Drug Supply for Adaptive Trials

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1 Drug Supply for Adaptive Trials Nitin R Patel Co-founder and Chairman, Cytel Inc.

2 Outline Challenge of planning drug supply for adaptive trials Combining statistical design simulation with drug supply simulation Example Single Site Multiple campaigns On-demand packaging of kits Multicenter trials Simulation Process: Planning and Implementation Stages Extensions Conclusions Drug Supply for Adaptive Trials 2

3 Challenges Since the number of subjects on each treatment arm is not known at the start of the trial, overage (excess) in drug supply can be very substantial unless the adaptive procedure is explicitly accounted for in planning drug supply. Deciding on an appropriate level of budget for drug supply in an adaptive trial is not simple. Drug Supply for Adaptive Trials 3

4 Simulation tools Simulation tools can be leveraged to reduce overage and estimate costs of drug supply for adaptive trials Adaptive design-drug supply simulation tools can also be used while the trial is running to adjust to deviations from planning assumptions ( e.g. lower than expected accruals at some centers) Drug Supply for Adaptive Trials 4

5 Example: Phase 2 dose-finding trial Placebo controlled, double blinded trial Sample size =120 (40 placebo, 80 drug). Seven doses of drug: 1, 2, 3, 4, 5, 6, 7 units. Endpoint is Normal with known standard deviation Single Dose with end point available quickly relative to recruitment rate Single Center, single campaign, single tablet per dose a) Two campaigns (2 manufacturing lots for tablets) b) Assemble dose kit from multiple tablets (pack-toorder) c) Both a) and b) Multiple centers supplied from one depot Drug Supply for Adaptive Trials 5

6 Bayesian Adaptive Design 1. Mean dose response modeled as four parameter logistic curve; non-informative prior distribution used for parameters 2. Each cohort has 12 subjects: 4 on placebo and 8 on drug. First cohort has 2 subjects on dose 4 and 1 each on all other doses. 3. Use responses of subjects in cohort to compute posterior distribution. 4. Apply a rule that uses the posterior distribution to assign doses to subjects in the next cohort. 5. Repeat 3. and 4. until 10 cohorts have been randomized (sample size = 120) Drug Supply for Adaptive Trials 6

7 Drug requirement for adaptive design For fixed equal allocation: Lot composition: 40 placebo kits, 12 kits each of doses 1, 2, 3, 4, 5, 6, 7 Total # kits required = x 7 = 124 (Overage = 4 kits) For adaptive design: We know 40 kits of placebo are required and also that for the first cohort we need 2 kits of dose 4 and 1 kit for doses 1, 2, 3, 5, 6, 7. We do not know how subjects in the 9 remaining cohorts will be assigned doses by the adaptive allocation process. A safe approach is to provide : 9 cohorts x 8 subjects/cohort = 72 kits for each dose. Total #kits = x6+72x7 = 552 Additional Overage for adaptive design = = 428 kits or 345% Drug Supply for Adaptive Trials 7

8 Using adaptive design simulations It seems very unlikely that the adaptive allocation will allocate all subjects after the first cohort to a single dose To design the adaptive trial a simulation tool was used to calculate the (frequentist) operating characteristics for a set of seven representative scenarios For planning drug supply we may wish to run many more scenarios. Drug Supply for Adaptive Trials 8

9 Likely Dose Response Scenarios 25 Mean Response Dose Scenario 1 Scenario 2 Scenario 3 Scenario 4 Scenario 5 Scenario 6 Scenario 7 Drug Supply for Adaptive Trials 9

10 Adaptive dose-allocations by Cohort Drug Supply for Adaptive Trials 10

11 Simulation of dose allocation (Sc. 7) Dose Allocation Output Sim # Subject # Cohort # Dose Resp(YY) Drug Supply for Adaptive Trials 11

12 500 simulated trials (Scenario 7) Drug Supply for Adaptive Trials 12

13 Simulation reduces overage Simulations show that the total #kits can be reduced from 552 to 286 if one accepts a probability of stock-out of about 1/500 = Additional overage comes down from 428 to 162 kits or from 345% to 131% Drug Supply for Adaptive Trials 13

14 Two campaigns Campaign 1 produces kits for cohorts 1-5 Campaign 2 produces extra kits to raise stock-on-hand to supply cohorts 6-10 Additional overage comes down to 125 kits or 101% compared to162 kits or 131% with one campaign and the same probability of stockout (0.002) Drug Supply for Adaptive Trials 14

15 Pack-to-order Suppose that the doses were made up from two tablet formulations: placebo and 1 unit tablet. Kits are dispensed or packed-to-order on demand from these two tablet forms Kits for doses will consist of 7 tablets and be made up by packing different combinations of the two tablet types as shown below. PBO D1 D2 D3 D4 D5 D6 D7 P tab tab Drug Supply for Adaptive Trials 15

16 Two tablet forms (Single campaign) Total tablets (adaptive)= 1090 Total tablets (fixed)= 868 Additional overage = 26% (222 tablets) Compared to 131% with pre-packed kits and the same probability of stockout (0.002) Drug Supply for Adaptive Trials 16

17 Two tablet forms (Two campaigns) Campaign 1 produces tablets for cohorts 1-5 Campaign 2 produce extra tablets for cohorts Total tablets (av.) = 1023 Consumed tablets = 868 Additional overage =18% (155 tablets) Compared to 26% with one campaign and the same probability of stockout (0.002) Drug Supply for Adaptive Trials 17

18 Combined Effect of Campaigns and Tablets/Kit 2 tablets kit made up of tablets 0 / 1 / 3 / 4 3 tablets kit made up of tablets 0 / 1 / 3 Drug Supply for Adaptive Trials 18

19 Multicenter trials Simulations will need to model the stocking and replenishment process at depots and centers. The floor/ceiling system of inventory control with joint replenishment is very commonly used for centers and depots Drug supply simulation software can be integrated with adaptive design simulation software to handle inventory control for multicenter adaptive trials Drug Supply for Adaptive Trials 19

20 Overage is Exacerbated by: Number of sites Low enrollment per site Fast or uneven enrollment (competitive) Local country depots Long shipping lead times Expiry, country labels Mitigated by: Short shipping lead times Multiple visits Slow, even enrollment (capped or controlled) Booklet labels Flexible packaging Pooled or pack to order Necessity tactics Forced randomization Site-to-site shipments Drug Supply for Adaptive Trials 20

21 Example extended to five centers Single depot, single campaign Subjects randomized at each center at a rate of 6 subjects per month following a Poisson process Delivery lead time from depot to each center is 7 days Cost per shipment = $100 per trip + $1 per kit Trial and error led us to a single campaign with lot size of 450 kits 1 tablet and 3 tablet doses Drug Supply for Adaptive Trials 21

22 Levels, Costs, and Stockouts (One tablet) Drug Supply for Adaptive Trials 22

23 Effect of Number of Centers Drug Supply for Adaptive Trials 23

24 Levels, Costs, and Stockouts (3-Tablets) #Shipments Total Qty Shipped Total Cost Pr(Stockout) Scenario $1, Scenario $1,945 < Scenario $1,932 < Scenario $1, Scenario $1, Scenario $2, Scenario $1, Drug Supply for Adaptive Trials 24

25 Effect of Number of Centers (3-Tablets) Drug Supply for Adaptive Trials 25

26 Effect of changing floor levels (Sc 6) Drug Supply for Adaptive Trials 26

27 Simulation Process After looking at overage, stock and cost for a supply chain configuration and drug supply plan use the sensitivity analysis to improve the plan by changing settings In our example run we may wish to rerun with the simulation with floor and ceiling levels set to 1 unit higher to bring down the probability of stock-out We are working on automatically generating solutions that will minimize overage subject to keeping the probability of stockout below a specified level for a given design and supply chain configuration

28 Simulation Process We examine several designs and supply chain configurations to arrive at a few design and supply chain configurations that are best in terms of the statistical performance and feasibility and cost of drug supply. At this stage we need to simulate the selected design at a finer level of detail to reflect more accurately aspects of drug supply that were not modeled earlier (e.g. shipments in standard boxes, damage in transit, uncertainties in visit times, alternate supply depots). Detailed simulation that interfaces easily with the IVRS system is especially important for monitoring the drug supply as the trial progresses and making modifications to the supply chain parameters to adjust to changes in factors (e.g. enrollment rates, lead times, randomization rates)

29 Detailed Simulations We feed the results from the simulations we have done so far into a detailed drug supply package. The detailed package takes much longer to run and requires more time to set up as many more input values have to be provided. It reflects details that are important for implementation and integration with IVRS but were not necessary for selecting a design and supply chain configuration. We have worked out the details for our simulation tool to work with fixed design drug supply simulation tools such as MedSim from ClinPhone and TcViz from Tortellotte Solutions to enable them to simulate adaptive designs.

30 MedSim Drug Supply for Adaptive Trials 30

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36 Re-simulation In ordinary phase 2, 3 and 4 trials we can gain great benefits from re-simulating our trials at mid point, or better yet, as frequently as possible. Enrollment rates become known Country performance and resupply needs can be evaluated Remaining uncertainty decreases as we approach end of enrollment In Adaptive trials, re-simulating implies an adaptive dose allocation re-simulation followed by a supply chain resimulation Adaptive re-sim enables better forecasts that learn from the responses observed to-date that will yield significantly lower drug requirements in some arms and alert for greater requirement in others Combined re-sim can bring overage down substantially Drug Supply for Adaptive Trials 36

37 Extensions We chose a simple trial as an example for clarity of exposition. The simulation approach we have discussed can be extended in various ways to apply to a wide range of trials There may be several depots such as country depots and there may be a central depot feeding them Accruals may not be at a constant rate Multiple kits for a subject multiple visits Drugs may have expiry dates Several trials may have common centers (pooling of shipments) Optimization of inventory control parameters Drug Supply for Adaptive Trials 37

38 Conclusions Simple approaches to planning drug supply for adaptive trials can lead to large overage Software tools that combine statistical simulation of the trial design with simulation of the drug supply system at two levels of granularity can substantially reduce overage and cost both at the planning stage and while the trial is in progress These tools also enable evaluation of trade-offs and estimation of a realistic budget for drug supply Drug Supply for Adaptive Trials 38

39 Thank you!