Transcript JackGuralnik_SPPB-FDApresentation3.14.12

The FDA: The Key to Moving
Forward. An overview of the
Letter of Intent and the SPPB
Jack M. Guralnik, MD, PhD
FDA and Drug Indications:
• Most indications are for the treatment,
prevention or diagnosis of recognized
diseases or conditions, or treatment of
manifestations or symptoms of recognized
conditions
• Are sarcopenia, weakness or limited function
in the older population potential indications
for drug approvals?
• When indication is established, need
outcome measure that reflects benefit for that
indication.
FDA Clinical Trial Outcome
Assessments (COAs)
• Used to provide substantiation for
treatment benefit claims
• Two processes for FDA submission and
review
– As part of a drug application review
– Under the Drug Development Tool (DDT)
Qualification Process
Objective Performance Measure
of Physical Functioning
Assessment instrument in which an individual
is asked to perform a specific task and is evaluated
in an objective, standardized manner using
predetermined criteria, which may include counting
of repetitions or timing of the activity
as appropriate.
Examples of Objective Performance Tests Used to
Evaluate Functional Limitations
 Pegboard test
 Picking up object
 Lifting 10 pounds
 Gait speed
 Chair rise – single and repeated
 Stair climb
Short Physical Performance Battery
 Timed standing balance (up to 10 seconds)
Side-by-side stand
Semi-tandem stand
Tandem stand
 Timed 4-meter walk
 Timed multiple (5) chair rises
Death Rates According to Individual Performance
Tests—Age and Sex Adjusted
Deaths per 100 Person-Years
15
11.7
10
9.0
7.8
6.6
5
6.1
4.5
4.3
4.4
3.2
3.0
3.6
2.5
1.9
0
Test Category
0
% Distribution
Walk
5 23 25 26 22
1
2
3
4
0
1
2
3
4
Chair Stands
22 19 20 20 19
0
1
2
3.0
3.0
3
4
Standing Balance
10 15 13 14 49
Death Rates According to Performance Test
Summary Score
Age and Sex Adjusted
15
Deaths per 100
Person–Years
12.3
10.0
10
7.2
5.6
6.4
6.2
5.7
5
4.2
3.6
2.7
2.5
2.0
1.3
0
0
1
2
3
4
5
6
7
8
9
10
Performance Test Summary Score
Guralnik JM, et al. J Gerontol Med Sci. 1994;49:M85-M94.
11
12
Nursing Home Admission Rates According to
Performance Test Summary Score
Nursing Home Admissions
per 100 Person–Years
Age and Sex Adjusted
25
20
22.5
19.6
17.5
15
12.8
11.6
10.2
10
6.0
7.2
4.6
5
4.8
2.7
0.8
0.7
11
12
0
0
1
2
3
4
5
6
7
8
9
10
Performance Test Summary Score
Guralnik JM, et al. J Gerontol Med Sci. 1994;49:M85-M94.
Three-Level Hierarchical Classification of
Disability Related to Lower Extremity Function
Baseline
Prevalence (%)
 Non-disabled
 Disabled in higher mobility
– Walking 1/2 mile
– Climbing stairs
 Disabled in ADLs + higher mobility
– Transfer from bed to chair
– Using toilet
– Bathing
– Walking across a small room
+
– Walking 1/2 mile
– Climbing stairs
61.3
23.9
14.8
ADLs = activities of daily living.
Disability Status at Four Years According to Baseline Gait
Speed Among Those Non-Disabled at Baseline
Iowa EPESE
Disability Status
(% of subjects)
100%
80%
NonDisabled
60%
Mobility
Disabled
40%
ADL +
Mobility Disabled
20%
0%
Category
1
 0.42
2
0.43 – 0.59
3
0.60 – 0.77
Walking Speed (m/sec)
ADL = activity of daily living
Guralnik JM, et al. N Engl J Med. 1995;332:556-561.
4
 0.78
Disability Status at Four Years According to Baseline
Summary Performance Score Among Those Non-Disabled at
Baseline
Percent
Iowa EPESE
100
NonDisabled
80
Mobility
Disabled
60
ADL +
Mobility
Disabled
40
20
0
4
5
6
7
8
9
10
11
Summary Performance Score
ADL = activity of daily living
Guralnik JM, et al. N Engl J Med. 1995;332:556-561.
12
Age and Sex-Adjusted Proportion of Participants Unable to Complete 400
Meter Walk at 3-Year Follow-Up by Baseline SPPB Score
Unable to walk 400m after three years (%)
InChianti Study
90
80
70
p for trend <0.001
60
50
40
30
20
10
0
<7
8
9
10
11
12
Baseline SPPB Score
n
18
18
40
47
126
284
Source: Vasunilashorn et al. J Gerontol Med Sci, in press.
Distribution of Change in Performance Score
(1992 Score – 1988 Score)
Iowa EPESE
Percent of Sample
20
15
10
5
0
-12 -11 -10 -9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
Change in Performance Score
Penninx BWJH, et al. JAMA. 1998;279:1720-1726.
4
5
6
7
8
Adjusted Mean Change in Physical Performance Score
(1992–1988) According to Level of Depressive Symptoms
Mean Change in
Performance Score
0.0
-0.5
-1.0
-1.5
–1.27
–1.48
*
-2.0
-2.5
–1.59
–1.75
**
–2.26
P trend =.001
***
0-2
3-6
7-12
13-19
20
N=342
N=305
N=289
N=213
N=137
Depressive Symptoms (CES-D Score)
Adjusted for baseline performance score, demographics, behavioral risk factors, and disease status.
*P < .1, **P < .05, ***P < .001 compared to CES-D = 0 – 2
Penninx BWJH, et al. JAMA. 1998;279:1720-1726.
Odds Ratio* for 1 Point Decline in SPPB Score over 3 Years
for 1st Quartile of Micronutrients vs. Upper 3 Quartiles
InChianti Study
2.5
2.0
1.5
1.0
0.5
0.0
Vitamin E
Vitamin B12
Vitamin B6
Folic acid
Vitamin D
Iron
*Adjusted for age, sex, education, marital status, household composition, smoking, physical
activity, number of diseases, BMI, depression, MMSE.
Source: Bartali et al. JAMA 2008;299:308-15.
Lifestyle Interventions and
Independence For Elders
A Randomized Clinical Trial of Exercise to
Prevent Mobility Disability in Non-disabled
Older Persons with Functional Limitations
To download: http://www.grc.nia.nih.gov/branches/ledb/sppb/index.htm
Age-Adjusted Hazard Ratio for Death per 0.1-m/s Higher Gait Speed
Studenski, S. et al. JAMA 2011;305:50-58
Copyright restrictions may apply.
Use of a Qualification
Qualification is a conclusion that within the stated context of use, the results
of assessment with a DDT can be relied upon to have a specific
interpretation and application in drug development and regulatory review.
Once qualified, the DDT can be used by drug developers for the qualified
context in IND and NDA/BLA submissions without requesting that the
relevant CDER review group reconsider and reconfirm the suitability of the
DDT.
Qualification also creates a collaborative setting where there can be
advantages for multiple interested parties (individuals or companies)
working together to develop a DDT for qualification.
Process for Qualification
Stage 1: Consultation and Advice
1. Letter of Intent (LOI)
2. DDT Briefing Package and Initial Meeting
If CDER accepts the DDT request, the submitter should then submit a briefing
package. At this point a Qualification Review Team (QRT) will be created to
provide ongoing advice to the DDT submitter about the evidence needed for
qualification. A QRT is composed of CDER review staff from various relevant
disciplines with expertise appropriate to review of the submission.
3. DDT Investigation and Development
Stage 2: Review for Qualification Decision
When the submitter believes the data are sufficiently complete to support a
conclusion that the DDT is qualified for a specific context of use (i.e., “fit for
purpose”) and CDER concurs that detailed, formal data review is warranted,
the submitter should submit a formal qualification package.
The QRT will review the qualification package, discuss the project at internal
meetings, and arrive at a QRT recommendation on the qualification
decision.