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FDA Anti-Infective Drugs Advisory Committee. Design Issues in ABS Trials: Surrogates Endpoints & Non-Inferiority Trials October 29, 2003 Thomas R. Fleming, Ph.D. Professor and Chair of Biostatistics University of Washington. Design Issues in ABS Trials. Criteria for Study Endpoints

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slide1

FDA Anti-Infective Drugs Advisory Committee

Design Issues in ABS Trials:

Surrogates Endpoints &

Non-Inferiority Trials

October 29, 2003

Thomas R. Fleming, Ph.D.

Professor and Chair of Biostatistics

University of Washington

slide2

Design Issues in ABS Trials

  • Criteria for Study Endpoints
  • Use of Surrogate Endpoints
  • Non-Inferiority Design Issues
      • Choice of the NI Margin
      • Bio-creep with Repeated NI Trials
  • Active vs.Placebo controlled trials
  • Time to Event Analyses in ABS Trials
slide3

Design Issues in ABS Trials

  • Criteria for Study Endpoints
  • Use of Surrogate Endpoints
  • Non-Inferiority Design Issues
      • Choice of the NI Margin
      • Bio-creep with Repeated NI Trials
  • Active vs. Placebo controlled trials
  • Time to Event Analyses in ABS Trials
slide4

Criteria for Study Endpointsin ABS Clinical Trials

• Measurable/Interpretable

• Sensitive

• Clinically relevant

~ Resolution/Improvement of ABS Symptoms

~ Reducing the time to Resolution

slide5

Design Issues in ABS Trials

  • Criteria for Study Endpoints
  • Use of Surrogate Endpoints
  • Non-Inferiority Design Issues
      • Choice of the NI Margin
      • Bio-creep with Repeated NI Trials
  • Active vs. Placebo controlled trials
  • Time to Event Analyses in ABS Trials
slide6

Use of Surrogate Endpoints

Treatment Effects on Surrogate Endpoints

eg:~Radiological Resolution of Disease

~Microbiological Outcomes

• Establishes Biological Activity

• But Not Necessarily Clinical Efficacy

slide7

Time

Intervention

Surrogate True Clinical

Endpoint Outcome

Disease

slide8

Illustration:

AIDS Patients with MAI Bacteremia

Clarithromycin Dose (mg bid)

500 1000 2000

Bacterial Load 145 34 25

12 wk Mortality 5.7% 25.5% 28.0%

Chaisson et al, 1994

slide9

Time

Intervention

Bacterial 12 week

Load Mortality

Disease

slide10

Validation of Surrogate Endpoints

Property of a Valid Surrogate

·Effect of the Intervention

on the Clinical Endpoint

is reliably predicted by the

Effect of the Intervention

on the Surrogate Endpoint

slide11

Prentice’s Sufficient Conditions

1.The surrogate endpoint

must be correlated with

the clinical outcome

2.The surrogate endpoint

must fully capture

the net effect of treatment

on the clinical outcome

slide12

Validation of Surrogate Endpoints

Statistical

·Meta-analyses of clinical trials data

Clinical

·Comprehensive understanding of the

~Causal pathways of the disease process

~Intervention’s intended and unintended

mechanisms of action

slide13

Clinical Endpoints & Surrogates in ABS Clinical Trials

•Clinical Endpoints:

~ Resolution/Improvement of ABS Symptoms

• Surrogate Endpoints:

~Radiological Resolution of Disease

~Microbiological Outcomes

Validation of Surrogate Endpoints requires

more than correlation with Clinical Endpoints

slide14

Design Issues in ABS Trials

  • Criteria for Study Endpoints
  • Use of Surrogate Endpoints
  • Non-Inferiority Design Issues
      • Choice of the NI Margin
      • Bio-creep with Repeated NI Trials
  • Active vs. Placebo controlled trials
  • Time to Event Analyses in ABS Trials
slide15

Dual Goals of Non-Inferiority Trials

• To enable a direct evaluation

of the clinical efficacy

of EXP relative to Active Control

• To contribute evidence to

the evaluation of efficacy

of EXP relative to Placebo

slide16

•Active Control Effect

ICH E9: “A suitable active comparator…

could be a widely used therapy

whose efficacy in the relevant indication

has been clearly established& quantified

in well-designed &

well documented superiority trials

& which can be reliably expected to have

similar efficacy in the contemplated AC trial.”

Non-Inferiority Trials… Some Requirements

slide17

Non-Inferiority Trials… Some Requirements

STD should have clinical efficacy

• that is of substantial magnitude

• that is precisely estimated

• with estimates that arerelevant to the setting

in which the non-inferiority trial

is being conducted

slide18

Factors Influencing Choice of Margin

• Active Control Effect

~magnitude of Active Control effect

Eg:  = 45% – 80% = –35%

~precision of estimate

Eg: 2 s.e. =  10% ( 175/arm )

~estimates relevant to setting of NI trial

•Population •Supportive care •Endpoint assessment

PLA – AC Cure Rate

*

(

)

–45% –35%–25% –12.5% 0%

slide19

Factors Influencing the Choice of Margin

and Interpretation of NI Trial Results

• Clinical Relevance of Changes in:

Benefits, Risks/Tolerance,

Convenience, Resistance, etc.

• Active Control Effect

slide20

Factors Influencing Choice of Margin

•Clinical Relevance of Changes in:

Benefits, Risks/Tolerance,

Convenience, Resistance, etc.

Clinical importance of:

- reduction in efficacy by 

- altered safety/tolerance profile

- altered convenience of administration

- altered resistance or drug/drug interactions

slide21

The Choice of the Margin in an NI Trial

ICH E10: “The determination of the margin

in a non-inferiority trial is based on

both statistical reasoning & clinical judgment,

and should reflect uncertainties

in the evidence on which the choice is based,

and should be suitably conservative.”

slide22

“Bio-creep” with Repeated NI Trials

Eg: Anti-viral Drugs Advisory Comm (10/4/01)

Empiric Anti-fungal therapy

of febrile neutropenic patients

•Amphotericin B Deoxycholate

•Ambisome vs Amphotericin B

49.9% v 49.1% Mycosis Study Gp #32

•Voriconazole vs Ambisome

23.7% v 30.1% 95% CI: (– 12, – 0.1)

slide23

Overview of Placebo-controlled ABS Trials

• Fourteen Placebo-controlled Trials

of Antimicrobials conducted in ’69 –’03

(with nine conducted since ’96)

• Outcome: Antimicrobial effect on

Resolution or improvement of ABS symptoms, assessed at fixed time between 7-14 days

slide24

70

50

30

10

-10

-30

-50

-70

1

14

2

11

3

4

10

7

5

12

6

8

9

16

13

15

Antimicrobial Efficacy ( 95% CI)

Study

slide25

NI Trials vs Placebo Controlled Superiority Trials

•ICH E10: “The determination of the margin

in a non-inferiority trial is based on

both statistical reasoning & clinical judgment,

should reflect uncertainties

in the evidence on which the choice is based,

and should be suitably conservative.”

• When one cannot justify a non-trivial margin,

placebo controlled trials provide

an ethically and scientifically reliable approach

to assessing the benefit-to-risk profile

slide26

Design Issues in ABS Trials

  • Criteria for Study Endpoints
  • Use of Surrogate Endpoints
  • Non-Inferiority Design Issues
      • Choice of the NI Margin
      • Bio-creep with Repeated NI Trials
  • Active vs Placebo controlled trials
  • Time to Event Analyses in ABS Trials
slide27

Time to Event Analyses in ABS Trials

  • “In self-resolving diseases, it may be
  • more appropriate to measure time to
  • resolution or improvement of symptoms”
  • To have 90% power to detect a reduction
  • in time to resolution from 7 days to 5 days
  • (with the standard 2.5% false positive error rate)
  • one needs approximately 200 pts/arm.
  • (Stat Significance if one obtains about 1.3 days )
slide28

Conclusions

  • Criteria for Study Endpoints
  • A Correlate does not a Surrogate Make
  • Non-Inferiority Design Issues
      • Choice of the NI Margin
      • Bio-creep with Repeated NI Trials
  • Placebo controlled trials
  • Time to Event Analyses in ABS Trials
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