1. 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

2. Conflict of Interest
No conflicts of interest to report.

3. 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

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

5. 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

6. 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

7. 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.

8. 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

9. 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

10. 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.

11. 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.

12. 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.

13. 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.

14. 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

15. 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

16. 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

17. 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

18. Rationale for Dissection Requirements
November 2013 Endovascular Today
P040043/S051
P100040/S012

19. 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?