The FDA: The Key to Moving The FDA: The Key to Moving Forward. An overview of the Forward. An overview of the Letter of Intent and the SPPBLetter of Intent and the SPPB

Jack M. Guralnik, MD, PhDJack 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 Objective Performance Measure of Physical Functioningof Physical Functioning

Assessment instrument in which an individual Assessment instrument in which an individual is asked to perform a specific task and is evaluated is asked to perform a specific task and is evaluated in an objective, standardized manner using in an objective, standardized manner using predetermined criteria, which may include counting predetermined criteria, which may include counting of repetitions or timing of the activity of repetitions or timing of the activity as appropriate.as appropriate.

Examples of Objective Performance Tests Used to Examples of Objective Performance Tests Used to Evaluate Functional LimitationsEvaluate Functional Limitations

Pegboard testPegboard test

Picking up objectPicking up object

Lifting 10 poundsLifting 10 pounds

Gait speedGait speed

Chair rise – single and repeatedChair rise – single and repeated

Stair climbStair climb

Short Physical Performance BatteryShort Physical Performance Battery

Timed standing balance (up to 10 seconds)Timed standing balance (up to 10 seconds)

Side-by-side standSide-by-side stand

Semi-tandem standSemi-tandem stand

Tandem standTandem stand

Timed 4-meter walkTimed 4-meter walk

Timed multiple (5) chair risesTimed multiple (5) chair rises

Death Rates According to Individual Performance Death Rates According to Individual Performance Tests—Age and Sex AdjustedTests—Age and Sex Adjusted

11.7

7.8

9.0

6.6

4.5

6.1

4.3

3.2

4.4

3.03.6

3.0

1.92.5

3.0

0

5

10

15

Dea

ths

per

100

Per

son

-Yea

rs

Walk Chair Stands Standing Balance% Distribution 5 23 25 26 22 22 19 20 20 19 10 15 13 14 49

0 1 2 3 4Test Category 0 1 2 3 4 0 1 2 3 4

10.0

7.2

5.66.4 6.2

5.7

4.23.6

2.7 2.5 2.01.3

12.3

0

5

10

15

0 1 2 3 4 5 6 7 8 9 10 11 12

Age and Sex Adjusted

De

ath

s p

er 1

00

Pe

rso

n–

Yea

rs

Performance Test Summary Score

Guralnik JM, et al. J Gerontol Med Sci. 1994;49:M85-M94.

Death Rates According to Performance Test Death Rates According to Performance Test Summary ScoreSummary Score

19.6

22.5

12.8

17.5

11.610.2

6.07.2

4.6 4.8

2.70.8 0.7

0

5

10

15

20

25

0 1 2 3 4 5 6 7 8 9 10 11 12

Performance Test Summary Score

Nu

rsin

g H

om

e A

dm

issi

on

s p

er 1

00 P

erso

n–Y

ears

Age and Sex Adjusted

Guralnik JM, et al. J Gerontol Med Sci. 1994;49:M85-M94.

Nursing Home Admission Rates According to Nursing Home Admission Rates According to Performance Test Summary ScorePerformance Test Summary Score

61.323.9

14.8

BaselinePrevalence (%)

Three-Level Hierarchical Classification of Three-Level Hierarchical Classification of Disability Related to Lower Extremity FunctionDisability Related to Lower Extremity Function

Non-disabledNon-disabled Disabled in higher mobilityDisabled in higher mobility

– Walking 1/2 mileWalking 1/2 mile– Climbing stairsClimbing stairs

Disabled in ADLs + higher mobilityDisabled in ADLs + higher mobility– Transfer from bed to chairTransfer from bed to chair– Using toiletUsing toilet– BathingBathing– Walking across a small roomWalking across a small room

++– Walking 1/2 mileWalking 1/2 mile– Climbing stairsClimbing stairs

ADLs = activities of daily living.

Disability Status at Four Years According to Baseline Gait Disability Status at Four Years According to Baseline Gait Speed Among Those Non-Disabled at BaselineSpeed Among Those Non-Disabled at Baseline

0%

20%

40%

60%

80%

100%

Dis

abil

ity

Sta

tus

(% o

f su

bje

cts)

Guralnik JM, et al. N Engl J Med. 1995;332:556-561.

0.42 0.43 – 0.59 0.60 – 0.77 0.78

Walking Speed (m/sec)

Iowa EPESE

ADL = activity of daily living

Category 1 2 3 4

Non-Disabled

Mobility Disabled

ADL + Mobility Disabled

Guralnik JM, et al. N Engl J Med. 1995;332:556-561.

Iowa EPESE

Disability Status at Four Years According to Baseline Disability Status at Four Years According to Baseline Summary Performance Score Among Those Non-Disabled at Summary Performance Score Among Those Non-Disabled at BaselineBaseline

0

20

40

60

80

100

4 5 6 7 8 9 10 11 12

Summary Performance Score

Pe

rce

nt

ADL = activity of daily living

Non-Disabled

Mobility Disabled

ADL + Mobility Disabled

Age and Sex-Adjusted Proportion of Participants Unable to Complete 400 Meter Walk at 3-Year Follow-Up by Baseline SPPB Score

InChianti Study

Baseline SPPB Score

Un

able

to

wal

k 40

0m a

fter

th

ree

year

s (%

)

0

10

20

30

40

50

60

70

80

90

< 7 8 9 10 11 12

p for trend <0.001

n 18 18 40 47 126 284

Source: Vasunilashorn et al. J Gerontol Med Sci, in press.

0

5

10

15

20

-12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8

Change in Performance Score

Per

cen

t o

f S

amp

le

Iowa EPESE

Penninx BWJH, et al. JAMA. 1998;279:1720-1726.

Distribution of Change in Performance Score Distribution of Change in Performance Score (1992 Score – 1988 Score)(1992 Score – 1988 Score)

Adjusted Mean Change in Physical Performance Score Adjusted Mean Change in Physical Performance Score (1992–1988) According to Level of Depressive Symptoms(1992–1988) According to Level of Depressive Symptoms

–2.26

–1.75–1.59

–1.48–1.27

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Depressive Symptoms (CES-D Score)

Mea

n C

han

ge

in

Per

form

ance

Sco

re

0-2N=342

3-6N=305

7-12N=289

13-19N=213

20N=137

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.

***P trend =.001

***

Odds Ratio* for 1 Point Decline in SPPB Score over 3 Years for 1st Quartile of Micronutrients vs. Upper 3 Quartiles

InChianti Study

*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.

0.0

0.5

1.0

1.5

2.0

2.5

Vitamin E Vitamin B12 Vitamin B6 Folic acid Vitamin D Iron

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

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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.

Use of a Qualification

Stage 1: Consultation and Advice

1. Letter of Intent (LOI)

2. DDT Briefing Package and Initial Meeting

Process for Qualification

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 DecisionWhen 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.