Balancing Pre and Postmarket Requirements Different Scenarios Dorothy Abel, BSBME and Andrew Farb, MD Division of Cardiovascular Devices Center for Devices and Radiological Health (CDRH) Food and Drug Administration Thank you for the opportunity to provide a reviewer perspective on this hot topic. FDA Town Hall CRT 2015 Washington, DC February 24, 2015

Conflict of Interest No conflicts of interest to report.

Objectives Why? Present the regulatory basis for balancing requirements How? Provide key considerations and examples of different approaches in balancing pre and postmarket requirements Should I’ll be addressing how and why we should and can balance pre and postmarket requirements, starting with the why. Can

Quoting Regulations I’m not a fan of quoting regulations, but but,…

Balancing Pre and Postmarket Requirements Obvious Reason Earlier access to beneficial medical devices #1 Public Health Benefit it’s worth mentioning that beyond the obvious public health benefits of having earlier access to beneficial medical devices, Worth

Section 513(a)(3)(C) of the FD&C Act Requires FDA to consider the use of postmarket controls in lieu of collecting and reviewing all effectiveness data prior to PMA approval.   Requires FDA to apply the least burdensome appropriate means of evaluating device effectiveness that would have a reasonable likelihood of resulting in approval Section 513(a)(3)(D)(ii) of the FD&C Act there are laws that say we must consider balancing pre and postmarket requirements and the least burdensome appropriate means of evaluating device effectiveness. The Food, Drug and Cosmetic Act specifically states that we need to consider the ability to use post-market controls rather than requiring all data under a PMA. It also states that we need to identify the least burdensome means for evaluating device effectiveness

Key Considerations Benefit-risk Principles How? Key Considerations Benefit-risk Principles Apply throughout regulatory decision making Consider the totality of the benefit/risk profile Disease condition (e.g., life-limiting, life-threatening) Limitations of and risks associated with currently available therapies Risks and benefits of the device Patient tolerance for risk and perspective on benefits The how hinges on applying benefit/risk principles throughout regulatory decision making, considering not only the benefits and risks of a device, but also the disease condition, limitations and risks associated with currently available therapies and patient’s tolerance for risk and perspective on benefits. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm267829.htm

Key Considerations Appropriate Level of Assurance With application of benefit/risk principles, can justify accepting more uncertainty premarket, obtaining greater assurance postmarket Require a reasonable assurance of safety and effectiveness You’re all familiar with our need to have a reasonable assurance of safety and effectiveness, but when trying to balance pre and post market requirements, with the application of benefit and risk principles, we are able to justify accepting more uncertainty premarket, and obtaining greater assurance postmarket premarket postmarket

New Process Expedited Access for Premarket Approval "Expedited Access PMA" or "EAP“ draft guidance Medical devices intended for unmet medical need for life threatening or irreversibly debilitating diseases or conditions Intended to further speed the availability of certain safe and effective medical devices that address unmet public health needs In recognition of this concept, a new process is being developed for an ‘expedited access PMA’ or ‘EAP.’ This process will be used to get earlier access to devices that fill unmet medical needs

EAP Balance Pre and Post-Market Requirements Determine whether certain data may be collected postmarket rather than premarket Within the benefit-risk framework discussed in the Benefit/Risk Guidance and in accordance with statutory and regulatory requirements To reach this goal, the EAP emphasizes the need to determine wheter certain data may be collected postmarket rather than premarket.

EAP Apply Least Burdensome Principles Premarket Use of intermediate and surrogate endpoints Having less statistically robust clinical studies Providing less manufacturing information or inspection requirements Premarket this may involve the use of intermediate and surrogate endpoints, having less statistically robust clinical studies, and providing less manufacturing information.

EAP Postmarket Requirements Condition of approval to continue evaluation and periodic reporting on the safety, effectiveness, and reliability of these devices for their intended uses Enables assessment of the risks and benefits of these devices with a higher degree of certainty and, if appropriate to protect patient safety, take appropriate enforcement action Postmarket, there will be a condition of approval to continue evaluation and for periotic reporting on the safety, effectiveness, and reliability of the device.

EAP Example Next Year? Concepts that will be applied have been tested under the Innovation Pathway 2.0 Will build on the current experience with balancing pre and postmarket requirements Although there aren’t examples of using this process, since the guidance is still in draft, some of the concepts that will be applied have been tested under the Innovation Pathway and through the other examples I’ll be talking about.

Next-generation Device Example Endovascular Graft Next-generation device with significant design differences that could affect clinical performance An expectation of comparable or better clinical performance compared to the current design Based on a foundation of knowledge of prior nonclinical evaluation and clinical experience with previous generations Nonclinical data are not adequate to fully assess the device As an example, there are some next-generation endovascular grafts that have design differences that could affect clinical performance, but we have an expectation that they will work as well or better than the current designs based on the knowledge the sponsor has from prior nonclinical evaluation and clinical experience. However, nonclincal data alone are not adequate to fully assess the device

Next-generation Endovascular Graft Regulatory Strategy Submit PMA supplement Including Explanation of how the prior experience is reflected in the new design Nonclinical testing on the new device 6-month clinical data demonstrate adequate clinical outcomes using descriptive statistics Provide regular updates as additional clinical information is obtained Submit postapproval report 12-month, hypothesis driven effectiveness assessment For these devices we plan to have the PMA supplement include an explanation of how the prior experience is reflected in the new design, nonclinical testing of the new device, and 6 month clinical data. The sponsor would provide regular clinical updates while the supplement is under review. The 12-month effectiveness data would be submitted postmarket

New Indication Example Endovascular Graft Initial approval of thoracic endovascular grafts was for treatment of aneurysms Regulatory challenges with expanding indications to include dissections Dissections were treated off-label Unanswered clinical question of when to treat an uncomplicated dissections Huge variability in clinical presentation Acute, sub-acute, chronic, complicated, uncomplicated, different extents We also have balanced pre and postmarket requirements when expanding the indications for endovascular grafts to include the treatment of dissections. Initially thoracic endovascular grafts were approved for treatment of aneurysms The Regulatory challenges associated with expanding the indications included The fact that Dissections were being treated off-label (essentially was the standard of care) There continue to be unanswered clinical questions as to when to treat an uncomplicated dissection and As you know, there is Huge variability in dissection clinical presentation

Dissection Indication Regulatory Strategy   Premarket Postmarket Question Treatment option for dissection? When to treat/best treatment? Population Acute complicated All dissections treated with EVGs Sponsor Individual Collaborative, using SVS VQI Registry # Patients 50 200 acute and 200 chronic (additional patients with 1 yr follow-up) Endpoint Primary 30-day mortality Several secondary endpoints Primary Safety (all devices combined) Freedom from dissection-related mortality at 5 years Primary Effectiveness (device-specific) Device technical success Device procedural success at 30 days Many secondary endpoints Follow-up 1 year 5-year

Rationale for Dissection Requirements November 2013 Endovascular Today P040043/S051 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=9347 P100040/S012 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=27966

Potential Discussion Points What questions should be answered with regulatory-based studies? Treatment option vs best treatment When to treat vs treatment option if treated What is the appropriate premarket depth of knowledge? What is the appropriate premarket breadth of knowledge?