1

 Rafia Bhore, Ph.D.
 Greg Soon, Ph.D.
 Division of Antiviral Drug Products
 Food and Drug Administration

2

 Phase 2/3 Clinical Trial Design: An Example
 Two Arms or Three Arms ?
 pvalue (Single Trial vs. Two Trials)
 Criteria for a “Win”/Success
 Power Considerations
 Sample Size Estimates
 Other Considerations

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 To establish safety and efficacy
of investigational microbicide in
preventing HIV infection
 Test Group Control Group 1 Control Group 2
 Microbicide “Placebo”
 + +
 Condom Condom Condomonly
(“notreatment”)

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 “Placebo” provides a means to blinding investigators and participants
 Maximizes the likelihood of obtaining an unbiased estimate of efficacy
 Can we assume “Placebo” is inert?
 Antimicrobial activity of “Placebo” not known/not proven.
 Protective effect or harmful effect?

7

 Established standard for prevention of HIV
 Provide comparison of “real world” effectiveness in preventing
transmission
 Data on sexual behaviors associated with use or nonuse of microbicide
products
 Single component of other arms containing gel + condom

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 Two trials (Regulatory Standards)
 Trial 1 pvalue < 0.05
(twosided)
 Trial 2 pvalue < 0.05
(twosided)
 Run in parallel or staggered in time?
 If staggered, how much gap in time?

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 Need to show as strong and robust evidence as two separate trials
 May not be repeatable
 One trial: pvalue < 0.001
(twosided)
 (because
2x[0.025^2]=0.00125)
 same as pvalue <
0.0005 (onesided)

12

 Probability of observing a statistically significant result (e.g. p <
0.05) upon repetition of a clinical trial when the effect size observed
in the first trial is assumed to be the true effect

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 pvalue < 0.001 considered
convincing
 pvalue >= 0.01 would be inadequate
 pvalue between 0.001 and 0.01 possibly adequate, provided that
 results are consistent across various subgroups
 other supportive evidence is strong

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 HIV infection rate in
 Microbicide < “Placebo” pvalue < 0.001
(twosided)
 AND
 Microbicide < Condomonly pvalue < 0.001
(twosided)

16

 If the HIV infection rate in
 Microbicide + Condom »
“Placebo”+Cond.
 Microbicide + Condom < Condom
 then is “Placebo” as effective as Microbicide? (does not prove efficacy
of microbicide)

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 If the HIV infection rate in
 Microbicide + Condom < “Placebo” + Cond.
 Microbicide + Condom » Condom
 then the use of microbicide in
conjunction with condom does not provide any additional
protection than condom alone

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 HIV infection rate in
 Microbicide < “Placebo” pvalue < 0.001
(twosided)
 AND
 Microbicide < Condomonly pvalue < 0.001
(twosided)

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 HIV Seroincidence Rates in Control
 0.5, 6, 7, 9 per 100 personyears
 Effect Size (33%, 50%, … )
 Length of Followup
 12 / 24 months for each participant
 Last patient completes 12 / 24 months
 Statistical Power (90%, 80%, …)

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 Test two sets of hypotheses
 H_{0}:
Microbicide+condom = “Placebo”+condom
 H_{A}:
Microbicide+condom < “Placebo”+condom
 H_{0}:
Microbicide+condom = Condomonly
 H_{A}:
Microbicide+condom < Condomonly
 Calculate samplesize
 Power for each test is 90% at 33% reduction in HIV infection rate from
condomonly arm

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 Continue study until last subject enrolled completes at least 12 months
on study
 Proactive in following participants
 actively pursue and identify reasons for dropouts (safety issues?)
 continue followup after study drug discontinuation

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 Collect data on use of condom and other barrier/drug use
 Efficacy evidence closely tied with compliance
 “Frequently” collect information on number of sexual acts

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 Microbicide : Placebo : Condomonly
 Standard practice is to randomize 1:1:1
 Alternatively randomize x: y: z
 e.g., 3:2:2 or 1.5:1:1
 More participants in microbicide arm than control groups. Same number in both control groups
 Alternative allocation ratios will optimize overall power to detect a
difference and increase safety data on microbicide arm.

29

 Threearm design will ensure that the first generation of microbicides
is appropriately studied
 Single trial to show same level of evidence as two separate trials
 Sample size depends on assumptions
 Length of followup important in observing HIV endpoints.

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 Dr. Teresa Wu, Medical Officer
 Dr. Debra Birnkrant, Director
 Division of Antiviral Drug Products, FDA
