DOSE SPACING IN EARLY DOSE RESPONSE CLINICAL TRIAL DESIGNS

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DOSE SPACING IN EARLY DOSE RESPONSE CLINICAL
TRIAL DESIGNS

• Naitee Ting, Ph. D.
• Associate Director
• Pfizer Global Research Development

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STUDY 1 - WHATS NEXT?
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STUDY 2
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Questions in Designing the First Dose Response
Study

• How many doses to be tested?
• What are the high and low doses?
• What are the spaces between the test doses (what
  is the dose spacing)?
• How frequent should subjects be dosed?
• How many subjects for the study?

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Dose Response Study Design

• Selection of control
• Selection of endpoints
• Fixed dose vs titration dose
• Two-stage designs vs Two designs

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Dose Response Study Design

• In early Phase II, drug first tested in patients
• Assume maximum tolerable dose (MTD) known, assume
  monotonicity
• Efficacy response, toxicity response
• Range and spacing of doses

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Limited Number of Fixed Doses

• Concerns in interpreting titration dose
• Multiple center designs
• Formulation considerations
• Placebo and maximum tolerable dose (MTD)
• Incorporate active control?

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Considerations in Dose Allocation

• Selecting a wide range of doses
• Find doses to capture the steepest increasing
  portion of efficacy dose response curve
• Use of some low doses to help identify the
  minimum effective dose (MinED)
• Not very high to be too close to MTD

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Binary Dose Spacing

• For 2 active doses, one above 1/2, one below
• Continue with this fashion to the lower end
• Any cut for 1/p, where p ? 2
• Non-parametric, model independent
• Applies to titration design, sequential design,
  active control, early or late Phase

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Compare to Optimal Designs

• For a given model, optimal design allocate doses
  according to D-optimality
• The most frequently used model is logistic
• Another model is normal cdf (with parameters m
  and s)

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Criteria for Comparison

• Provide a steeper slope from placebo
• Identify a minimum effective dose (MinED)

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Simulation Procedure

• Ten and fifty obs. generated from each dose
• Each obs. is normal with mean from model and
  standard deviation of 0.1 0.025
• Slopes from placebo to each dose
• Assuming minimum effect is 0.2, MinED is obtained
  from lower 95 confidence limit

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Table 1. Treatment Group Means, Slopes From
Placebo To Each Dose, And 95 Confidence Limits
From Simulated Data Under Different Sample Sizes
And Standard Deviations   Simulation based on
Model with q1 1.565 and q2 4.174   BDS
doses Low 0.125, Medium 0.375, High
0.750 Optimal doses Low 0.082, Medium
0.375, High 0.668    n/group
10 n/group
50 std. dev. 0.1 std. dev. 0.25
std. dev. 0.1 std. dev. 0.25 BDS
Opt. BDS Opt. BDS
Opt. BDS Opt.   Mean (Pcbo)
0.1804 0.1516 0.1813 0.1926 0.1508
0.1747 0.1626 0.1802   Mean (Low)
0.2468 0.2315 0.3351 0.2153 0.2724
0.2439 0.2799 0.1382 Lower L
-0.0153 -0.0133 -0.1039 -0.2009 0.0833
0.0311 0.0253 -0.1420 Mean (Med) 0.5223
0.5533 0.4792 0.4787 0.5133 0.4995
0.4834 0.4883 Lower L 0.2588 0.2958
-0.0451 0.0652 0.3261 0.2829
0.2230 0.2173 Mean (High) 1.8610 0.7624
0.8148 0.8436 0.8170 0.7544 0.7871
0.8005 Lower L 0.6068 0.5111 0.3679
0.4890 0.6292 0.5350 0.5164 0.5266
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Table 2. Simulation Results with 3 Active Doses
Using a Logistic Model to Compare D-optimal Dose
Spacing and Binary Dose Spacing of ½ distance  
?1 ?2 Low Medium High
Overall MinED 2 4 B O
B B BD2 2 6 B
O O O OP2 2 8
B B O O OP2 2
10 B B O O BD1
2 12 B O O O
BD1 2 14 B O O
O BD1 2 16 B O
O O OP2 2 18 B O
O O OP2 3 6 O
O B O BD2 3 8
O B O O OP2 3
10 O B O O OP2
3 12 O B O O
OP2 3 14 B B O
O OP2 3 16 B O
O O OP1 3 18 B O
O O BD1 4 6 O
O O O OP1 4 8
O O O O OP1 4
10 O O O O OP1
4 12 O B O O
OP1 4 14 O B O
O OP1 4 16 O B
O O OP1 4 18 O B
O O OP1
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Table 3. Simulation Results with 4 Active Doses
Using a Normal Model to Compare D-optimal Dose
Spacing and Binary Dose Spacing of ½
distance   ?1 ?2 Low Low
Med. Hign Med. High Overall MinED
. 0.1 0.1 B B O O
O BD1 0.2 0.1 O B O
O O OP2 0.2 0.2 B
B O O O OP2 0.3
0.1 O O B O O
OP1 0.3 0.2 O O B
O O BD2 0.3 0.3 B B
B O O BD2 0.4 0.1
O O O O O OP1
0.4 0.2 O O O O
O OP2 0.4 0.3 B O O
O O OP2 0.4 0.4 O
O O B B OP2 0.5
0.1 O O O O B
OP1 0.5 0.2 O O O
O O OP1 0.5 0.3 O O
O O O BD3 0.5 0.4
O O O B B BD3
0.5 0.5 B B O B
B OP2 0.6 0.1 O O O
B B OP1 0.6 0.2 O
O O O B OP1 0.6
0.3 B O O B O
BD3 0.6 0.4 B O O
B O BD3
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Table 4. Treatment Group Means, Slopes From
Placebo To Each Dose, And 95 Confidence Limits
From Simulated Data When The Underlying Model Is
Mis-specified     True Model q1 .38 and q2
.32. Using optimal design, this model was
mis-specified as q1 .32 and q2 .38 BDS doses
Low 0.125, Medium 0.375, High
0.750 Optimal doses (mis-specified model) Low
0.010, Medium 0.320, High 0.630 (the correct
doses should be Low 0.119, Medium 0.380, High
0.641) Simulation performed with n20 per group
and std. dev. 0.25.     BDS Dose
Allocation Optimal Dose Allocation
Point Point Lower L estimate Upper
L Lower L estimate Upper L   Mean (Pcbo)
0.1123 0.1976 Mean (Low)
0.0675 0.1958 0.0021 0.2141 Mean (Med)
0.3648 0.4955 0.2865 0.4997 Mean (High)
0.7420 0.8699 0.5797 0.7904   Slope
Low 0.540 0.668 0.796 0.202
1.575 2.948 Slope Med 0.973 1.022
1.071 0.895 0.944 0.993 Slope High
0.989 1.010 1.031 0.921 0.942
0.962
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Conclusion

• Assume MTD known and monotonic relationship
• Intuitive and with wide applications
• Model independent approach vs parametric
  optimality - Not much of a comparison
• A general recommendation, not one size fits all

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Analysis of Dose Response Studies

• Multiple comparison adjustment
• Placebo control, active control, or both
• Dunnetts method, Step down method
• Linear, quadratic dose response
• Minimum effective dose (MinED)

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Analysis of Dose Response Studies

• Drug safety in dose response studies
• Estimation vs hypothesis testing
• Exploratory vs confirmatory
• Analysis of the entire database