Intercenter institutes may be created for a The latest draft of the legislation, one or more” intercenter institutes for a number of activities, according to the bill. which was approved in the House of major disease area or areas. Whether FDA They include: Representatives on Nov. 30, includes a will be able to or want to create multiple provision requiring the agency to create institutes remains to be seen, which may •• Coordination of staff expertise in a cross-center groupings to better coordi- be why the legislation does not mandate major disease area; nate its handling of major diseases. The a more widespread implementation of •• Streamlining when appropriate “the re- “intercenter institutes” are intended to the idea. view of medical products to diagnose, streamline activities among the centers A number of stakeholders have em- cure, mitigate, treat, or prevent the for drug evaluation and research, biolog- braced the opportunity to potentially use specific diseases” in a specific area; ics evaluation and research and devices the legislation to reorganize FDA around Promotion of scientific programs within and radiological health. diseases instead of product areas. But •• centers related to a major disease area; The provision appears similar to a Sen- there have been questions about wheth- ate bill introduced earlier this year. And er such a radical change would actually •• Development of programs to recruit, the model already has been made famous be more efficient. train and provide continuing education

6 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Legislation

for expert personnel; A center of However, a center of excellence for or- •• Enhancement of patient interactions; phan products may already have been and excellence for orphan created indirectly as part of the prescription drug user fee renewal. FDA agreed •• Facilitation of collaborative relationships products may already to place rare disease staff within review with other agencies within HHS have been created divisions where necessary to enhance ap- The agency also must allow a public com- plication review. ment period while an institute is being cre- indirectly as part of Reorganizations also can take years to ated as well as give notice at least 60 days be- implement. FDA’s Program Alignment fore one is terminated, according to the bill. PDUFA renewal. Group process, which will include the in- Improving patient interaction could pro- tegration of Office of Regulatory Affairs vide an interesting impetus for creating a likely will be the Oncology Center of Excel- cross-center group. FDA has been work- lence, which is now being established. field staff into the product centers, began ing on a number of avenues for increasing Richard Pazdur, director of the Office of in 2013 and is not yet completed. patient input in drug development for the Hematology and Oncology Products, has FDA also could have a new commission- past several years, such as conducting pub- been named the center of excellence’s act- er arriving in the coming months once the lic meetings to gather patient views on spe- ing director. He also will maintain his drug Trump Administration begins. The new cific diseases. review and approval duties. agency head may not be willing or able Rare disease advocates have been look- Jeff Allen, president and CEO of the to change the complexion of the agency ing for more consistent access to FDA staff Friends of Cancer Research, told the Pink right away. Sheet that FDA could use the oncology at conferences and other forums and the FDA Commissioner Robert Califf is push- center of excellence as a pilot project be- idea of a patient-facing institute would be ing establishment of the Oncology Center in keeping with other themes in the legis- fore considering using the concept for of Excellence, but otherwise has not made lation, which also requires FDA to release other disease areas. significant organizational changes. When a summary of the patient experience data Many other diseases areas have been he hired Rachel Sherman to become dep- that was considered for product approval. suggested for intercenter institute treatment, such as infectious diseases, neuro- uty commissioner for medical products Will Oncology Be science and cardiovascular disease. and tobacco, he continued the practice of The Only One? Another candidate could be rare dis- having the center directors report directly It seems possible that only one intercenter eases. Some stakeholders have suggested to him, rather than have them report to institute may be created in the near future. the agency create rare disease-focused Sherman. Indeed, only one must be completed staff to make orphan product reviews within a year of the bill’s enactment. That more consistent. Published online November 28, 2016

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pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 7 Legislation 21st Century Cures Revisions Tell FDA To Highlight ‘Patient Experience Data’ M. Nielsen Hobbs [email protected]

ovember 30 was the day! That’s when the House passed (another version of) the 21st Century Cures legislation. But In what could be a significant move Nunlike the version that flew through the House last sum- to encourage the agency’s own mer only to stop as the Senate crafted its own bill, this time both chambers appear in alignment, and the Senate is expected to pass research efforts, the legislation the bill shortly. Given the somewhat more staid chronometer of the upper chamber, that means probably sometime next month. “exempts FDA from going through The revised Cures bill runs just under a thousand pages and ad- the Paperwork Reduction Act dresses everything from contractor fraud to mental health coverage parity, and the significance of the legislation is highlighted by clearance process when requesting the fact that negotiations seemed to have extended through the Thanksgiving holiday and agreement on the revisions were an- information from patients regarding nounced in a Saturday press release. Among the additions to the bill is the requirement that fol- their disease or treatments, allowing lowing the approval of a product, FDA “shall make public a brief FDA to get more timely feedback statement regarding the patient experience data and related information, if any, submitted and reviewed as part of” the applica- from patients instructs FDA.” tion, the bill states. The statement needs to be issued within six months of approval, and the legislative instructions don’t in and of themselves change product review standards, but they send a through public workshops and other less formal means, but the clear message to FDA and industry: Congress expects you to take contentious approval of Sarepta Therapeutics Inc.’s Exondys 51 patient input seriously. (eteplirsen) included intense personal criticism of some reviewers The Cures legislation also directs FDA to issue guidance on the by Duchenne muscular dystrophy advocacy groups, and the whole collection of patient experience data, a requirement similar to episode seemed like it might sour the drug center staff’s view on provisions in the user fee commitment letter that have already patient interactions. prompted the next iteration of the Prescription Drug User Fee Act to be dubbed “Patient-UFA.” Moonshot, Precision, And The Brain In what could be a significant move to encourage the agency’s The announcement of the legislative agreement by House Energy own research efforts, the legislation also “exempts FDA from go- and Commerce Committee Chairman Fred Upton (R-Mich.) and ing through the Paperwork Reduction Act clearance process when Senate HELP Chairman Lamar Alexander (R-Tenn.) highlighted sev- requesting information from patients regarding their disease or eral key aspects of the bill: treatments, allowing FDA to get more timely feedback from pa- •• “Help bring drugs and devices to market more quickly and at tients instructs FDA,” a summary of the bill states. less cost by making needed reforms to the FDA, including: ex- The agency has been steadily increasing its patient outreach pedited review for breakthrough devices, increased patient in- volvement in the drug approval process, a streamlined review more about 21st Century Cures process for combination products that are both a drug and de- Visit our website at www.thepinksheet.com to read vice, and freedom from red tape for software like fitbit or calorie more online about the 21st Century Cures bill: counting apps.

CLICK Regenerative Medicine In Cures: •• “Provide $4.8 billion to National Institutes of Health, including: Conditional Approval Dropped In Lieu $1.4 billion for President Obama’s Precision Medicine Initiative Of ‘Breakthrough’-Style Approach to drive research into the genetic, lifestyle and environmen- tal variations of disease; $1.8 billion for Vice President Biden’s The Evolution Of 21st Century Cures “Cancer Moonshot” to speed research; and $1.6 billion for the Legislation BRAIN initiative to improve our understanding of diseases like Alzheimer’s and speed diagnosis and treatment.

8 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Legislation

•• “Provide $500 million to the Food and Drug Administration. GPhA will push other legislation •• “Provide $1 billion in grants to states to address the opioid crisis. aimed at allowing ANDA sponsors •• “Address the country’s mental health crisis and help the one out of five adult Americans suffering from mental illness and access to samples of brand drugs substance abuse disorders receive the care they need.” even if the products have a restricted

Generic Association Disappointed, distribution program through a REMS. But Supportive enactment of the bi-partisan CREATES Act sponsored by Senators The Generic Pharmaceutical Association (GPhA) released a same- Grassley, Lee, Leahy, and Klobuchar and the FAST Generics Act day statement that “We congratulate Chairman Upton, Ranking sponsored by Representatives Stivers and Welch.” Member Pallone, Representative DeGette, Chairman Alexander The CREATES Act and the related FAST Generics Act are both and Ranking Member Murray on the release of the final draft of aimed at allowing ANDA sponsors access to samples of brand the 21st Century Cures Act. GPhA recognizes this bill is a biparti- drugs even if the products have a restricted distribution program san achievement that should spur innovation and benefit patients. through a REMS. Notably, the package includes important funding to support the The legislation hasn’t proven especially popular, so not being Comprehensive Addiction and Recovery (CARA) Act which will included in a Cures package which was the subject of lengthy ne- help address the public health crisis surrounding prescription drug gotiations to ensure smooth passage isn’t surprising. The fact that abuse. We urge Congress to expeditiously pass this bill.” GPhA chose to issue a Saturday press release highlighting the ab- The statement by GPhA CEO Chip Davis notes that “while the sence suggests the association wants to make the bills a center- 21st Century Cures Act released today does not include provisions piece of its legislative agenda in the policy debates that will unfold GPhA supports to increase prescription drug pricing competition, next year as part of the renewal of the user fee programs and what- we will continue working with Congress to find solutions to rising ever legislation passes as part of the Republican pledge to repeal drug costs that bring safe and effective generic drugs to market and replace the Affordable Care Act. more quickly and ensure more patients and payers have access to them. Towards that end, GPhA will continue to support and seek Published online November 27, 2016

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pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 9 regulatory update Brexit: EMA Could Lose Up To Half Its Staff If It Has To Move Maureen Kenny [email protected]

he European Medicines Agency could lose up to half its nearly T 900-strong staff if the agency moves from London following the depar- ture of the UK from the EU. Nonetheless, the agency is determined to avoid disruption to its operations and to continue to meet its public health obligations, both in the run-up to Brexit and following it. “What we cannot afford – no matter what happens – is a disruption of our operations” or a delay in the evaluation and pharmacovigilance of medicines for which the EMA is responsible, Noel Wathion, the EMA’s deputy executive director, said. The figure of potential staff losses of “up to 50%” comes from the EMA having sur- Shutterstock: Octavus Shutterstock: veyed its staff and looked at other agencies facing similar situations, Wathion told a conference in London*. Losing UK exper- “We cannot afford – no matter what happens – a tise completely and losing a considerable disruption of our operations.” Noel Wathion, EMA number of other staff members would be a worst-case scenario for the agency, but it may have to prepare for just that, he said. decision is taken late on in the process and The task force will have to adapt depend- UK nationals account for 60 (6.68%) of the the agency has little time in which to pre- ing on the information the EMA receives agency’s total workforce of 890. In addition, pare to move, Wathion said. throughout the negotiation process. the UK medicines regulator, the MHRA, deals The timing of the decision will deter- with around 20% of the EMA’s workload. mine when the EMA invokes its business Impact assessment continuity plan (BCP), the EMA deputy The task force of which Wathion is a co-chair Various scenarios head continued. The agency has only had is in the process of preparing an extensive The two key issues are the location of the to use its BCP once before – during the impact assessment with regard to the po- EMA post Brexit and the future relationship 2009 influenza pandemic – and it is being tential implications of Brexit on the agency. between the UK and the EU in the area of adjusted for use in this new situation. The EMA’s Tony Humphreys, another co- medicines regulation. Wathion, who is one Assessing the impact of Brexit on the chair of the task force, described Brexit as of the co-chairs of the Brexit task force the capacity and capability of the EMA and “a big joker in the pack in terms of desta- EMA set up following the surprise result of more broadly the European medicines bilization and uncertainty.” While we can the UK referendum on the EU on June 23, regulatory network is also hard at this hope for the best option, we need to pre- outlined various scenarios for both issues. stage. If the UK remains in the European pare for the worst option, he said, as to do Theresa May, the UK prime minister, Economic Area, the impact on the work- otherwise would be indefensible. insists that the formal two-year negotia- load of the EMA would be minimal, said *Noel Wathion and Tony Humphreys were tion process that will lead to the UK leav- Wathion. If the UK does not remain within speaking at the Annual European Medicines ing the EU will begin by the end of March the EEA, “there are so many different sce- Agency Review of the Year and Outlook for 2017. One scenario is that the decision on narios” and the eventual situation, he said, 2017, which is organized jointly by the EMA whether to move the EMA and where it will depend on the ultimate outcome of and The Organisation for Professionals in will go is made early in the formal Brexit the negotiations that take place among Regulatory Affairs and which is taking place negotiations. In that case, the agency EU member states. in London on Dec. 1 and 2. could have “a lengthy period” of around “We are planning for the best-possible sce- two years in which to prepare. However, it nario – the UK remaining in the EEA – and for Published online December 2, 2016. will be a “completely different story” if that the worst-case scenario,” said Wathion. From the editors of Scrip Regulatory Affairs.

10 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Regulatory Update

EMA’s PRIME To Speed Sage’s Plans For Postpartum Depression

Neena Brizmohun [email protected]

drug being developed to treat prises the cautious use of pharmacological postpartum depression has be- therapies, but there are no drugs approved Acome the first product for a psy- specifically for the condition. chiatric condition to secure designation SAGE-547 is an allosteric modulator of under the European Medicines Agency’s both synaptic and extra-synaptic GABA-A PRIME scheme for the priority review of receptors. Data suggest that women with medicines for unmet medical needs. PPD may be unusually sensitive to the rap- There are currently no approved thera- id decline in allopregnanolone that occurs pies specifically for postpartum depres- after childbirth, potentially causing GA- KieferPix Shutterstock: sion (PPD), according to the drug’s devel- BA-A-system mediated mood disruption, oper, Sage Therapeutics, which having met Sage explained. The company noted that ment at the time of application for a mar- PRIME’s rigorous entry criteria will now re- allopregnanolone is found at its highest keting authorization. ceive enhanced support from the EMA and levels in women during the third trimester the chance of accelerated assessment. of pregnancy, returning to normal levels US Breakthrough The designation, revealed by the EMA generally within 24 hours of giving birth. Designation earlier this month, means that Sage will SAGE-547’s mode of administration is an As with a number of other PRIME-desig- have shown the agency that its investiga- intravenous infusion, Elsayed said, adding nated products, Sage-547 has also been tional product, SAGE-547, might offer a that “while this formulation is not neces- granted breakthrough therapy designa- major therapeutic advantage over exist- sarily an advantage considering these pa- tion (BTD) by the US Food and Drug Ad- ing treatments, or benefit patients without tients can also take oral antidepressants, ministration for PPD. PRIME and BTD are treatment options. SAGE-547 is the 14th the data so far indicate a far more impres- similar in that they provide companies product to be accepted for PRIME since the sive efficacy profile.” with enhanced support during their prod- scheme was launched in March this year. Jonas said that Sage-547 could be a uct’s development so that innovative new To be accepted for PRIME, a medicine good option for women who might be medicines can reach patients faster. has to show its potential to benefit pa- concerned about taking antidepressants “Obtaining PRIME and breakthrough tients with unmet medical needs based on while they are breast feeding. Sage-547 designations from both EMA and FDA re- early clinical data. has a short half-life. It is given as an infu- spectively underscore the urgent need for Sage used “promising clinical data from sion for 60 hours and breast feeding can providing treatment options for these pa- our Phase II study” to support the PRIME resume seven days after the last dosing. tients,” Elsayed commented. designation, said the company’s CEO, Jeff “We hope that is another major potential The company could be looking at a Jonas, adding that its acceptance on the advantage for mothers,” Jonas said, add- US launch for Sage-547 in PPD within 24 scheme “reflects the urgent need for treating that the company will be doing further months, according to Jonas. He hopes ment options for women suffering with testing on breast milk of patients who have that the current Phase II trials in moder- postpartum depression.” The company said received treatment with Sage 547. ate and severe PPD patients will meet re- it was initiating “planning for our European Under PRIME, Sage will get early and quirements for US approval. “We think the operations and clinical trial infrastructure.” proactive support from the EMA to help design of the current Phase II trials along Datamonitor analyst Maha Elsayed optimize the generation of robust data with the controlled Phase II data we have agreed that the “the Phase II data for SAGE- on its product’s benefits and risks. Devel- reported for PPD previously should be 547 are very encouraging.” The data indi- opers are assigned a dedicated contact sufficient for a US filing, pending regula- cate “strong efficacy and safety potential,” point and a rapporteur from the agency’s tory communication. If the FDA agrees, we Elsayed said. scientific committee, the CHMP, as well as would anticipate enlarging the trials cur- a meeting with a multidisciplinary group rently under way, possibly by another 80- Impressive Efficacy Profile of experts to provide “broader guidance 100 women. We would then project that PPD is a distinct and readily identified ma- on the overall development plan and data from a Phase III PPD program could jor depressive disorder affecting a small regulatory strategy,” the company noted. be available in 2017. However, the final de- percentage of women after childbirth. Cur- Medicines eligible for PRIME are also po- cision regarding the Phase III program will rent standard of care for severe PPD com- tentially eligible for accelerated assess- await receipt of FDA minutes.” pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 11 Regulatory Update

The company is more circumspect Six other applications were also reviewed products with PRIME designation indicates about whether its US PPD 547 program during the meeting, but these were all that of 14 products designated as of Sept. will be enough for EU regulators. Given rejected. The other applications covered 21, none have been withdrawn from the the nature of Sage-547, its mode of ad- products for treating mesothelioma, To- scheme or no longer meet the eligibility ministration and the lack of treatments ap- urette syndrome, non-alcoholic steatohep- criteria. Some 46 applications reviewed by proved for PPD, Jonas believes the data so atitis, critical limb ischemia in diabetics, and the CHMP have been rejected and four far obtained will mean that the company heart failure patients undergoing coronary applications were “not started” by EMA as can take the same approach that it hopes arterial bypass grafts. Applicants who do they were deemed outside the scope of to take in the US. not qualify for PRIME support continue to the scheme or with a format and content be able to request scientific advice/protocol inadequate to support their review. Six PRIME Rejections assistance and may also benefit from other Sage’s application for PRIME was reviewed support tools from the agency. From the editors of Scrip Regulatory Affairs. by the CHMP during its Nov. 7-10 meeting. The EMA’s recently published list of Published online November 27, 2016

Japan’s PMDA Hits Markers On Path To Key Performance Targets Ian Haydock [email protected]

ong-running industry concerns over the “drug lag” in Japan compared with Lother major markets have largely evaporated in recent years, with a hand- ful of new products now even approved for the first time globally in this key Asian country every year, helped by a steady trend towards faster approval times. The main US research-based association, the Pharmaceutical Research and Manufacturers of America, for instance, noted earlier this year that it expects the lag between US/EU and Japanese approvals to fall to an average of around five months over the 2015-19 period. Kanuman Shutterstock: For many individual products, there is now virtually no delay before approval in Ja- Japan PMDA Approvals FY2011-15 pan, helped by companies’ now routine in- FY2011 FY2012 FY2013 FY2014 FY2015 clusion of Japanese sites in international si- multaneous clinical development programs. NDAs approved 130 134 138 118 116 In its new annual report and performance review for fiscal 2015 (ended March (Of which priority reviews) 50 53 42 44 37 31, 2016), data from Japan’s Pharmaceuti- cals and Medical Devices Agency (PMDA) bear out these improvements, showing NDAs Filed With Japan PMDA FY2011-15 that review periods for both standard and FY2011 FY2012 FY2013 FY2014 FY2015 priority products are moving towards its own internal performance targets. NDAs filed 130 140 123 128 127 Overall, 116 new drug applications in the period, roughly on a par with the 118 Total NDAs approved 128 135 118 116 29 in the previous fiscal year.

12 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Regulatory Update

PMDA Standard Review Times For New Drugs FY2011 FY2012 FY2013 FY2014 FY2015

Percentile 50 50 50 60 70

Total review time 11.5 [15.7] 10.3 [11.9] 11.3 [12.3] 11.9 [12.3] 11.3 [11.7] (months)/[80th percentile]

Number of approved applications 80 81 96 73 79

The regulator said earlier in the year that For the 37 priority review products ap- said it exceeded its goal of finalizing con- the approvals in the period included 39 new proved in fiscal 2015, the time was 8.7 sultation records within 30 business days of active ingredients, down from 52 in the pre- months (60th percentile), again achieving the consultation for 80% of products. vious fiscal year but dominated by oncology the target time against the percentile target. and including several global first approvals For new (first time) generics, PMDA’s Global Trials such as Shionogi & Co. Ltd.’s TPO receptor target is to approve 50% of applications In line with the internationalization of clini- agonist Mulpleta (lusutrombopag). within a target review time of 10 months in cal development, the report states that the “PMDA intends to take an active approach Increased staffing has boosted performance: to global clinical trials” and that the agency completed 66 consultations in relation to as of this April 1 the agency employed 873 people, these in fiscal 2015. Consultations for glob- up from 521 in 2009, with a goal to reach 1,065 al trials have remained fairly constant in the mid-60s over the past few years. employees by April 2018. 657 clinical trial notifications were submitted in the fiscal year, of which 276 were The number of NDAs filed was about the fiscal 2018. Last fiscal year, the median re- for global studies, a big rise from the 181 in same as in fiscal 2014 at 127 (of which 29 view time was already down to 8.2 months the previous year. were approved in the same 12-month peri- for the 635 approved products. The agency is also leading a roadmap od), while 37 drugs within the total received In line with wider government policy to initiative on such trials at the Asia-Pacific priority reviews, down from 44 in fiscal 2014. encourage generic use, PMDA has been Economic Cooperation grouping, and has Note: some approvals may be for prod- taking other steps to build its expertise, set up an Asian training center at its Tokyo ucts filed in the previous fiscal year. and set up a dedicated Office of Generic headquarters to help build expertise at Drugs around two years ago. drug and device regulators across Asia. Review Time Targets PMDA has over the past few years been Staffing, Consultations Experts, ADRs making strides towards its targets for re- The performance is due in large part to Among the other activities highlighted in ducing review times, which it defines as steady increases in staffing at the agency, the lengthy report is the increased use of the gap between application and approval which as of this April 1 employed 873 external experts to act as advisors to help dates, comprising both agency review and people in total, up from 521 on the same speed reviews of filings in specialist areas applicants’ response time. date in 2009, and including 560 in the re- such as genomics and regenerative medi- The goals have been set at nine months view section (up from 350 in 2009). The cine; the PMDA now has close to 1,400 for priority reviews and 12 months for stan- overall target is to expand total employ- such commissioned experts. dard reviews, and the percentile achieve- ees to 1,065 on April 2018. The annual review notes that 399,852 ment rates for these targets have been ris- Another major factor is the use of pre- reports were filed by marketing authori- ing incrementally to a target of 80% by fiscal IND and pre-approval filing consultations zation holders relating to adverse reac- 2018. In fiscal 2015, the percentile for new to discuss and agree issues related to trial tions occurring globally, including around active ingredients was set at 70% for stan- design and clarify data requirements. 51,000 in Japan. The PMDA received 1,566 dard reviews and 60% for priority reviews. In the fiscal year under review for exam- claims for fiscal relief for adverse drug reac- The PMDA said that the total median ple, 371 consultations on clinical trials were tions in Japan under its ADR compensation review time for standard reviews (79 conducted (versus 411 in FY2014), includ- scheme, of which 1,279 were approved. products) was 11.3 months (including 5.1 ing 73 in oncology. There was an average months of “applicant time”), achieving the two-month wait from request to consulta- From the editors of PharmAsia News. target for the year. tion, in line with target, and the regulator Published online November 28, 2016 pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 13 Generic Drugs FDA’s ANDA Approvals

Sponsor Active Ingredient Dosage; Formulation Approval Date Novel Labs Hydrocodone bitartrate/acetaminophen 300 mg/5 mg, 300 mg/7.5 mg and 300 mg/10 mg; tablet 11/14/2016

Appco Lamivudine 150 mg and 300 mg; tablet 11/21/2016

Teva Tolterodine tartrate 2 mg capsule and 4 mg extended-release capsule 11/22/

Lannett Metaxalone 800 mg; tablet 11/22/2016

Apotex Memantine HCl 7 mg, 14 mg, 21 mg and 28 mg, extended-release capsule 11/22/2016

Accord Drospirenone/ ethinyl estradiol 3 mg/0.03 mg; oral-28 tablet 11/22/2016

Aiping Ibuprofen 400 mg, 600 mg and 800 mg; tablet 11/23/2016

5 mg, 20 mg, 100 mg, 140 mg, 180 mg and 250 mg; Chemi Temozolomide 11/23/2016 capsule

Par Entecavir 0.5 mg; tablet 11/23/2016

Alvogen Malta Budesonide 3 mg; capsule 11/23/2016

Cadila Rosuvastatin Calcium 5 mg, 10 mg, 20 mg and 40 mg; tablet 11/23/2016

Wes Pharma Oxycodone HCl 5 mg/5 mL; oral solution 11/23/2016

Aurobindo Nevirapine 100 mg; extended-release tablet 11/23/2016

Amlodipine besylate; olmesartan EQ 5 mg base/20 mg, EQ 5 mg base/40 mg, EQ 10 mg Torrent 11/25/2016 medoxomil base/20 mg and EQ 10 mg base/40 mg; tablet

Amneal Diclofenac sodium/ misoprostol 50 mg/0.2 mg and 75 mg/0.2 mg; delayed-release tablet 11/25/2016

EQ 25 mg tartrate, EQ 50 mg tartrate, EQ 100 mg tartrate Actavis Elizabeth Metroprolol succinate 11/25/2016 and EQ 200 mg tartrate; extended-release tablet

Natco Armodafinil 50 mg, 150 mg and 250 mg; tablet 11/28/2016

Accord Zoledronic acid EQ 4 mg base/5 mL; injectable, infusion 11/28/2016

1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 Inventia Iloperidone 11/28/2016 mg; tablet

Gland Dexrazone HCl EQ 500 mg base/vial; injection 11/28/2016

Macleods Risedronate sodium 5 mg, 30 mg and 35 mg; table 11/29/2016

Tentative Approvals Aurobindo Fingolimod 0.5 mg; capsule 11/1/2016

Lupin Abacavir sulfate/lamivudine 600 mg/300 mg; tablet 11/21/2016

Sodium picosulfate/ magnesium oxide/ Par 10 mg/3.5 gm/12 mg; oral solution 11/21/2016 anhydrous citric acid

Lupin Armodafinil 50 mg, 100 mg, 150 mg, 200 mg and 250 mg; tablet 11/28/2016

75 mg, 100 mg, 150 mg, 200 mg, 225 mg and 30 mg; Alkem Pregabalin 11/30/2016 capsule

14 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Clinical Trials

New French Clinical Trial Rules Focus on Phase I

Ian Schofield [email protected]

Volunteer Studies Some of the new provisions have been included as a result of the Phase I trial with Bial’s FAAH inhibitor in January this year when which one volunteer died and several others were hospitalized. For example, research sites are authorized for only three years at a time, rather than seven, where first-in-human studies are conducted, while the seven-year period will be retained for other studies. For all trials, serious unexpected side-effects that pose a threat to life or result in death must be notified immediately. For those involving healthy volunteers, sponsors must immediately declare all serious adverse events (whether expected or not), including those that result in death, put the person’s life in danger, require hospital- ization, or cause a significant or lasting disability. harmaceutical and medtech firms conducting clinical trials in Also introduced is a clearer definition of “new information” France have some new rules to contend with in areas such as emerging during the course of a clinical trial to cover any informa- Penhanced safety reporting in Phase I studies, authorization of tion that could result in a re-evaluation of the benefit-risk of the trial sites, the role of ethics committees, and contracts with public drug or the trial, changes in the use of the product, the suspension health establishments. or stopping of the trial, or changes to the protocol. The changes are aimed at bringing French clinical research rules In the case of first-in-human (FIH) studies, all serious undesir- into line with the new EU Clinical Trial Regulation (CTR), which will able events are considered “new information.” All new information take full effect in October 2018, and to incorporate lessons learned regarding healthy volunteers must be notified by the sponsor to from the Phase I episode in January this year. the ANSM, the ethics committee and the director general of the The new rules are in the form of two decrees that were published regional health agencies. If it concerns FIH administration, the in late November as well as a government order of June 2016 that sponsor must suspend administration of the drug, take appropri- implemented law No 2012-300 on research involving humans (the ate emergency steps, and immediately inform the competent au- “Loi Jardé” of March 2012). Implementation of the Loi Jardé had thority and the ethics committee. been put on hold pending adoption of the CTR. The first decree As a result of the Phase I Bial trial in France, the European Medicines implements further aspects of the Loi Jardé, while the second cov- Agency drafted a concept paper in July with a view to reviewing its ers trial contracts. guideline on FIH studies. A consultation on the concept paper, which Under the changes to the law, the concept of “biomedical re- includes proposals such as better use of non-clinical data in conduct- search” has been replaced by a new definition – “research involving ing the overall risk assessment for Phase I studies and determining the the human person” – covering both interventional and non-inter- therapeutic dose and dose escalation strategies, ended on Sept. 30. ventional research. Trials are split into three categories: interventional studies involv- Contracts ing some risk to the participants, including those using medicines The second decree explains the procedures for signing contracts or other health products; less invasive trials with minimal risks in- under which commercial sponsors conduct interventional clinical tended to evaluate existing interventions; and observational stud- trials in public health establishments. Such contracts are signed by ies. The first type must be approved by the regulatory body (the the sponsor and the trial site, and apply any new commercial trials ANSM) and an ethics committee, while the second and third kinds for which a draft contract had been made after the decree’s publi- require only a go-ahead from an ethics committee. cation date (Nov. 17, 2016). The role and functioning of the national commission for research Alongside changes to its own rules on clinical trials, France ran involving humans have been more clearly spelled out, including a pilot project in 2015-2016 to stress-test the new trial application the coordination of ethics committees. The secretariat of this com- procedures that will be brought in by the CTR in 2018. The pilot mission is responsible for the random selection of an ethics com- involved a single notification to the sponsor comprising the opin- mittee to oversee a particular clinical trial. ion of both the ANSM and the ethics committee, the aim being to Communications between sponsors and ethics committees will allow companies and other players to familiarize themselves with be managed by the secretariat of the national commission once a the new procedures and to see how best to ensure proper coordi- new IT system allowing this has been set up. This should be up and nation between ANSM and the ethics committees.

Shutterstock: Gustavo Frazao Gustavo Shutterstock: running and sponsors notified by Dec. 31, 2017 at the latest. Published online November 28, 2016

pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 15 Clinical Trials Second French Trial Tragedy Verdict: No Danger Signs In Lower Dose Triallists Ian Schofield [email protected]

he French medicines regulator, ANSM, has published another report T on the Phase I study with Bial’s FAAH inhibitor, BIA 10-2474, this time on clinical and cerebral MRI data on about 80 volunteers who took lower doses of the product than those in trial cohort number five, in which one volunteer died and four others were hospitalized with neurological damage. The report concludes that about half of the 80 volunteers did show some symptoms but that they were in line with what might be expected in a first-in-human (FIH) study and did not resemble those observed in the volunteers in cohort five, who were given 50mg doses of the ex-

perimental drug in the multiple ascending Gunnar Pippel Shutterstock: dose (MAD) stage of the trial. ANSM will be hoping that this latest report will at least help to quash claims made I study), ANSM, the volunteers, the neurolo- pharmacology and radiology. It had access in October by Le Figaro newspaper that gists who examined the volunteers and the to a summary of the adverse events report- some data from the trial had been con- local neuro-radiologists who conducted the ed by volunteers during the trial, informa- cealed and that some neurological side-ef- MRI scans.” The experts on the committee tion on volunteers who agreed to attend a fects at lower doses had gone unreported. worked on a voluntary basis, it added. consultation, and the cerebral MRI scans. Following the claims in Le Figaro, ANSM In its report, published on Nov. 25, the issued a statement denying that any such committee notes the conclusion of the first The Clinical and MRI Evidence information had been withheld, whether CSST that the adverse neurological events The committee noted that during the from the general social affairs inspectorate seen in five volunteers in cohort five (in- Phase I trial, a total of 84 volunteers had (IGAS) or from the judicial authorities. The cluding the one who died and four others received BIA 10-2474. Neurological clinical agency added that independent experts on who were hospitalized) were “clearly linked data were made available for 80 of them the temporary specialized scientific com- to the substance tested”, even though the and MRI data for 79. mittee (CSST) set up after the trial ended exact mechanism of action had not been Looking at the clinical data, the commit- had produced a report in April that exam- elucidated. Cohort five involved a total of tee found that 40 of the volunteers showed ined the entire preclinical, toxicological six volunteers, one of whom had no neuro- no neurological symptoms. Of the remain- and pharmacological dossier and found no logical damage. der, 28 had symptoms that either resolved signals that would have precluded moving Following the suspension of the trial, (21) or persisted for a certain period (7). from preclinical to clinical studies with BIA health minister Marisol Touraine said that The first type included headache, ver- 10-2474. all volunteers who had received the drug tiginous sensations associated with or- should have a clinical assessment and ce- thostatic hypotension or fever, visual New Committee, New Report rebral MRI, which took place between Jan. disturbances, lumbar pain, paresthesia, Announcing this latest report, which was 20 and Feb. 19. Anomalies were detected dilation of the pupils, problems concen- produced by a second CSST set up by ANSM in one volunteer suggesting a cerebro- trating, etc. to look specifically at clinical and MRI data, vascular accident, so in May the minister The second type included headache, as- the agency went out of its way to stress asked for a separate independent assess- thenia, difficulty concentrating, sleeping that the committee’s work was conducted ment of all the results. problems, pain in the hands, etc. Twelve “in total independence with regard to Bial, A new CSST was subsequently set up by volunteers reported similar symptoms ap- Biotrial (the CRO that conducted the Phase ANSM comprising experts in neurology, pearing more than 15 days after finishing

16 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Clinical Trials

the trial. Neurological examinations were volunteers were “in line with data from the the volunteers who received BIA 10-2474 normal in all of the volunteers who exhib- medical literature in volunteers taking part were “in line with those observed in first- ited symptoms, the committee found. in first-in-human trials.” in-human studies and do not resemble, As for the MRI scans, the results were Moreover, it said, no signs potentially either in their description or their sever- considered normal in 37 volunteers, while signalling cerebral damage were seen in ity, those observed in the volunteers who in the other 42 one or more anomalies the clinical examination by neurologists were hospitalized in the MAD cohort five.” were seen by at least one of the two ra- between one and six months after the Moreover, it added, the anomalies re- diologists on the panel. These anomalies volunteers took part in the study, “even in vealed by MRI scans were “in line with included T2/FLAIR white matter hyper- the seven volunteers who reported per- those discovered fortuitously in healthy intensities and choroid plexus cysts, and sistence of certain symptoms.” volunteers taking part in biomedical re- punctiform hyposignals. It added that the frequency of anomalies search. They differ radically from the very There was also a case of cerebellar in- seen in the MRI scans was also in line with distinctive cerebral lesions observed in the farct sequelae in one volunteer – the com- data from the medical literature “which MAD cohort five.” mittee noted that while it was not possible report such anomalies in about 50% of Biotrial told the Pink Sheet that the re- to exclude a causal link between admin- healthy volunteers of average age taking port was consistent with what the com- istration of the trial drug and the stroke, part in biomedical research.” The most fre- pany had been saying from the start and this seemed unlikely because the sequelae quent incidents were T2/FLAIR white mat- “confirms that the molecule toxicity hap- were different from the lesions seen in the ter hyperintensities which it said were not pened in an unforeseeable way.” It added MAD cohort five, and suggested a stroke of specific to any particular mechanism or that the findings in the earlier cohorts were thromboembolic origin. disease but tended to increase with factors “unrelated to what happened in the 50mg such as age, vascular risk, and the better cohort both in terms of symptomatology Conclusions special resolution offered by more power- and of MRI scans.” Looking at the clinical evidence overall, the ful MRI equipment. committee said that the undesirable neu- In conclusion, it said that the nature and From the editors of Scrip Regulatory Affairs. rological events that occurred in 28 of the frequency of the symptoms reported by Published online November 28, 2016

Regulatory Update ‘Regulatory Risk’: A New Factor In Risk/Benefit Equation At US FDA? Cole Werble [email protected]

DA is trying to formalize the inherently subjective process of Several senior FDA officials described that calculus recently dur- weighing risks against benefits when making a drug approval ing the Prevision Policy/Friends of Cancer Research Biopharma Con- Fdecision by developing and implementing a structured risk/ gress on Nov. 4 and again during FOCR’s annual meeting on Nov. 16. benefit assessment as a routine part of the review process. Two officials used the phrase “regulatory risk” to explain the balance That calculation necessarily relies on relatively formal, quantifi- of assessing the number of patients that might be at an increased able criteria: an analysis of the condition, current treatment op- safety risk from a new therapy compared to the opportunity for tions, summaries of the known risks and benefits, and approaches treating a previously untreated or poorly treated condition. to risk management. Richard Pazdur, director of the Office of Hematology & Oncology But it is also bringing forth from FDA attempts to express what Products, director-designate of the new Oncology Center of Excel- have often been unstated elements of an approval determination. lence and unofficial spokesperson for new ways of viewing the In particular, senior officials at the agency are starting to sound risks of approval versus non-approval, said “there is a thing called more comfortable acknowledging that the decision to approve a regulatory risk.” He distinguished between the judgments on a drug for a limited population often includes a calculation on the drug for broad use (“for hypertension or something where millions impact of a mistake in the regulatory decision. That is, the risk that would be exposed”) and drugs for “a very small group of patients.” the agency will take too cautious a stance and cut off a potentially Drawing from his experience in oncology – with its increasingly effective therapy in a context that is very different from the public smaller and ever more carefully defined patient populations – Paz- health risk associated with a serious adverse event that arises from dur observed that FDA has to be sensitive to what type of trial and a more widely used drug. data to push for in an initial approval.

pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 17 regulatory update

The phrase appears to connote a small initial study in perspective for accelerated approval. FDA esti- mates that 12,300 new cases of soft tissue sarcoma are diagnosed calculation of how much risk FDA is yearly in the US with about 5,000 deaths per year. That defines a limited population with a very serious disease. willing to take on to try to serve an McKee pointed out that the risk that an approval would nega- tively impact treatment of control patients in the confirmatory trial underserved patient group – and that (the 460-patient Phase III ANNOUNCE trial) was reduced because may be a significant change in emphasis. of the presence of the standard of care as the comparator and because of the advanced status of the confirmatory trial at the time of the approval decision. “We, the agency, knew where the enrollment was for the larger “One has to take a look at the context and the bigger picture,” trial” when FDA made the early accelerated approval decision. Pazdur said. “What can be done; what is realistic to ask the sponsor McKee said that contextual knowledge made the approval deci- to do and what do patients really want. … Patients will accept a sion not a “big leap.” Clinicaltrials.gov describes the ANNOUNCE higher degree of toxicity and unknowns when they do not have confirmatory trial as ongoing but closed to patient enrollment. any other therapies available to them.” The comparative nature of the confirmatory study meant that pa- “Regulatory risk” may just be an FDA short-hand to restate the bal- tients “weren’t going to be losing out,” McKee said. The confirmatory trial ancing of potential benefits to patients versus the risks – the stan- assured at least treatment with standard of care by testing the two-drug dard benefit-risk analysis at the heart of many FDA approval deci- regimen (olaratumab and doxorubicin) versus doxorubicin alone. sions. However, the phrase appears to connote a calculation of how much risk FDA is willing to take on to try to serve an underserved Validating The Exondys Approach patient group – and that may be a significant change in emphasis. The top statistician at the Center for Drug Evaluation & Research, Lisa LaVange, also used the term “regulatory risk” to explain the Lartruvo Case Study balancing decision when trying to decide what flexibility the agen- Amy McKee, acting deputy director at OHOP, backed up Pazdur’s cy can show in the methods of statistical analysis for drugs which comments by explaining how the regulatory risk calculation show a “momentous” effect in early-stage trials. worked in practice with the Oct. 19 accelerated approval for Eli “All the sudden you get a result you weren’t expecting. It’s mo- Lilly & Co.’s Lartruvo (olaratumab) for add-on treatment with mentous. You now have pressure: if this drug is really that spectac- doxorubicin for soft tissue sarcoma. ular,” LaVange observed, “we need to get it to the patients as soon Larturvo was backed by a solid base of preliminary survival data as we can. But we need enough rigor to make sure we can take a from a 133-patient study: an 11.8 month improvement in overall regulatory action without too much regulatory risk.” survival in a 133-patient study compared to doxorubicin alone – a The attempts to explain FDA oncology decisions in terms of regula- separation of survival curves that one FDA reviewer described as tory risk put CDER Director Janet Woodcock’s decision to override the large enough “to drive a truck through.” review team and approve Sarepta’s Exondys-51 (eteplirsen) in a broad- McKee described the process of predicting the potential risks to er perspective. While she clearly had sharp differences of opinion with patients from an early approval of a drug with significant early re- the leadership of the Office of Drug Evaluation I on the substance, de- sults. She noted on the risk side that the Lilly product is a monoclo- sign and results of the eteplirsen development, her reading of the reg- nal antibody and therefore could be viewed by FDA as a relatively ulatory risk from a positive decision falls close to the oncology view. low toxicity risk. “It did not add the same level of toxicity as adding Woodcock’s approval memo for Exondys-51 stresses some of another chemotherapy drug.” the same assessments of regulatory risk discussed by the oncology FDA’s formal risk assessment of the drug from the internal ap- staff at the Friends of Cancer Research event. As such, it seems at- proval memos notes that the major safety risk was from IRRs – infu- tuned to a developing strain of review philosophy – primarily cen- sion related reactions (about 3% serious reactions from olaratum- tered in the oncology review group. ab) – which are generally well understood by practitioners. Woodcock specifically cited the unmet need and the limited num- “Oncologists are familiar with IRRs and manage this risk by giv- ber of patients who would be put at risk from use of the product. She ing steroids and antihistamines as necessary,” FDA notes. “There enumerated the contextual issues of the intended population: “the was one death due to an IRR in a patient who received olaratumab life-threatening nature of the disease; the lack of available therapy; after doxorubicin. That patient did not receive any pre-medication.” the fact that the intended population is a small subset of an already The Lilly monoclonal-doxorubicin combo is also associated with an rare disease; and the fact that this is a fatal disease in children.” 8% frequency of severe musculoskeletal pain compared to 2% for Woodcock further assessed a low toxicity risk from the small the chemotherapeutic drug alone – again a side effect that FDA studies to date. “Of note, the therapy has been relatively safe in the said can be managed by supportive care. clinic, although intravenous administration always carries risk.” McKee also observed that the “context of the disease and the overall development program” further allowed FDA to put the From the editors of the RPM Report. Published online November 28, 2016

18 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Manufacturing Quality FDA’s Revised Quality Metrics Program: Voluntary Now, Mandatory Later Bowman Cox [email protected]

The voluntary program is stripped of controversial elements, giving FDA and industry practice with this novel type of agency-industry interaction before the agency embarks on formal rulemaking. Shutterstock: Shutterstock: Yochi Akura

DA will require quality metrics report- science and data analytics involved and the agency plan for eventual rulemaking in ing by rule rather than by guidance, potentially challenging reporting burden. this area, the notice said. Fthe agency said Nov. 25 in revised draft She also said PhRMA worried that After evaluating results from the volun- guidance on its quality metrics program. launching the program through guidance tary phase in 2018, FDA said it “intends to The revised draft establishes a voluntary would raise questions about the agency’s initiate notice-and-comment rulemaking program stripped of controversial ele- legal authority to require reporting of under existing statutory authority to de- ments that will give FDA and the pharma- quality metrics data, as it “is not currently a velop a mandatory quality metrics report- ceutical industry practice with this novel requirement in the cGMP regulations.” ing program.” type of agency-industry interaction before For this reason, she said, “if FDA seeks a The agency noted as well that the volun- the agency embarks on formal rulemaking. mandatory program, the agency should tary phase will give excipient manufactur- Gone for now are not only mandatory re- promulgate new requirements through ers an opportunity to participate. porting, but also quality culture metrics and binding rulemaking.” Keeping in mind that there may not be an on-time product review metric. Addition- The industry group suggested that FDA enough data during the voluntary phase ally, FDA is no longer insisting on product start with a small number of metrics and to achieve some of the program’s purpos- metrics, allowing a site metric alternative. proceed in a stepwise fashion, updating es, such as assessing the industry’s overall The revised draft replaces the initial July the GMP regulations by rule if it wants to state of quality, and that what data is re- 2015 draft, which would have required man- mandate reporting. ceived might reflect a self-selection bias, datory reporting of quality metrics data. The revised draft guidance shows the FDA says it will focus its efforts during that agency has taken this advice to heart. phase on these three objectives: PhRMA Sought Switch To Rule •• Preventing drug shortages. FDA’s decision to mandate quality metrics by FDA Starts With Voluntary •• Preparing for and directing inspections. rule had been advocated by the Pharmaceu- Reporting tical and Research Manufacturers of America. Under the revised draft, FDA will start with •• Encouraging lifecycle manufacturing Commenting on the first draft guidance a voluntary phase of the quality metrics re- improvement. at an August 2015 FDA public meeting, porting program. This will give the agency The metrics will factor into the agency’s PhRMA’s Camille Jackson said the group time to evaluate a limited set of metrics, risk-based surveillance inspection plan- would rather see stepwise implementation related analytics and industry feedback, a ning model. of quality metrics through rulemaking. Nov. 25 Federal Register notice explains. There are even plans to share publicly how Jackson gave as reasons the fluid state of The voluntary phase will also help the strong metrics reduce inspection frequency.

pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 19 Manufacturing Quality

FDA Starts With Fewer Data cases where measurement aberrations Elements led to the invalidation of OOS results: The agency has reduced the number of data •• “The number of OOS test results for lot elements to lessen the reporting burden. release and long-term stability testing In the first draft, there were four prima- FDA has made invalidated by the covered establish- ry metrics and three optional ones. Now ment due to an aberration of the mea- there are just three metrics, none optional. significant revisions surement process divided by the total The fourth metric has been a moving to the three core number of lot release and long-term target, and its absence is by no means nec- stability OOS test results in the current essarily permanent: it went from recalls to metrics it has retained: reporting timeframe.” right-first-time to an on-time rate for annual product reviews and product quality lot acceptance rate, Hands Off Internal Metrics reviews that many commenters criticized. product quality The revised draft adds a footnote assuring in- The three metrics the agency now is dustry that FDA won’t routinely review qual- starting with are: complaint rate and ity metrics data used internally for lifecycle •• Lot acceptance rate; invalidated out-of- process validation and pharmaceutical qual- •• Product quality complaint rate; and ity systems assessment, as per the agency’s •• Invalidated out-of-specification rate. specification rate. June 2007 Compliance Policy Guide Section The agency remains interested in qual- 130.300, “FDA Access to Results of Quality As- ity system robustness and quality culture (PQCR) in terms of complaints per lot: surance Program Audits and Inspections.” even though it has set aside the previously •• “The number of product quality com- The footnote says the CPG section “de- proposed optional metrics addressing plaints received for the product divided scribes our policy that during routine in- those areas in terms of senior manage- by the total number of lots of the prod- spections and investigations, FDA will not ment engagement, corrective action and uct released in the same timeframe.” review or copy these specific reports and records to encourage firms to conduct can- preventive action (CAPA) effectiveness, Now FDA is clarifying that this rate is •• did and meaningful audits and inspections.” and process capability/performance. an indicator of patient or customer The footnote goes on to distinguish the FDA said it will continue to focus on feedback and is proposing it in terms quality metrics data FDA wants firms to these culture and systems areas during fa- of complaints per distributed dosage report from the data they use internally, cility inspections, and may add metrics for units, which will remove lot size as a saying, “the voluntary submission of qual- them as the program matures. variable in the complaint equation: ity metrics data described in this guidance •• “The number of product quality com- FDA Has Adjusted The Metrics will be for specific data that are maintained plaints received for the product divided by FDA has made significant revisions to the on-site, routinely reviewed during inspec- the total number of dosage units distrib- three core metrics it has retained. tions, and not subject to a request for the uted in the current reporting timeframe.” Lot Acceptance Rate. FDA first proposed results of an internal audit.” the lot acceptance rate (LAR) in terms of re- Invalidated Out-Of-Specification Rate. jected lots: FDA factored the total number of tests Site-Reporting Option •• “1 – x (x = the number of specification- performed into the invalidated OOS rate it Offered related rejected lots in a timeframe di- initially proposed: FDA has added support for site reports, vided by the number of lots attempted •• “The number of OOS test results for the while expressing a continued preference finished product invalidated by the es- by the same establishment in the same for product reports. When the focus was tablishment divided by the total num- timeframe).” only on product reports, there were objec- ber of OOS test results divided by the tions due to the difficulty many companies •• Now the agency is clarifying that this rate total number of tests performed by the would have in pulling together product- is an indicator of manufacturing process establishment in the same timeframe.” specific data from site-specific systems. performance, and is proposing it in terms The agency now is clarifying that this is FDA said it will allow either product re- of accepted lots: •• an indicator of the operation of a labo- ports segmented by site or site reports •• “The number of accepted lots in a time- ratory, it’s using a new acronym for it, segmented by product, but added in the frame divided by the number of lots IOOSR, and it has removed the total Nov. 25 notice that it “intends to encour- started by the same covered establish- number of tests from the equation. It age product reporting because it dem- ment in the current reporting timeframe.” has also added some clarifications and onstrates a certain level of oversight and Product Quality Complaint Rate. FDA first qualifiers to the definition – it includes controls over the manufacturing of drug proposed the product quality complaint rate stability testing and only focuses on products across the supply chain.”

20 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Manufacturing Quality

The agency added that “we believe that agency added that it may at some point and a list of quality metrics reporters. a product report is better suited to identify consider establishing a set of codes to There will be an opportunity for report- potential drug supply disruptions.” standardize the comments. ing or covered establishments to correct Use of such codes could enable auto- errors via email, as described in the proj- FDA’s Public Listing Incentive mated review of comments. In a similar but ect’s technical conformance guide. FDA will publish a list of quality metrics re- unrelated initiative, the agency is looking porters, which it views as an incentive. Com- to standardize terminology for risk mitiga- OMB Approval May Be panies that report all metrics on their prod- tion measures described in the quality sec- Required ucts will appear on a “top-tier” list. Reporting tion of drug applications. To the extent that the draft guidance calls some metrics on their products puts them for industry to conduct new or materially on a “mid-tier” list and just reporting site data Non-Application Drugs modified information collections, FDA ac- would put them on a lower list. The agency There is also some clarification for non-ap- knowledged in the notice that it will have said in the notice that it “intends to provide plication and over-the-counter drugs. to obtain approval from the Office of Man- an opportunity for both types of establish- FDA has proposed to group non-appli- agement and Budget under the Paperwork ments to benefit from this incentive.” cation drugs into product families defined Reduction Act before proceeding. by National Drug Code product code seg- OMB approval could be harder to obtain Reporting Timeframes ments, each family comprising drugs with in the Trump administration than it would FDA considered switching to flexible re- the same active pharmaceutical ingredient have been in the Obama administration. porting timeframes for quality metrics re- and dose form. During the campaign, President-elect Don- porting after industry complained about Similarly, the agency would group APIs ald Trump has signaled an anti-regulatory the first draft guidance document’s focus into families defined by NDC product code bias toward FDA and other federal agencies. on a common timeframe. segments. One item on his initial agenda, for example, Many firms wanted to align quality met- The product code segment, one of three is to require the removal of two regulations rics and annual product review reporting. segments in the 10-digit NDC code, “iden- for every new regulation approved. However, the agency concluded that it tifies a specific strength, dosage form, and Industry criticized the burden estimate should stick with common time frame ap- formulation of a drug for a particular firm,” FDA published in a July 28 notice announc- proach, at least for the voluntary phase. As FDA explains on its website. ing availability of the first draft quality for switching to flexible timeframes, the metrics guidance, saying that compliance agency said that would not be feasible ex- Analytics To Put OTC would require many more person-hours of cept with product-based reporting during Complaints In Perspective time that the agency estimated. the mandatory phase of the program. The agency acknowledged concerns raised The Nov. 25 notice did not give a revised by OTC drug manufacturers that consum- burden estimate. Only volunteers incur any Comment Field Expanded ers complain more frequently about their burden under the revised draft guidance. FDA has proposed to offer 300-word free products than about prescription drugs, However, the rule FDA plans to propose for text comment fields. That’s three times often over non-quality-related issues. a mandatory quality metrics program will the size of the comment fields on which it FDA assured OTC firms in the notice that have to revisit the issue of regulatory burden. originally sought comments. “we anticipate that our analytics will account Industry wholeheartedly supported this for this imbalance in reporting type between Comments Sought proposal, as many feared their FDA-report- prescription and OTC drug products.” The agency wants comments on the re- ed metrics might look worse than they revised draft by Jan. 24 so that it can consider ally are, and wanted a way to explain their When Metrics Reporting them before developing a final version of unique circumstances, which the com- Begins the guidance. ment field provides. FDA is planning to open an electronic The notice, the revised draft guidance FDA appears to acknowledge this con- portal in January 2018 for voluntary sub- and the comments on it will all appear cern in the notice, saying that it “may refer mission of quality metrics data, which the online in Docket No. FDA-2015-D-2537 at to the comments if unusual data or trends agency is encouraging companies to sub- regulations.gov. are identified or as preparation for an on- mit on a quarterly basis. Key contacts are Tara Gooen Bizjak of site inspection.” The agency will provide further instruc- FDA’s Center for Drug Evaluation and Re- FDA elaborated in the revised draft tions in the Federal Register by December search, 301-796-3257, and Stephen Ripley guidance that comments could be used 2017 on how and when to submit volun- of the agency’s Center for Biologics Evalua- to explain “special situations” like natural tary metrics data. tion and Research, 240-402-7911. disasters or new technologies that achieve At a point to be shared in that notice, FDA greater lot uniformity but temporar- will close the voluntary portal. Then it will From the editors of the Gold Sheet. ily increase OOS results. In the notice, the analyze the data and publish initial findings Published online November 28, 2016 pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 21 Consumer Drugs

OTC Monograph Application Reviews Get Deadlines, Not GRASE Flexibility

Malcolm Spicer [email protected]

etting deadlines for FDA reviews of The OTC drug review process allows time and extent applications to add firms to market products without premar- Singredients or indications to OTC ket clearance as long as the products are monographs doesn’t solve the problem formulated and manufactured according that industry stakeholders say has crippled to directions provided in a monograph. the monograph process. Non-monograph OTCs are approved Stakeholders say changes to FDA’s inter- through new drug applications, processes pretation of the generally recognized as that do not require a rulemaking, usually safe and effective standard it uses to evalu- for ingredients being switched from Rx to ate ingredient proposals would go further nonprescription status and less often for to opening the monograph process, or OTC different formulations or combinations of drug review, to innovation and progress. OTC ingredients. “That’s probably the great flaw in the Food and drug attorney Frederick Stearns whole arrangement here,” said food and Clarifying A Stalled drug attorney Frederick Stearns. Process FDA on Nov. 23 published a final rule FDA also included in the rule definitions establishing changes required by the Sun- and clarifying and conforming changes screen Innovation Act in the agency’s re- to the TEA regulation the agency estab- view and evaluations of TEAs submitted for lished in 2002 to allow firms to propose adding non-sunscreen ingredients to the The TEA process is OTC drug ingredients for US approval monograph. “not something that based on their use to a material time and The SIA required specific timelines and extent in other countries. performance metrics for sunscreen ingre- I would recommend Like firms interested in adding other dient TEAs. The rule now establishes those OTC ingredients to the monograph, spon- timelines and metrics for reviews of TEAs anybody base their sors of sunscreen TEAs have questioned for other OTC ingredients; adds provisions business plans on.” FDA’s standards on showing GRASE for an for sponsors’ filing determination require- ingredient; however, the agency’s Center ments; and details the process for withdraw- for Drug Review and Evaluation did not ing TEAs and safety and effectiveness data alter its expectations in a final guidance submissions. FDA added some clarifications “I think that what you really see is that published recently on supporting data for and explanatory language but the timelines FDA’s standards have increased over the sunscreen TEAs, along with other guidanc- in the final rule (see box) are unchanged years even though the nominal threshold, es required by the SIA. from the proposal published in March. generally recognized as safe and effective, The final rule notes that the sunscreen No ingredients have yet been approved is the same as it always was. But what that TEA guidances “may also be useful to per- through the TEA process, a procedure to actually means in practice, FDA’s interpre- sons preparing safety and effectiveness add a product or a product condition – such tation of that has become more stringent data submissions for” other TEAs. as an active ingredient or botanical drug and more demanding,” he added in an in- CDER also stated that a comment on substance – to an OTC drug monograph; terview. the proposed rule requested guidance and little change through other regulatory Monograph changes, or amendments, on information from foreign data sources pathways has been made since the initial also can be suggested in citizen petitions needed in safety and effectiveness data block of monograph approvals in the mid- and FDA can propose changes in response submissions was outside the scope of this 1970s after the OTC drug review’s launch. to a petition or on its own. TEA and amend- rulemaking, however FDA “will consider “I think this just reflects the fact that ment processes both start with proposals providing additional guidance to address ‘generally recognized as safe and effec- and, when FDA considers an ingredient this issue.” tive’ is an extremely high threshold,” said appropriate for use, continue to proposed FDA returned eight TEAs for sunscreen Stearns, a partner at Keller and Heckman rulemaking, with notice and comment, ingredients to the sponsors in February LLP in Washington. and to final rule stages. 2015 as its first action subject to an SIA-

22 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Consumer Drugs established deadline, and imposing dead- OTC monographs has stalled due to the lines on the agency’s reviews isn’t likely to length of the process. A Timeline push any TEA to approval. “We look forward to engaging with For “There’s not been a single new ingredi- members of Congress and FDA on ways Every TEA Step ent that has been added to a monograph to improve the OTC monograph system because FDA has consistently found that to streamline or remove steps in the rule,” According to the final rule, FDA the submitted data don’t rise to the level of CHPA said. showing generally recognized as safe and CHPA and numerous drug firms as well will issue: effective,” said Stearns. as other stakeholder groups also have • a notice of eligibility or post “Given the track record, it’s certainly submitted comments on FDA’s look at po- very difficult to suggest to a company that tential changes to the monograph process to the docket a letter of there’s a realistic and practical method for and its separate consideration of creating ineligibility within 180 days getting some new ingredient into a mono- a user fee program to pay for its work. The of submission of a TEA; graph because we’ve got 12, 13 years of final rule required by the SIA for FDA’s re- experience here and nothing has actually view and evaluations of TEAs submitted for • a filing determination been added,” Stearns said. adding non-sunscreen ingredients to the within 90 days of receipt of a He noted that he has worked with cli- monograph is not linked to either of those safety and effectiveness data ents on preparing OTC monograph TEAs FDA initiatives. submission that a sponsor, for FDA’s review. “In the end I don’t get “Because this rule is limited to the TEA the sense that FDA is particularly anxious process and not the overall monograph though the 90-day clock will to add any ingredients to monographs regulatory framework, changes to the OTC not start until a sponsor “has through this process,” he said, adding, “It’s monograph process that in turn could af- confirmed that it considers not something that I would recommend fect the timelines established in this rule the submission to contain anybody base their business plans on.” are outside the scope of this rulemaking,” all data and information” The Consumer Healthcare Products As- CDER states in the final rule. sociation also expects little impact from needed for FDA’s review. monograph review deadlines. “While Faster Path To Same Result? For safety and effectiveness data having timelines and metrics is good for The obstacles to improving TEA sponsors’ submissions made simultane- sponsors, we remain concerned with the chances for approval aren’t removed by re- overall length of time to get through the view deadlines or by additional FDA fund- ously with a TEA for a condition process, which could potentially be a dis- ing to support the work, and lowering the deemed eligible for considera- incentive to innovation,” said the trade GRASE threshold isn’t an option. tion, FDA will issue a filing de- group in a statement. “It seems to me that there’s no easy an- termination within 90 days after In the final rule, CDER noted concerns swer to the question of how do we get issuing the notice of eligibility. stated in comments that the proposed more ingredients into the OTC mono- rule’s requirements “could delay TEA re- graph,” Stearns said. When an ingredient or other views and actions many years beyond the “Ratcheting down the data expectations condition initially is determined established timelines.” really could be a difficult change for FDA However, the center also explains that to make and wouldn’t do a whole lot to not to be GRASE, the agency will timelines for TEA reviews reflect FDA pub- inspire public confidence in the safety of inform the sponsor and other lic health priorities; take into consideration the products and it seems to me that, even interested parties who have its resources available for carrying out with the coming change in the adminis- submitted data of its determina- those priorities, including necessary re- tration, it’s the sort of thing that Congress tion by feedback letter within 730 views and other procedures; and are rea- would be somewhat leery about trying to sonable, “taking into account the required force on FDA.” days, generally 24 months, from consideration of priorities and resources.” While CHPA executives and representa- the date of filing. CDER also notes that it expects a “more tives from drug firms since July have been efficient and sensible” overall monograph meeting regularly to iron out a potential system by not setting different timelines for proposal to ask Congress to authorize an submissions of varying content, complexity OTC monograph user fee, funding isn’t the and format but to set one general timeline only part of the solution. for reviews for each stage of the TEA process. “If all it does is it allows FDA to hire peo- CHPA noted that in its comments on the ple to review documents more quickly, proposed rule, it explained that amending then tell you, ‘you don’t have enough data pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 23 Consumer Drugs and here’s what your shortcomings are,’ Stearns doesn’t expect FDA to make that that’s not really a process that’s going to move, though. help anybody a whole lot,” Stearns said. “I’m not really sure how the agency as “Without some change in the structure an institution gets comfortable with that for how we’re going to evaluate ingredi- “While having or how anybody legislatively imposes or ents and decide to add more to the mono- mandates some sort of change” that ac- graphs, putting a user fee program in place timelines and metrics knowledges “a GRASE finding by some doesn’t seem to me like it’s really going to lower threshold than they’ve currently accomplish a whole lot because FDA will is good for sponsors, been applying,” he said. just be doing faster what it’s currently do- we remain concerned Not only is the reason for a demanding ing, but what it’s currently doing is saying GRASE standard clear, though, so is the to everybody, ‘no you can’t do it’.” with the overall length reason TEAs fail. “The whole idea of an OTC product is Approval Standard ‘Creep’ of time to get through that these are things that present relatively GRASE should be an effective threshold the process, which low risks and therefore they are intended for determining whether drug ingredients to deal with relatively minor conditions. … are allowed for use in OTC monograph could potentially You don’t want products that are out there products because the standard indicates available for anyone and everyone that are a consensus among experts in the science be a disincentive to going to be present some sort of risk that based on evaluation of public data. innovation.” – CHPA outweigh the benefit,” Stearns said. CDER officials have explained, at multi- However, TEA sponsors are finding that ple times since opening a docket for com- ingredients with histories of safe, nonpre- ments on improving the monograph pro- process, but I think if you were to go back scription use in other countries are not cess, that the agency’s knowledge about and look at some of the monographs and passing FDA scrutiny because the evidence potential long-term problems from using some of the ingredients that are in the used to gain approval in other markets is what are considered safe drug ingredients monographs now and compare to some not available to support their US proposals. has increased since the OTC drug review of the data submissions that FDA has re- “I think it’s just a matter of the extent to process began. They note that some in- ceived, I think you might be hard-pressed which products get approved in other ju- gredients previously approved for an OTC to see, if FDA were looking at some of risdictions and they’re on the market often monograph have been removed and that those ingredients today, would they in fact as a result of proprietary work that com- the agency is reviewing other currently ap- agree that generally recognized as safe panies have done to support those clear- proved monograph ingredients. and effective has been found?” he said. ances and unfortunately those proprietary However, Stearns says FDA’s use of Making the TEA process viable could studies can’t be used to support a gener- GRASE is an example of what he calls “reg- depend on FDA examining its history of ally recognized argument,” Stearns said. ulatory creep.” OTC monograph decisions and evaluating “The same standard has been in place whether the level of support for GRASE it is From the editors of the Tan Sheet. from the outside of the OTC drug review requiring has increased. Published online November 30, 2016

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24 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Drug review profile / An inside look at key lessons learned from recent FDA approvals. Gilead’s Epclusa: FDA Sought To Push Efficacy Bar Higher In Hepatitis C Sue Sutter Sutter [email protected]

ar from being a passive regulator, tance-associated polymorphisms that the US FDA is sometimes the one limit future treatment options,” Division Fpushing the efficacy bar higher in a of Antiviral Products Director Debra therapeutic category. Birnkrant said in a June 16 review. Such was the case in the regulatory review of Gilead Sciences Inc.’s hepatitis Landscape Evolves During C combination therapy Epclusa (sofos- NDA Review buvir/velpatasvir). Despite a plethora of Epclusa combines two direct-acting an- highly effective treatments approved tivirals (DAAs): sofosbuvir (Sovaldi), a nu- in the past few years and impressive cleotide analog NS5B polymerase inhibi- efficacy with the fixed-dose combina- tor, and velpatasvir, an NS5A inhibitor. tion in clinical trials, FDA staff debated “Whether or not to consider the FDA approved Epclusa June 28 for whether steps could be taken to further use of RBV in HCV GT3 subjects GT1-6 patients without cirrhosis or with improve Epclusa’s efficacy in one HCV compensated cirrhosis, and for use in patient subpopulation. with compensated cirrhosis combination with ribavirin in patients At issue was whether labeling for with decompensated cirrhosis. the pan-genotypic treatment should as a footnote to the Dosage With the approval, Epclusa became include a recommendation for dos- the third leg of Gilead’s mega block- ing with ribavirin in HCV genotype and Administration table was buster HCV franchise, joining Sovaldi, 3 patients without cirrhosis or with challenging for the review approved in December 2013, and Har- compensated cirrhosis. In the pivotal voni (sofosbuvir/ledipasvir), approved ASTRAL-3 trial, Epclusa demonstrated team.” – FDA’s Struble in October 2014. a 12-week sustained virologic response Gilead is preparing to seek approval rate (SVR12) of 95% in GT3 patients, the for yet a fourth HCV treatment – a three- highest rate seen to date in this geno- drug pill combining sofosbuvir, velpa- type. Nevertheless, the agency wondered whether it would be tasvir and voxilaprevir (GS-9857). However, the triple therapy is the possible to further maximize this benefit by adding ribavirin. last HCV treatment the company intends to develop because the Since concomitant use with ribavirin was not studied in the AS- unmet need in the condition will have been met globally by the pan- TRAL-3 trial, FDA took the initiative to look at whether other evi- genotypic regimen. dence from across the development program would support a rec- The Epclusa NDA review documents note the speed at which the ommendation for concomitant ribavirin use in GT3 patients. HCV therapeutic landscape has been changing. “Whether or not to consider the use of RBV in HCV GT3 subjects “Several DAA regimens were approved during this NDA review cy- with compensated cirrhosis as a footnote to the Dosage and Ad- cle that confer SVR12 rates greater than 93% for HCV genotype (GT) 1, ministration table was challenging for the review team,” Cross-Dis- 3, 4, 5, or 6-infected patients with compensated liver disease, defined cipline Team Leader Kimberly Struble said in a June 1 review. as the absence of cirrhosis or compensated cirrhosis,” Birnkrant said. “Different perspectives from the review disciplines were dis- In addition, two regimens for treatment of GT1 or GT3 patients cussed at several meetings and included the strength of evidence with decompensated cirrhosis or liver transplant were approved from the Phase 2 trial GS-US-342-0109, the applicability of leverag- during the Epclusa review: Harvoni plus ribavirin for 12 weeks in ing data from other populations in ASTRAL-1 and ASTRAL-4 and GT1-infected pre-transplant subjects; and Bristol-Myers Squibb the clinical safety considerations for use of RBV in the setting of Co.’s Daklinza (daclatasvir) plus sofosbuvir and ribavirin for 12 >90% efficacy without RBV,” Struble said. weeks in GT1 and GT3 patients. Ultimately, FDA concluded a recommendation for dosing with The availability of new and highly efficacious HCV treatments ribavirin in GT3 patients was not supported, but it required Gilead impacted Epclusa’s breakthrough designation even before the to study the issue as a postmarketing requirement. NDA was submitted. “Data from a clinical trial evaluating the SOF/VEL versus SOF/VEL Yet, despite these advances, gaps in HCV treatment remain. + ribavirin will help inform whether the addition of ribavirin can “While great progress has been made in improving SVR12 rates

Shutterstock: Bluebay Shutterstock: mitigate the risk of treatment failure and the development of resis- among patients with all stages of hepatic dysfunction, better treat-

pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 25 Drug review profile ment options for patients with non-GT1 HCV are needed, espe- Virology Team Favors Ribavirin cially for HCV GT3,” Birnkrant said. “The need for better treatment Recommendation … options is even greater among subjects with decompensated cir- The agency’s virology reviewer favored adding a footnote to the rhosis regardless of HCV GT.” Dosage and Administration section of labeling stating that adding ribavirin to a 12-week regimen of sofosbuvir/velpatasvir can be ‘Room For Improvement’ In GT3 Patients considered for GT3 patients with compensated cirrhosis. The Epclusa NDA was supported by data from four Phase III trials “Because of the concern for the consequences of virologic failure that spanned genotype and cirrhotic status. However, FDA’s review with development of Y93H in all failures and loss of subsequent attention focused on the results in GT3 patients. treatment options, we pushed for a consideration for adding RBV Use in this population was supported by ASTRAL-3, a Phase III, ran- to 12-week SOF/VEL in the GT3 compensated cirrhotic population,” domized, open-label, active-controlled trial consisting of treatment- virology reviewer Lisa Naeger said in a March 17 review. (See chart naïve or treatment-experienced GT3 patients, without cirrhosis or of reviewers.) with compensated cirrhosis. A 12-week regimen of Epclusa was Relapse rates could be reduced for GT3 patients with compen- studied against a 24-week regimen of sofosbuvir and ribavirin. In the sated cirrhosis who take ribavirin, Naeger said, citing a statistical Epclusa group, 95% of patients achieved SVR12, compared to 80% in reviewer’s bridging assessment suggesting that relapse rates of the sofosbuvir/ribavirin arm. 9% for GT3 cirrhotics seen in ASTRAL-3 could be reduced to 2%-3% When stratified by presence of cirrhosis and prior treatment, with the addition of ribavirin. SVR12 rates in the Epclusa arm ranged from 89% for treatment- In addition, relapse rates were 33% for compensated cirrhotics experienced patients with compensated cirrhosis to 98% for treat- with baseline NS5A resistance-associated polymorphisms (RAPs), ment-naïve patients without cirrhosis. so adding ribavirin would be a better option for these individuals, “The SVR12 rates observed in ASTRAL-3 represent the highest Naeger said. Ribavirin also could reduce failure with the Y93H re- rates observed to date across all DAA development programs for sistance substitution, the presence of which has consequences for GT3, particularly for TE and cirrhotic subjects, and approval of the future treatment options with NS5A inhibitors. proposed 12-week SOF/VEL regimen would substantially improve the standard of care in this population,” clinical reviewers Prabha … But Medical Team Finds Clinical Viswanathan and Sarah Connelly said in a March 29 review. Support Lacking “However, there is room for improvement,” the reviewers added. However, the medical review team found clinical evidence lacking “The need to optimize treatment and improve SVR12 rates, par- to support such a dosing recommendation. ticularly for HCV GT3 cirrhotics, is acknowledged,” Struble wrote in A Phase II trial, GS-US-342-0109, provided the only available data her cross-discipline review. “The consequence of virologic failure is in the Epclusa development program on ribavirin use among GT3 the development of the NS5A resistance substitution specifically, cirrhotics. This was a randomized, open-label, dose-ranging trial Y93H, and the potential loss of subsequent treatment options.” evaluating two velpatasvir doses in combination with sofosbuvir, Gilead’s Phase III program did not specifically study the use of with or without ribavirin, in treatment-experienced subjects with ribavirin in combination with Epclusa in GT3 patients without cir- GT1 or GT3 infection with or without cirrhosis. rhosis or with compensated cirrhosis. “As a result, much of the re- Among GT3 cirrhotics, 89% of patients receiving sofosbuvir/ view discussions centered on results from additional analyses re- velpatasvir achieved SVR12, with a relapse rate of 11.5%. In com- garding the impact of baseline factors on higher relapse rates and parison, the SVR12 rate among patients who received sofosbuvir/ if the addition of RBV could minimize the risk of relapse based on velpatasvir and ribavirin was 96%, with a relapse rate of 3.8%. data from other trial populations,” Struble said. Despite the numerically higher SVR12 rate in ribavirin-containing Agency staff sought Gilead’s views arm, “these results do not definitively on the issue of optimal dosing regi- Although FDA staff believed demonstrate that the addition of RBV men in the GT3 population. improves SVR12 for GT3 cirrhotics,” FDA raised the question of dosing the proposed dosing regimen Viswanathan and Connelly said, noting recommendations, and the addition of that the study’s sample size was small, ribavirin, for GT3 cirrhotics during the would substantially improve and the difference in SVR12 between mid-cycle meeting. Although much the two groups was not statistically of the discussion in the meeting min- standard of care in GT3 cirrhotic significant. “It is also noteworthy that utes is redacted, Gilead said it would patients, they also saw room the addition of RBV did not preclude conduct a trial to answer the agency’s emergence of the Y93H NS5A RAP at questions about optimal dosing rec- for improvement given the the time of failure.” ommendations. The clinical team also considered The agency raised the issue again consequences of virologic failure. the safety impact of adding ribavirin. with Gilead ahead of the late-cycle In the Phase II study, more subjects meeting. (See timeline, p. 29) in the ribavirin-containing arm had

26 | Pink Sheet | December 5, 2016 © Informa UK Ltd 2016 Drug review profile adverse drug reactions and adverse The risk/benefit consideration “Such strategies are only helpful if the events overall compared to the group test result guides a change in manage- that did not receive ribavirin. for adding ribavirin is different ment strategy for subjects with RAPs The reviewers examined the results (e.g. treatment with a different DAA from ASTRAL-4, a trial that evaluated for the decompensated regimen, prolonging the course of treat- three different sofosbuvir/velpatas- ment, or adding another agent such as vir regimens in GT1-6-infected sub- and compensated cirrhotic RBV),” Viswanathan and Connelly said. jects with decompensated cirrhosis. populations. The only other approved regimens “Though this trial studied a different for GT3 are sofosbuvir with ribavirin, population with more advanced he- and daclatasvir with sofosbuvir, “nei- patic disease, cirrhosis is a spectrum of ther of which would be superior to illness, and results from the decompensated population may help SOF/VEL,” the reviewers said. In addition, daclatasvir is vulnerable inform efficacy (but not necessarily safety) among compensated to the same NS5A RAPs as velpatasvir, and sofosbuvir/velpatasvir cirrhotics,” the reviewers said. was superior to sofosbuvir plus ribavirin in ASTRAL-3. In this study, the addition of ribavirin resulted in numerically “Hence, baseline screening would not provide actionable infor- higher SVR12 rates among GT3 subjects compared to 12 or 24 mation and is therefore not recommended,” they said. weeks of sofosbuvir/velpatasvir alone, but the difference in SVR12 The reviewers concluded that the totality of the data are “insuffi- rates between groups was not statistically significant. cient to satisfy the regulatory requirements for recommending the The clinical reviewers noted that while risk/benefit consider- addition of RBV to SOF/VEL for GT3 compensated cirrhotics, a regi- ations unique to the decompensated population support the use men that was not formally studied in the pivotal trials.” of ribavirin in GT3 patients, the assessment is different for subjects “The results from ASTRAL-3 demonstrate > 90% efficacy without with compensated cirrhosis, “who have much higher SVR12 rates RBV, and therefore a general recommendation to add RBV to all with SOF/VEL x 12 weeks (91% in ASTRAL-3 compared to 50% in compensated cirrhotics would introduce RBV-associated toxicity ASTRAL-4 for decompensated subjects), in general have better that is likely unneeded for the majority of subjects,” Viswanathan overall health status, and may have a better chance of successful and Connelly said. retreatment in the event that they fail or relapse.” The clinical team’s view ultimately prevailed, and Epclusa label- The reviewers also looked at SVR12 rates among cirrhotic GT1 ing does not include a recommendation for ribavirin dosing in GT3 subjects in ASTRAL-1 and ASTRAL-4 but concluded these results subjects without cirrhosis or with compensated cirrhosis. “do not provide additional insight into the possible benefit of RBV However, the results from Gilead’s required postmarketing study for GT3 subjects.” could inform future labeling changes on optimal dosing in GT3 cirrhotics. The trial started in July and is targeted to enroll 200 pa- Screening Would Not Lead To tients, according to ClinicalTrials.gov. The study is due to complete Different Treatment by June 2017, with a final report to be submitted by June 2018, The clinical reviewers considered whether identification of sub- FDA’s approval letter states. jects with baseline RAPs may help predict their chances for successful treatment. Published online November 25, 2016 Epclusa FDA Reviewers FDA staff who participated in the review of Gilead’s pan-genotypic hepatitis C drug.

Medical Prabha Viswanathan; Sarah Connelly

Chemistry Larry Bai; George Lunn; Sithamalli Chandramouli; Ying Wang

Clinical Pharmacology Jenny Zheng; Abhay Joshi; Fang Li

Microbiology/Virology Lisa Naeger; Eric Donaldson

Pharmacology/Toxicology John Dubinion

Statistics Karen Qi; Thamban Valappil

Cross-Discipline Team Leader Kim Struble

Regulatory Project Manager Linda Onaga

pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 27 Drug review profile Harvoni Approval Led To Narrowing Of Epclusa’s Breakthrough Status Sue Sutter [email protected]

ilead Sciences Inc.’s break- states. “While your sofosbuvir/GS- through therapy designation 5816 fixed-dose combination tablet Gexperience with its hepatitis product may show an incremental C treatment Epclusa (sofosbuvir/vel- benefit in terms of frequency or type patasvir) reflects the fluidity of the of adverse events or laboratory ab- expedited program in a fast-moving Gilead may be the only normalities, a substantial improve- therapeutic area. ment in overall safety profile over The original breakthrough designa- company in the HCV space to available therapies is no longer dem- tion granted to Epclusa was subse- onstrated.” quently narrowed by FDA due to the see a breakthrough designation On April 1, 2015, FDA formally availability of other safe and effective narrowed due to the efficacy and rescinded the designation for GT1 HCV treatments, including one of Gil- patients and asked Gilead to notify ead’s own products. safety of one of its own products. the agency of its intent to continue Epclusa combines the nucleotide the breakthrough therapy designa- analog NS5B polymerase inhibitor tion drug development program in sofosbuvir (Sovaldi) with the NS5A in- treatment-naïve patients with GT3, 4, hibitor velpatasvir (formerly known as GS-5816). It was approved in 5 and 6 infections. FDA issued a new letter for breakthrough des- June for treatment of HCV genotype 1-6 patients without cirrhosis ignation in this population on May 15, 2015. or with compensated cirrhosis, and for use in combination with ribavirin in patients with decompensated cirrhosis. Merck, Bristol Designations Also Impacted It was the first pan-genotypic HCV regimen approved, the first Gilead is not the first player in the HCV space to see its break- single-tablet regimen for patients with GT2 or GT3 infection, and through therapy designation narrowed or reshaped. However, the first treatment specifically indicated for GT2, 4, 5 and 6 decom- the company appears to be only one that has suffered this fate pensated cirrhotics. due, in part, to the efficacy and safety profile of one of its own previously approved products. Breakthrough Criteria ‘No Longer Being Met’ (See the Pink Sheet’s online ‘Breakthrough Therapy’ chart on the FDA Epclusa received Fast Track designation on Sept. 30, 2013 and Performance Tracker for detailed information on products receiving breakthrough therapy designation for GT1, 3, 4, 5 and 6 treatment- the designation.) naïve patients on April 22, 2014. As in the case of Epclusa, FDA has shown a willingness to retain However, on Feb. 4, 2015, FDA notified Gilead of its intent to re- the designation for some HCV patient subgroups even when an scind the designation in GT1 treatment-naïve patients “because initial designation is rescinded. the criteria for designation are no longer being met.” At roughly the same time that FDA notified Gilead of its intent to FDA pointed to the recent availability of two new HCV therapies: rescind, the agency similarly moved to rescind the designation for Gilead’s own Harvoni (ledipasvir/sofosbuvir), approved in October Merck & Co. Inc.’s Zepatier (grazoprevir/elbasvir), citing the availability 2014; and AbbVie Inc.’s Viekira Pak (dasabuvir/ombitasvir/parita- of other recently approved treatments for GT1 patients. The designa- previr/ritonavir), approved in December 2014. tion was subsequently narrowed to patients with GT4 infection, and Harvoni and Viekira Pak have demonstrated 12-week sustained GT1 patients with end-stage renal disease who are on hemodialysis. virologic response (SVR12) rates in GT1 patients ranging from 94%- FDA also rescinded the designation for two regimens contain- 100% depending on prior treatment history and GT1 subtype, FDA ing Bristol-Myers Squibb Co.’s Daklinza (daclatasvir) in GT1 patients. said. “The data you have provided to support sofosbuvir/GS-5816 It subsequently granted the designation for use of daclatasvir in fixed-dose combination tablet no longer demonstrates substantial combination with Gilead’s sofosbuvir for GT1 patients with ad- improvement in SVR12 rates compared to these currently available vanced cirrhosis or recurrent HCV after liver transplant. therapies for CHC genotype 1 infection,” the agency said. Despite the therapeutic progress in HCV, FDA continues to push FDA’s letter also notes the favorable safety profiles for Harvoni the efficacy bar higher in this category, particularly for harder-to- and Viekira Pak. treat subpopulations. “Discontinuation rates due to adverse events are <1% even when ribavirin is included in one of the regimens,” the letter Published online November 25, 2016

Epclusa Clinical Development Timeline Chronicle of the development and FDA review of Gilead’s fixed-dose combination of sofosbuvir and velpatasvir for hepatitis C.

Date Action IND Chronology (#118605)

8/13/2013 IND submitted

9/30/2013 Fast Track designation granted for treatment of chronic hepatitis C genotype 1-6 infection

12/6/2013 Gilead’s Sovaldi (sofosbuvir) approved for treatment of chronic HCV infection as a component of a combination antiviral treatment

3/24/2014 Gilead requests breakthrough therapy designation

4/22/2014 Breakthrough therapy designation granted for treatment of chronic HCV GT1, 3, 4, 5, 6 infections in t reatment-naïve patients

6/5/2014 End-of-Phase II meeting; FDA recommends Gilead evaluate a longer treatment duration (>12 weeks) in ASTRAL-3 to optimize sustained virologic response rates in “harder-to-treat” patient populations, such as GT3 cirrhotic patients

10/10/2014 Gilead’s Harvoni (ledipasvir/sofosbuvir) approved for treatment of chronic HCV GT1 infection

12/19/2014 AbbVie’s Viekira Pak (dasabuvir/ombitasvir/paritaprevir/ritonavir) approved for treatment of chronic HCV GT1 infection

2/4/2015 FDA notifies Gilead of intent to rescind breakthrough designation because the criteria are no longer met for GT1 infection in treatment-naïve patients due to availability of Harvoni and Viekira Pak

4/1/2015 Breakthrough therapy designation rescinded in GT1 infection

4/8/2015 Gilead letter expressing intent to continue breakthrough therapy designation drug development program for treatment of GT3, 4, 5, 6 infections in treatment-naïve patients

5/15/2015 Breakthrough therapy designation granted for GT3, 4, 5, 6 infections in treatment-naïve patients

5/26/2015 Pre-NDA meeting teleconference

7/22/2015 Rolling review designation granted

9/21/2015 Scheduled Type B meeting to discuss topline data from ASTRAL-1, ASTRAL-2, ASTRAL-3 and ASTRAL-4 trials, and key review issues to be addressed in planned NDA submission (cancelled by Gilead because review division’s preliminary comments addressed company’s concerns)

NDA Chronology (#208341)

10/28/2015 NDA submitted

12/23/2015 Filing communication; priority review granted with user fee goal date of 6/28/2016

1/11/2016 Proprietary name Epclusa deemed acceptable

2/11/2016 Mid-cycle meeting teleconference

4/1/2016 FDA requests Gilead provide its thoughts on available data to support use of ribavirin for certain GT3-infected patients, such as cirrhotics, and potential revisions to Dosage and Administration section of labeling

4/19/2016 Late-cycle meeting teleconference; review division queries Gilead about company’s perspective on adding ribavirin for GT3 cirrhotic patients

6/28/2016 NDA approved on PDUFA goal date

pink.pharmamedtechbi.com December 5, 2016 | Pink Sheet | 29 Advisory Committees

Recent And Upcoming FDA Advisory Committees

Topic Advisory Committee Date

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

Strategies, approaches and challenges in model-informed drug development, includ- Pharmaceutical Science and March 15 ing use of physiologically-based pharmacokinetic modeling and simulation through- Clinical Pharmacology out a drug’s life cycle and mechanistic model-informed safety evaluations

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