Download Procedural Success

Possible Approval Pathways for
Mitral Valve Device Therapies
FDA View
John Laschinger, M.D.
Medical Officer
Structural Heart Device Branch
DCD/ODE/CDRH
[email protected]
Disclosures and Disclaimer
John C. Laschinger, M.D.
I am a full time employee of
the FDA. I have no financial
conflicts of interest to report.
The views expressed in this
presentation are those of the
presenter and do not represent
the official policies of the FDA.
Mitral Regurgitation (MR)
Simple Problem (valve leaks), Complex Disease
Primary (Degenerative) MR
Secondary(Functional) MR
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Valve complex is the Disease
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Primarily a disease of the ventricle
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Annulus, Leaflet and/or Chordae
Pathology
– LV enlarged and Papillary muscle(s)
displaced
restricted leaflet motion
– Annular dilatation
– e.g. Barlow’s, Marfan, Fibroelastic
deficiency
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Surgery is gold standard
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Patients with Class I Indication
Individual Surgeon skill/experience a
factor
Underutilized
Optimal repair (MR < mild) essential
No Gold Standard Therapy
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Early restoration of MV competence is
“curative”
Device Repair/Replacement requires
RCT proof of clinical equivalence
MV Repair is Comparator
Valve leaflets typically normal
Progressive LV Dysfunction - Is MR Cause or
Effect?
– MR Correction - not curative - palliative??
– Is MR reduction palliative, does it halt
progression?
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Optimal comparator therapy – Uncertain
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Medical Therapy (GDMT)
‒ Titration and adherence
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MR reduction - devices
MR correction
‒ Surgical Repair - Prone to recurrence
‒ Surgery and Device Replacement – higher
initial risks
Clinical Evidence Acquisition Plan
Enrollment and Data Quality Assurance
Identification of Appropriate Study Sites
– Patient mix*
– Facility resources*
– Track record of performance in clinical research studies (personnel,
enrollment, protocol adherence, complete and accurate data, etc)
Identification of appropriate patients
– Central Steering Committee
Assurance of Appropriate Personnel
– Heart Team – minimum composition
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Skilled* Interventionalist
Skilled* Surgeon
Heart Failure Physician
Skilled* Echocardiographer available in Cath lab/OR
Adjudication of Critical Data
– Primary Endpoint Outcomes, Major Adverse Events
– Imaging Endpoints
*based on disease/therapies
What is Control Therapy
Choice of Comparator for MR trials
• Dictated by Indication for Use
– Disease (intended use)
• Availability of standard of care (SOC) therapy
• Unmet clinical need
– Population of Use (conditions of use)
• Cause of valvular dysfunction - Primary vs. Secondary MR (ischemic or
non-ischemic)
• Operative risk status
• Timing in Disease Course
– Severity of resulting or underlying ventricular remodeling and
dysfunction
– Severity of symptoms
• Importance of Heart Failure Team
– Assurance of uniform treatment application & compliance
• Control Rx - adequacy and adherence
• Test Rx – Operator/interventionalist skills
– Appropriate utilization of GDMT (+ CRT and/or CAD-Rx) in all
patients
What is Safety
Factors to Consider
• Safety Profile Differences - Balanced Primary Safety Endpoints
– Timing of Outcome determinations
• Short Term
• Long term
– Account for variable risks by therapy
• Drug
• Transcatheter Device
• Open Surgery
• Procedural AE’s
– Mortality
– Bleeding
– Cardiovascular (MI, Arrhythmias)
- Neurological Events
- Acute Kidney Injury
- Access Injury/Tamponade
• Specific device-related technical failure issues and complications
– Adjudicated for Device relatedness
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Access – Vascular, apical, septal, open surgical
Anchor points - Tissue Disruption; Device Misplacement, Malfunction, Embolism
Durability – Fracture, thrombosis
Damage or interaction with surrounding tissues (e.g. mitral apparatus, coronary compression)
Infection
Paravalvular leak
Hemolysis
Unplanned additional devices
Need for emergent unplanned intervention or surgery
Judging Effectiveness
Depends on Disease, Device, Available Rx and Timing
Required:
• Alive , with
• Expected device/surgery performance for MR therapy:
– Correction (MR < mild)
– Reduction (MR decrease > 1 grade)
• Clinically meaningful benefit:
Durable over time
Low/no MR recurrence
(MR increase > 1 Grade)
Hemodynamic
Success
– Prevention or delay in the clinical progression of the effects of the disease:
• Survival Advantage
• Fewer Morbid Events
– Reduction in HF events (Hospitalization & equivalents)
– Reduced need for chronic medications
– Clinical improvement(s) of value to the patient:
• Symptoms (e.g. NYHA Class)
• Function (e.g. 6MWT)
• Quality of life (e.g. KCCQ)
Helpful:
• Supportive Secondary Endpoints
– Favorable trends in biomarkers
– Improvements in Ventricular volume or function
– Prevention of deterioration in ventricular function or volume
Transcatheter Valve Repair and Replacement
Traditional Hierarchy of Importance for Effectiveness Measures
• Increased survival
• Prevention or delay of the clinical
effects of the disease – HF
hospitalization
• Significant improvements
 Symptoms
 Daily function
 Quality of life
• Longitudinal Hemodynamic success
• Prevention or Delay in the progression
of the anatomic effects of the disease
Highest
Lowest
Secondary
Mechanistic
Transcatheter Valve Repair and Replacement
What’s important to the Patient?
• Increased survival
• Prevention or delay of the clinical
effects of the disease – HF
hospitalization
• Longitudinal Hemodynamic success
• Significant improvements
“Years of Life” vs. “Life in Years”
Lowest
Highest
Minimally
Symptomatic
Patient,
“Curable”
Patient
 Symptoms
 Daily function
 Quality of life
• Prevention or Delay in the progression
of the anatomic effects of the disease
Lowest
Severe
Symptoms,
Failed Medical
Rx Patient
Highest
Secondary
Mechanistic
Patient Centered Outcomes
Customized based on Device Indications for Use*
Outcome
% of Patients Alive
with…
Technical
Success
…successful implant of the single
intended device without
additional unplanned emergency
procedure/intervention
Procedural
Success
…technical/Device Success and
no major adverse events (MAE’s)
Device
Success
… the original implant in place
performing structurally and
functionally as intended, without
device related complications or
need for additional procedures
Individual
Patient Success
…device Success and return to
pre-procedure environment and
meaningful clinical improvement
in Symptoms, Function, or
Quality of Life (QoL)
Timing of
Measurement
Relevant patient
questions
At exit from
Procedure
(OR or Cath lab)
How successful is the procedure
to implant the device?
At discharge (D/C)
from hospital or 30
days, whichever is
later
What are my chances of having
the device placed successfully
without major complications?
All post-procedure
time intervals
starting at D/C or 30
days
Once the device is in place, does
it break or fail? Can it cause
problems over time? How long
does it last?
All post-procedure
intervals starting at
6 months
If my device works, will I be able
to resume my normal life and
stay out of the hospital? Will
this improve how I feel and
function and my QoL? For how
Long?
*Adapted from Stone GW et al. J Am Coll Cardiol 2015;66:308–321
Valve Repair and Replacement
Effectiveness Measures for Symptomatic Valve Disease
For Diseases where Device Therapy is proven to be clinically effective vs. the
natural history of underlying disease, one or more of the following clinically
meaningful changes is observed:
“Traditional” Outcomes
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Hemodynamic success
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Significant improvements
 Symptoms
 Daily function
 Quality of life
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Expected
Observation
Time
Prevention or decreased incidence of
the clinical effects of the disease
Prevention or Delay in the anatomic
progression of the effects of the disease
Increased survival
Early
(OR to 30 days)
Patient Centered Outcomes
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Technical Success (OR exit)
Procedural Success (30 day)
Device Success
(all time intervals > 30 days)
Durability of device
Mid
(6mo – 1 year)
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Individual Patient Success
(all intervals > 6 months)
Durability of benefit
Late
Stability over time
(1 year to Years)
Curative or Palliative
Valve Approval
Remaining Relevant Questions (2017)
• Is there anything about the valve that makes it more
difficult or less safe to insert
Procedural Success at 30 days
• Is the valve structure and performance durable over
time
Device Success - 30 days and yearly
• Does correction of the underlying valve disorder
result in meaningful and durable clinical benefits to
the patient
Individual Patient Success 6months and yearly
PMA Approval - Clinical Decision
Accounting for Unmet Need and Patient Preference
Benefit-Risk Determination
Thank You!
John Laschinger, MD
Medical Officer, SHDB
301.796.1210
[email protected]
14
Hemodynamic Performance
Effectiveness
• Hemodynamic Success (Valve Dependent)
– Mean gradient
• 30 day
• 1 year
30 day and 1 year Device Success: Aortic < 20mmHG
Mitral < 5mmHg
Device Failure (both): Increase > 25% increase over post-procedure baseline
– Indexed Effective Orifice Area – change over time
• 30 day
• 1 year
30 day and 1 year Device Success:
Stenosis: Increase in EOAI > 50% over pre-procedure baseline
Regurgitation: EOAI in normal range post-procedure
Device Failure (both) = decrease > 10% of post-procedure baseline
– Central Insufficiency – change over time
• 30 day
• 1 year
Device Success: Central Regurgitation < Mild
PVL < mild
Total Regurgitation < Mild
Device Failure: Central Regurgitation > Mild
PVL > mild
Total Regurgitation > Mild
Imaging Durability
Evidence of Bioprosthetic Valve Disease
a. Hemodynamic deterioration (mild, moderate,
severe; + Symptoms)
b. Thrombotic leaflet thickening responding to
anticoagulation - HALT or HAM; + HD, + Symptoms
c. Imaging evidence of persistent Structural Valve
Deterioration (e.g. Loss of leaflet or frame structure,
integrity or function; + HD – stenosis and/or
insufficiency; + Symptoms)
d. Prosthetic Valve Failure (referral for Explant, valve
related death or SVD discovered at autopsy; Cause –
a or c above)