Competitive Industry Needs & Research Infrastructure: Is Partnering Possible?

Trans-Radial Education and Therapeutics (TREAT) IV

FDA Headquarters

White Oak, MD

July 29, 2013

CHIP HANCE

Partnering is Needed!!!

Disclosures• 2012-13 CDRH FDA Entrepreneur-in-

Residence• No access or involvement with individual

company submissions• Views expressed are my own

• Retired employee of Abbott Laboratories• Most recently President of Abbott Vascular

• Beginning new position (9/2013) as CEO for a global supplier to the medical device industry

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Increasing Challenges in Clinical Research

THE IMPACTS•Widespread industry discouragement with conducting trials in the U.S.

•Rising U.S./Int’l gap in new product approvals

•Declining Clinician interest in conducting research

•Growing concern with FDA and other stakeholders with the clinical trial ecosystem

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The mission to provide innovative therapies is increasingly constrained

THE CHALLENGES

• Difficult to define studies with FDA

• Difficult to set up U.S. sites

• Difficult to enroll patients

Timing differences driven mostly by clinical trials

A Growing Gap Between CE & PMA Approvalsfor Cardiovascular Devices

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Cypher DES•CE Mark 4/02•PMA Apprv. 4/03•Randomized•>1,000 patients

Xience DES•CE Mark 1/06•PMA Apprv. 7/08•Randomized•>1,000 patients

Heartmate II LVAD•CE Mark 11/05•PMA Apprv. 4/08

2ND ERA, 1-2 YEAR GAP

Bx Velocity BMS•CE Mark 6/00•PMA Apprv. 7/00•Single arm study•< 200 patients

Multi-Link Vision BMS•CE Mark 2/03•PMA Apprv.7/03

1ST ERA, < 1 YEAR GAP

Sapien TAVI•CE Mark 9/07•PMA Approval 11/11

3RD ERA, 3-5 YEAR GAPXience Nano•CE Mark 3/08•PMA Approval 5/11

MitraClip Mitral Valve Repair•CE Mark 3/08•PMA Approval TBD

Symplicity Renal Denervation•CE Mark 4/10•PMA Approval TBD

1st to 2nd Eras, 2000 – Mid-decade

Slowing of all processes for initiating and completing studies•Increasing FDA preclinical requirements prior to initiating clinical studies•Longer deliberations with FDA on Study Design•Lengthier contract negotiations and IRB reviews with sites•Reduced CMS support for studies•Challenging consent forms for patients•Reduced site dedication to clinical research•Slower enrollment

2nd to 3rd Eras, Mid-decade to Present

What’s Driving The Gap?

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Greater rigor in studies• Randomized, well

controlled studies• Improved statistical plans• Narrower patient

inclusion/exclusion criteria

• Longer follow-up (6 months to 1 year, or longer)

If company has more employees or higher expense rate, costs can be significantly greater

Source: Versant Ventures

Delays Have Real Costs

Expense to Company

8 Week Delay in Scheduling a Meeting $1.8 MM

Additional 20 Animal Study (6 months) $5.5 MM

Extra Year in Negotiating an IDE $10.8 MM

Additional 100 patient study with 1 year Follow-up (24 months)

$24.1 MM

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Estimated Cost of FDA Decisions on a 30 Employee Company

Entrepreneurs-in-ResidenceProgram Two (Oct 2012 - April 2013)

• Overview: The Entrepreneurs-in-Residence (EIR) program at CDRH is a time-limited recruitment of world-class entrepreneurs and innovators to join highly-qualified internal government employees in the development of solutions in areas that impact innovation.

• Goal: The EIR goal is to deliver transformational change by combining the best internal and external talent applying the principles of lean engineering in rapidly testing, validating and scaling new approaches.

• Focus: This year’s EIR team is confronting three challenging areas that have the potential to better support a more robust environment for medical device innovation:

• Streamlining clinical trials

• Streamlining FDA approval to reimbursement

• Striking the right balance between pre- and post-market requirements

7Source: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHInnovation/InnovationPathway/ucm286138.htm

Clinical Research within the Device Development Pathway

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Device Development & Trial Ideation

• Pre-clinical testing

• Bench testing• Animal studies• Explore study

concepts with Thought Leaders

• Trial protocol development

StudyPlanning &IDENegotiation

StudyStartup

StudyConduct

Study Evaluation& Device Review

PostReview

• Pre-IDE meetings w/FDA

• Establish study oversight (PI, DSMB, etc.)

• Statistical analysis• Site selection

PATHWAY STEPS

• Contracting with Sites, CRO and Committees

• Site IRB approvals

• CMS reimbursement

• Investigator training

• Patient enrollment• Monitoring of

sites and reporting events

• Regular DSMB review of events

• Sharing enrollment success between sites

• Data analysis• Study submission

together with marketing application

• FDA review• FDA Panel (as

needed)• Device clearance

• Post-approval commitments

• Annual reporting of clinical research

• CMS Reimbursement

• Surveillance monitoring

Example Activities:

Project Focus

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Metrics:“If you can’t measure it,

you can’t manage it.”- Peter Drucker

Metrics:“If you can’t measure it,

you can’t manage it.”- Peter Drucker

What are the differences in IDE approval times by company size, study type, etc.?

How effective are pre-IDE discussions with FDA in achieving more rapid IDE approvals?

What is the average time for a site to negotiate a contract with a sponsor?

How variable are IRB approval times? What drives the differences?

DATA TRANSPARENCY

PROCESS IMPROVEMENT

BEST PRACTICES

BENCHMARKING

Interesting Findings

• Significant variability in IDE FDA approval times based on:• Sponsor type (startups vs. multinationals)

• Pivotal vs. feasibility IDE’s

• Consistency in reviewers

• Quality of submission

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If industry sponsors and FDA are aware of issues, both can organize appropriately for a

streamlined process

Interesting Findings

• FDA and sponsors spend significant resources on repeat submissions:

• Multiple repeat cycles (3 and more reviews) consume as much as half of FDA’s IDE resource

• Highlights the need for effective decisions in 1st and 2nd review cycles

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FDA/industry sponsors need to work on clear two-way communications and effective

expectation setting to drive to one- and two-cycle reviews

Interesting Findings

• Dramatic variability in site performance across all studies:• ~45% of device studies fail to meet

enrollment targets• ~15% of sites across all studies fail to

enroll a single subject; more than half under enroll

• Significant variability in contracting and IRB processes

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If sites and industry sponsors could have clear visibility to standards of performance, could a virtuous cycle of self-improvement

begin?

Initiatives to Drive Improvement• Clinical Trials Transformation Initiative (CTTI)

• FDA/Duke initiative (2007)• Recognition increasingly longer study start-up times, slowing enrollment of patients

into trials, increasing clinical trial costs, and declining investigator interest in participating in clinical trials

• To identify practices that will improve the quality and efficiency of clinical trials• More than 60 Member Organizations in a Public-Private partnership

• Medical Device Innovation Consortium (MDIC)• New Public-Private partnership between industry, FDA and other government bodies

focused on Regulatory Science (Jan 2013)• One of first working groups targeting Clinical Research• Membership includes 21 Med Device companies, FDA, NIH, CMS, NVCA and Pew

Charitable Trusts

• Internal FDA Steps• Efforts taken to implement Innovation Pathway recommendations

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Conclusions• Clinical trials of new medical devices have played and

will continue to play an increasing role in the advancement of medicine

• The U.S. ecosystem for conducting medical device clinical trials has become increasingly cumbersome• Has efficiency been sacrificed for rigor?• What is the unintended consequence of the heavy burdens

placed on clinical research?• There is a growing recognition of the need for broad-

based improvement• FDA is taking an active role in trying to facilitate

improvement across the clinical trials ecosystem• Collaboration between all stakeholders (sponsors,

medical societies, institutions, FDA, CMS, etc.) will be necessary to make meaningful improvement

• Unfortunately, process improvement is a long journey, not a short-term exercise

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Backup

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THEN

Final validations before start of U.S. pivotal study; study starts later in product development cycle

3-9 month study negotiation with FDA

Extensive discussions with sites on contracting and IRB reviews

A large fraction of sites blocked from enrolling Medicare patients due to variable CMS reimbursement

Complex consent forms

Many sites no longer have hospital administration support

Slower, variable enrollment

NOW

Increasingly Challenging to Initiate and Complete Studies

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Established product design to enter clinical studies; final product validations completed prior to PMA submission

1-3 month study negotiation with FDA

Straightforward contract negotiations and IRB approvals

CMS reimbursement a given

Straightforward consent form

Committed investigators and sites

Rapid enrollment