fda/gpha quarterly meeting on gdfua - strategic …/media/supporting... · · 2015-04-14–...
TRANSCRIPT
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FDA/GPhA Quarterly Meeting on GDFUA
March 23, 2015
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Meeting Agenda I. Introductions All II. OPQ Organizational Structure FDA III. Time To Approval/Action FDA IV. GDUFA 1 Operations Update FDA
Break V. QMS Update FDA VI. Mechanics and timing of Paragraph III and IV approvals FDA V. Wrap-up and Next Steps All
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OPQ Organization Structure
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Office of Pharmaceutical Quality
Office of Program and Regulatory Operations
Acting Director: Giuseppe Randazzo
Immediate Office Acting Director: Janet Woodcock
Deputy Director: Lawrence Yu
Office of Policy for Pharmaceutical Quality
Acting Director: Ashley Boam
Office of Lifecycle Drug Products
Acting Director: Susan Rosencrance
Office of Process and Facilities
Acting Director: Christine Moore
Office of New Drug Products
Acting Director: Sarah Pope Miksinski
Office of Surveillance
Acting Director: Theresa Mullin
Office of Biotechno-logy Products
Director: Steven Kozlowski
Office of Testing and Research
Acting Director: Lucinda Buhse
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Time to Approval/Action
• Ryan Conrad
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Meaningful Measurements of ANDA Review Timelines
23 March 2015 – FDA/GPhA Quarterly Meeting Prepared and presented by: Ryan Conrad, PhD, Office of Strategic Programs, CDER
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The market for generic drugs has expanded greatly over time
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Time to approval has increased – but consider review times Time to approval ≠ review time
• Many factors are related to how long it takes for an ANDA to be granted approval
– Incomplete or insufficient applications can result in multiple review cycles
– Reviewer workload
• We will consider two ways to look at review times – Submission to approval (full and tentative) – Submission to end of first review cycle event
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Compare approval to first cycle review outcomes • We define the end of the first review cycle to occur
when one of the following actions occurs: 1. Full or tentative approval (AP, TA) 2. Complete response or withdrawal (CR, WD)
• Tentative approvals are issued when patents or exclusivities are blocking full approval, application is otherwise complete
• Complete responses are issued when applications have deficiencies that must be corrected
• Withdrawals are only considered here when no other action (CR, TA, AP) has been taken
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The first review cycle has changed since CR was introduced
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Submission Tentative Approval
Full Approval
Complete Response
End of 1st Cycle
Month= 0 12 24 36
Discipline-Specific Deficiency Letters
Submission Tentative Approval
End of 1st Cycle
Full Approval
Month= 0 6 10 14 24 36
1. Before the Complete Response Era (Before Oct 2010)
2. After the Complete Response Era (After Oct 2010)
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We analyze reviews for all ANDAs submitted from FY 2008-2014 • 6,780 total ANDA submissions
• Looks at outcomes stratified on fiscal year of submission
• Plot two survival curves comparing submission cohorts 1. Time to approval or tentative approval 2. Time to first action (CR, WD, TA, AP)
• Note: CRs not issued until FY2011
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FY of ANDA Submission 2008 2009 2010 2011 2012 2013 2014
Submissions 827 850 798 885 1,077 925 1,418
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Time to tentative or full approval
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Time to earliest of CR, WD, TA, or Full Approval
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Let’s now briefly consider the current status of all ANDA submissions since 2008…
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Current status of ANDA submissions since 2008
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GDUFA 1 Operations Update
• Edward Sherwood • Carol Holquist • Denise McKan-Toyer
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Next Steps: • Assign Target Action Dates (TADs) to all pre-Year 3 submissions.
(With caveats, and not all at once. See next slide.) • Base TADs on workload management factors, with one exception:
For big first generics, assign TADs roughly corresponding with expiry.
• In early CY15, start notifying applicants of TADs. • “Launch planning updates” for big first generics 6 and 3 months
before TAD. • Certain other pre-launch “go/no go” communications. • Iterative, “real-time communications” re deficiencies in current
review cycle. Already started in CMC, scale this out to Bio next. • Update Communications with Industry MAPP to formalize and
clarify these changes.
From the Last Meeting
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Operations Activities • Filing Decision • Target Action Dates (TADs)
– Setting – Communicating
• No Go • Information Requests (a.k.a. Real Time Communications) • Easily Correctable Deficiencies • Health of Application/Status Update (a.k.a. Launch Planning) • Go/Action Letter Expected • Complete Responses
– Post CR meetings • Approval/Tentative Approvals
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Caveat
• Notification of a Target Action Date does not constitute a commitment or guarantee that FDA will take action on the application by the Target Action Date.
• Any amendments submitted after the notification may affect whether FDA will take action on the application by the Target Action Date.
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Caveat • When contacted for an additional status
update 3 or 6 months prior to the Target Action Date, RPM will provide the total number of discipline reviews needed for the application and the number of reviews pending. – RPM cannot provide specifics on which disciplines are
pending.
• All outstanding ECDs and IRs must be addressed before action can be taken.
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Caveat • When an application is in the clearance
phase, RPM will notify the applicant by phone that FDA is on track to provide an action. – RPM may request assurance that the application’s
labeling, patent information, Type II DMFs, and inspections are up-to-date.
– RPM cannot provide additional information other than that the application is on track to receive an action.
– Not a guarantee of approval.
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Controls
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Controls as of 3/3/2015
• Controls Closed 309 • Controls – open 212 • Not a Control 229
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Closed Controlled Correspondences FY15
Updated 3/17/2015 24
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Original ANDA Stats
Actions Oct. 14 Nov. 14 Dec. 14 Jan. 15 Feb. 15
CR 43 76 95 104 100
TA 10 7 5 5 13
AP 45 28 29 25 28
Total 98 111 129 134 141
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Filing Decision Time for Y3 ANDAs
27 days
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Break Time
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Quality Management System (QMS) Update
• Edward Sherwood • Ashley Boam • Giuseppe Randazzo
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SUCCESSFULLY IMPLEMENTING GDUFA …BUILDING A QUALITY SYSTEM
• Hire & Train • Process & Policy • Inspectorate • Informatics
(“Platform”) • Regulatory Excellence • Agency Alignment
PLAN
DO
CHECK
ACT
From the Last Meeting
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What Does the CDER ANDA Program Mean by QMS?
• The ANDA QMS is a collection of processes and procedures designed to facilitate the making of safe, effective, quality generic drug products available to the American public.
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Elements • Say what you do
– Create shared understanding of mission, work, tools/resources, policies and procedures
– Capture and document the understanding
• Do what you say – Train to the understanding – Execute, perform to the understanding
PLAN
DO
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Elements (cont.) • Prove it
– Check – Audit
• Improve it – Understand impact (internal and external) of
current activities on systems and policies – Align quality policies, objectives, and processes – Re-evaluate, recapture, retrain, repeat…
CHECK
ACT
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Capture and Document • Process mapping
– Drafting of SOPs* – Creation of documents (forms, checklists, etc.) – Standardization of letter templates – Cross-division/office (collaborative) revision
of documents and communication templates • Shared CDER/ORA electronic document
and workflow management through the CDER Informatics Platform
* SOP: Standard Operating Procedures
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Training • All staff
– GDUFA requirements met – New & newly mapped processes and procedures (concepts
such as team based review, risk based approaches, integrated quality assessment)
– New & revised resources/tools
• New employees – Formal series of orientations – Resources/tools – Long-term mentorship
• New managers – roles and responsibilities 33
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Continue to Improve
Document
Share
Train
Audit
• All content, expectations, processes, procedures, etc.
• All levels of the ANDA organizations
• All staff members involved with ANDAs
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Monitoring for Consistency • OPQ/OGD provide formalized QMS activities • Regular assessments of completed
applications will: – Monitor for consistency of decisions across
similar products/applications with established policies
– Identify opportunities for improvement in quality assessment processes and/or approaches, need for additional training and/or reviewer tools
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Mechanics and timing of Paragraph III and IV approvals
• Maryll Toufanian • Marty Shimer
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First Generics
March 23, 2015 FDA/GPhA Board Quarterly Meeting
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Goal of Today’s Discussion
• Review complex issues relating to First Generic ANDAs
• Discuss mechanisms to ensure timely First Generic approvals
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Why We Are Here • Timely approval of First Generic
ANDAs is in everyone’s best interest • Commitment Letter addresses First
Generics, but not in detail
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Today’s Agenda I. Overview of Hatch-Waxman: How It Works II. GDUFA and First Generics III. Institutionalizing Prioritization of First
Generics IV. Managing Complexity and Unpredictability
of First Generic Landscape V. Next Steps
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I. Overview of Hatch-Waxman:
How It Works
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Hatch-Waxman Amendments Grand bargain for Brand and Generic Industries • Brand Industry Gains:
– 5-year New Chemical Entity (NCE) Exclusivity – 3-year New Clinical Studies Exclusivity – Patent Term Extension to account for time patented
product is under review by FDA • Generic Industry Gains:
– Ability to challenge brand drug patents prior to marketing in court
– 180-day Generic Drug Exclusivity
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I. How Hatch-Waxman Works What brand must do: “list” patents
• NDA sponsor must identify in NDA those patents reasonably related to drug product, drug substance, or method of using drug for which approval is sought.
• FDA “lists” patents identified by NDA sponsors in “Orange Book” (OB).
• NDA referred to as “reference listed drug” or RLD.
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I. How Hatch-Waxman Works What generics must do: “certify”
• Certify with respect to each patent listed for that RLD in the OB: • patent information has not been filed (“paragraph I
certification”) = FDA can approve ANDA when ready • the patent has expired (“paragraph II certification”) = FDA
can approve ANDA when ready • the date the patent will expire (“paragraph III certification”)
= FDA can approve ANDA when patent expires and ANDA is ready
• the patent is invalid or not infringed by the drug product proposed in the ANDA (“paragraph IV certification”) = complex approval landscape
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I. How Hatch-Waxman Works What follows from PIV certification
• After FDA notifies applicant that ANDA is sufficiently complete to review, applicant must notify NDA/patent holder of Paragraph IV certification.
• NDA sponsor can sue when it receives notice.
• Infringement lawsuit can start prior to ANDA approval and marketing
• If NDA sponsor sues within 45 days of notice, ANDA approval is stayed for 30 months.
• No lawsuit with 45 days = FDA can approve ANDA when ready
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I. How Hatch-Waxman Works What follows from PIV certification
• ANDA approval depends on patent litigation Litigation Status Regulatory Action
Lawsuit pending before 30-month stay expires
We can only tentatively approve ANDA
Lawsuit still pending at 30 months We can approve ANDA
Generic wins We can approve ANDA
Dismissal/Settlement We can usually approve ANDA on agreed date
Brand wins We can only tentatively approve ANDA
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I. How Hatch-Waxman Works Tentative Approval
• ANDA ready for approval but blocked by patent, exclusivity, or stay = only eligible for tentative approval (TA)
• Full approval not automatic after TA – must show ANDA still meets requirements for approval at time of full approval, e.g., cGMPs still good
• TA’d ANDAs must request full approval 47
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I. How Hatch-Waxman Works 180-day Exclusivity
• Reward for ANDA applicants that challenge patents, potentially hastening generic market entry
• 180-day exclusivity is only available to “First to File” (FTF) ANDAs containing PIV certification
• Commonly there are multiple FTFs = shared exclusivity for FTF cohort
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I. How Hatch-Waxman Works Shared 180-day exclusivity
• FTF ANDAs may enter market at once if approval-ready
• or sequentially, depending on approvability
• or sequentially depending on intent to market
• All exclusivity ends at first triggered 180-day mark
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ANDA A, ANDA B, ANDA C
0 180 days
180 days 0
ANDA A ANDA B ANDA C
52 60
ANDA A ANDA B ANDA C
180 days
0 52 60
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I. How Hatch-Waxman Works Other Important Concepts: Forfeiture FTF can forfeit 180-day exclusivity: • Failure to obtain a tentative approval in 30
months – impacted by multiple factors external to FDA
• Failure to market within a specified time after approval
• Expiration of all patents with which exclusivity is associated
• Withdrawal of the ANDA or all paragraph IV certifications
• Entering into an agreement that is in violation of antitrust laws as determined by FTC
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Pediatric Exclusivity Exclusivity for pediatric studies requested under Best Pharmaceuticals for Children Act (BPCA) • Will result in six months of exclusivity when sponsor
“fairly responds” to the written request regardless of changes to labeling
• Attaches to existing NCE and three-year exclusivity and most patents
• Study that results in six months of pediatric exclusivity may also result three-year exclusivity for pediatric patients
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II. GDUFA and First Generics
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Background on GDUFA Commitment Letter
Pursuant to CL, FDA has three obligations re review prioritization for First Generics #1: expedite year 1 + 2 FTF #2: expedite all FTF ANDAs within 30 months of submission to avoid forfeiture – The above obligations overlap and are
familiar. We have always tried to make sure FTFs don’t “slip through the cracks.”
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Background on CL (cont.) #3: Expedite at submission and over course of review applications that are/become eligible for approval as a result of no blocking exclusivities, patents and/or applicable stays • This is new. It usually concerns not FTFs, but – instead
– subsequent applicants that become eligible for FA based on change with FTF.
• Impacted by variables outside FDA control.
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III. Institutionalizing Prioritization of First Generics
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Opened First Generics Docket Challenge: “First Generic” means different things to different people • Received informal statements demonstrating
different understandings, desired definition • Opened First Generics docket to enhance
transparency and gain clear industry expectations • Expansive definition (discussed below) well-received
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Patent and Exclusivity Team Established dedicated group within OGD Policy • A-team: DLRS Deputy Director, a former team leader
in regulatory support branch, and pharmacists with significant ANDA regulatory management experience
• Purpose: proactively identify, track, and facilitate timely resolution of issues related to First Generic approvals
• Driving long-term planning in First Generic Space
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DLRS Regulatory Counsels Built team of dedicated, experienced regulatory counsels • Recruited from within: OCC, OGD, and experienced
FDA regulatory counsel management • Recruited from private sector: Attorneys from highly
credentialed law firms, patent litigation firms, with Hatch-Waxman knowledge
• Purpose: Analyze Hatch-Waxman issues and document decisions to ensure timely First Generic approvals
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IT Enhancements Significant enhancement to IT underway to support efficient analysis of First Generics issues. • Data tracking, updating functions • Nimble, real-time information available
to decision makers
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OGD Hatch-Waxman Training • Providing training to all OGD disciplines on Hatch-
Waxman, including regulatory project managers and operations team.
• Providing updated information on developments in legal and regulatory space
Take away – We are strongly institutionalizing the First Generics function that previously was ad-hoc and under-resourced.
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IV. Managing Complexity and Unpredictability of First Generic
Landscape
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Proposed Criteria for First Generic Prioritization Category
Any received ANDA: • that is eligible for 180-day exclusivity (FTF);
OR • for which there are no (or no longer)
blocking patents or exclusivities AND there is no previously-approved ANDA for the drug product.
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Benefits and Challenge of Proposed Criteria
Benefits: • Focuses on getting generics to market as fast as possible • Consistent with broad scope of Commitment Letter • Adds focus on quick approval of subsequent applicant
given 180-day forfeiture, other shifts in landscape Challenge: • Variables outside of FDA control affect status over
lifetime of ANDA; can change often and quickly • FDA does not control approvability (e.g., quality of
submissions, inspection status, timing of industry response to deficiencies, patent litigation)
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Variables in Determining First-Generic Status
• Changes in patent certification, litigation status, and settlement agreements/waivers between the NDA holder and ANDA applicant(s) can immediately delay or accelerate approval dates. • Change by first applicant could result in multiple subsequent applicants
becoming immediately eligible for full approval • Order by court could temporarily or significantly delay ability to approve
• Forfeitures by FTF PIV applicants can result in subsequent applicants becoming immediately eligible for full approval.
• Late-in-the-game submission of revised patent information; added pediatric or 3-year exclusivity
• Approvability of ANDAs
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Case Study
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Key Take-Aways from Case Study • ANDAs submitted on the same day won’t
necessarily be approved on the same day. • Each ANDA in a FTF cohort has a distinct
patent/legal status. • This status can change often, and without our
knowledge. • Multiple variables – most outside of FDA’s control –
need to be tracked and updated in real time.
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V. Next Steps
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• FDA will continue to develop, enhance capacity to ensure timely First Generic Approval
• FDA seeks a conversation with industry on continued improvement:
– What else FDA can do? – What can Industry do?
Next Steps on First Generics
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Wrap-Up and Next Steps Next Meeting: • June 11, 1-4pm, WO75, RM 1540 Agenda: • Mutual Reliance Update • ORA Inspection Update • Surveillance Selection • Office of Process and Facilities Inspection (pre-approval and
post-approval)
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