FUTURE of PHASE 1, 2, and 3 TRIALS

July 2001 1

FUTURE of PHASE 1, 2, and 3 TRIALS

Philip Colangelo, Pharm.D., Ph.D.

Office of Clinical Pharmacology & Biopharmaceutics

FDA / CDER

July 2001 2

FDA Review Division Organization• Office of Drug Evaluation IV (ODE IV)

– Division of Anti-Infective Drug Products– Division of Anti-Viral Drug Products– Division of Special Pathogen & Immunologic Drug Products

• Division Review Teams– Medical Officers– Statistics – Microbiology– Clinical Pharmacology and Biopharmaceutics – Pre Clinical Pharmacology and Toxicology – Chemistry

July 2001 3

OUTLINE• General Overview of Clinical Studies

• Example - Antibiotic X (Ab-X)– Dose-Response in Phase 2 for Efficacy/Safety– PK/PD in Phase 3 for Efficacy– Exposure-Response in Phase 1 for Safety

• Future of Phase 1, 2, and 3 Trials for Anti-Infective Drug Development– Key Considerations– Other Considerations/Tools for the Future

July 2001 4

CAUTION !• This talk contains no hard and fast answers

• Many questions remain regarding how clinical trials should be performed in the future to expeditiously obtain information

• However, for a given patient with a given infection and pathogen, we all want to know:– Right Drug?– Right Dosage Regimen?– Right Duration?

July 2001 5

General Overview: Phase 1 PK Studies• Goal: Understand the PK and Identify

Possible Sources/Determinants of PK Variability

• Healthy Subjects and Patients (Phase 3)– Oral Absorption– Distribution and Disposition– In Vitro and In Vivo Metabolism– Excretion

July 2001 6

Phase 1 Clinical Pharmacology

• Special Populations (Intrinsic Factors) – Renal Impairment– Hepatic Impairment– Age (Elderly; Pediatrics)– Gender – Race

July 2001 7

Phase 1 Clinical Pharmacology

• Drug - Drug Interactions (Extrinsic Factors)– Based on In Vitro Studies– Based on Drug Class (e.g., chelation effects on

fluoroquinolones by cations)

• Special Safety Studies– Further Investigation of AE’s Observed in

Clinical Trials (e.g., phototoxicity, skin rash, QT effects, hypo- / hyperglycemia)

July 2001 8

Phase 2 Trials • Goal: Right Dose and Right Duration

– Proof of Concept (in vitro/pre clinical)

• Exploration of Exposure-Response Relationship– “Exposure” = drug input, i.e., dose; plasma conc.

(e.g., Cmax, Cmin, Css, AUC)– “Response” = drug effect, i.e., desired (e.g.,

clinical / bacteriological cure) or undesired (e.g., QT prolongation)

July 2001 9

Phase 2 Trials (cont.)• Limitations:

– For anti-infectives dose-response difficult to do over broad range of doses (>2-3 doses) for ethical reasons (sub-therapeutic doses)

– Small N

• When May Dose-Response be Appropriate:– No Active Control Exists

• No approved agent

• No recognized standard of care

– Treatment Failure Mortality or Serious / Irreversible Morbidity

July 2001 10

Phase 2 Trials (cont.)• Information from Dose-Response

– Assess Activity Over Several Doses • Minimal Effective Dose

• Maximal Beneficial Dose

– Safety Information Over Several Doses – PK/PD Information (Exposure-Response)

• Identify appropriate parameter(s) to predict outcomes and design dosage regimen in Phase 3

• Define magnitude of the parameter - ideally want lower dose to be sufficiently distinct from higher dose

July 2001 11

Phase 3 Trials

• Primary Goal: Confirmation of the Right Dose and Duration by Demonstration of Adequate Efficacy and Safety– Benefit vs. Risk

July 2001 12

Phase 3 Trials (cont.)• Secondary and Potentially Useful (?)

Information: PK/PD • PK in Target Patient Population(s) via Sparse

Sampling and Pop PK Approach• Most often retrospective analysis

• Often combined with Pop PK from Phase 1 healthy subjects

• Assessment of systemic exposure and PK variability in patients vs. healthy subjects

• Exploration of covariates that may influence PK variability in patients

July 2001 13

Phase 3 Trials (cont.)• PK/PD in the Target Population(s)

– A Good Way to Present Raw Data• Individual Patient MIC Values and Pathogen ID

• Individual Post-Hoc Bayesian PK Estimates

• Calculated PK/PD Parameters

• Individual Outcomes (Clinical and Bacteriological)

– Relationship between PK/PD Parameter(s) and Outcomes; Preferably Both Successes and Failures

– Relationship between PK Parameters and AE’s (incidence and/or severity)

July 2001 14

EXAMPLE

• NDA - Antibiotic X (Ab-X) – Dose-Response for Efficacy & Safety in

Phase 2 • 2 Trials (R, DB/DD, MC, Parallel Group):

– (1) RTI @ Daily Doses 0.25X, 0.5X, 1X Proposed Clinical Dose (N=200) vs. Comparator (N=70) x 10 Days

– (2) SSSI @ Daily Doses 0.5X, 1X proposed Clinical Dose (N=72) vs. Comparator (N=37) x 10 Days

– Clinical & Bacteriological Efficacy @ End of Therapy (EOT) & Post Therapy Follow-Up Visits (TOC)

July 2001 15

EXAMPLE• NDA - Ab-X

– Dose-Response for Efficacy & Safety-Phase 2• Overall Efficacy Results @ TOC

– RTI

» Clinical Efficacy: 0.5X and 1X doses equivalent; 0.25X dose success rates lower

» Bacteriological Efficacy: 0.5X and 1X doses equivalent; 0.25X dose not equivalent

– SSSI

» Clinical Efficacy: 0.5X and 1X doses equivalent (0.5X success rate less vs. comparator)

» Bacteriological Efficacy: 0.5X and 1X doses equivalent (inconclusive vs. comparator)

• Overall Safety/AE Results (RTI + SSSI)– Approximately equal % of AE’s across all doses

– Patient withdrawals due to AE’s greater @1X dose vs. 0.5X and 0.25X doses

July 2001 16


– PK/PD Relationships for Efficacy in Phase 3• 3 Trials for Respiratory Tract Infections using

Proposed Clinical Dosage Regimen

• Post-Hoc Bayesian Estimates of AUC• Individual Patient MIC and Pathogen ID

• Individual AUC/MIC Ratios

• Outcomes at End of Therapy (EOT) Visit and Post Therapy Follow-Up Visit for Test of Cure (TOC)

– Clinical Success and Failure

– Bacteriological Success and Failure

July 2001 17

Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

AUC(0-24)(ghr/mL)

MIC(g/mL)

AUC/MIC

All NMedian

MinMax

4338.283.33

42.71

4330.0150.0018.00

4336660.79

22922

Gram (-) NMedian

MinMax

2678.553.39

34.82

2670.0080.0018.000

2678990.79

22922

Gram (+) NMedian

MinMax

1667.583.33

42.71

1660.0150.0022.00

1665682.915537

July 2001 18


AUC/MIC Ratios for All Patients with Gm(-) or Gm(+) Infections (Total N=433)

0

20

40

60

80

100

120

140

0 - 30 30 - 50 50 - 150 150-300 300-500 500-1000 >1000AUC/MIC Ratio

Nu

mb

ers

of

Pat

ien

ts (

n)

Gram (-) Infections

Gram (+) Infections

July 2001 19

Ab-X: PK/PD in Phase 3 Trials for Respiratory InfectionsSuccessful Outcomes vs. AUC/MIC

for All Organisms

0

20

40

60

80

100

0 - 30 30 - 50 50 -150

150 -300

300 -500

500-1000

>1000

AUC/MIC

Su

cc

es

sfu

l O

utc

om

e (

%)

Clinical TOC

Bacteriologic TOC

July 2001 20

Ab-X: PK/PD in Phase 3 Trials for Respiratory InfectionsSuccessful Outcomes vs. AUC/MIC:

Gram (-) Organsims

0

20

40

60

80

100

0 - 30 30 - 50 50 -150

150 -300

300-500

500 -1000

>1000

AUC/MIC

Suc

essf

ul O

utco

me

(%)

Clinical TOC

Bacteriologic TOC

July 2001 21

Ab-X: PK/PD in Phase 3 Trials for Respiratory InfectionsSuccessful Outcomes vs. AUC/MIC:

Gram (+) Organisms

0

20

40

60

80

100

0 - 30 30 - 50 50 -150

150-300

300-500

500-1000

>1000

AUC/MIC

Su

cess

ful O

utc

om

e (%

)

Clinical TOC

Bacteriologic TOC

July 2001 22


Grm(-) Clinical Successes vs. FailuresSuccess AUC MIC AUC/MICN 234 234 234Median 8.65 0.008 848Min 3.39 0.001 0.79Max 34.82 8.000 22922FailureN 33 33 33Median 8.24 0.008 1039Min 4.67 0.001 1.61Max 15.87 4.000 14118

July 2001 23


Grm (+) Clinical Successes vs. Failures Success AUC MIC AUC/MICN 144 144 144Median 7.56 0.015 568Min 3.33 0.002 2.91Max 42.71 2.000 5537FailureN 22 22 22Median 7.73 0.015 549Min 3.98 0.004 5.19Max 32.74 2.000 4092

July 2001 24


• Conclusions– Majority of patients attained AUC/MIC >150

– Majority of patients had clinical and/or bacteriological successes at the proposed clinical dosage regimen

– Data suggested AUC/MIC >50 for successful outcome

• Limitations– Small numbers of patients with AUC/MIC ratios <100

– Not able to assess Cmax/MIC because of limitations to sparse sampling design (Pop PK)

– Limited and widely overlapping AUC/MIC ratios for failures vs. successes

– No PK/PD data for other dose regimens (lower dose)

July 2001 25


– Exposure-Response Relationships for Safety• Meta Analysis of Dose-QTc Response from 5

Phase 1 Clinical Pharmacology Trials (Sponsor) – Healthy Young Males and Females

– Healthy Elderly Males and Females

– Healthy Young Japanese

– Multiples of Clinical Dose: 0.5X, 1X, 1.5X, 2X; Placebo

• Regression Analyses of Cp-QTc Response (FDA Request)

– Regression 1: Delta QTc at Time of Observed Cmax (QTc vs. Cmax)

– Regression 2: Maximum Delta QTc and Corresponding Cp (MaxQTc vs. Cp)

July 2001 26

Ab-X: Meta Analysis of QTc QTc Single Dose vs. Placebo

Comparison # of Studies(N: FQ-X / Placebo)

Point Estimate(msec)

90% C. I.(msec)

1X – Placebo 3(55 / 12)

3.71 (0.04, 7.38)

1.5X – Placebo 3(24 / 20)

5.81 (0.88, 10.74)

2X – Placebo 3(54 / 8)

3.30 (-1.31, 7.92)

QTc Repeat Dose vs. Placebo

Comparison # of Studies(N: FQ-X / Placebo)

Point Estimate(msec)

90% C. I.(msec)

1X – Placebo 2(14 / 17)

-4.92 (-12.28, 2.44)

1.5X – Placebo 2(12 / 20)

5.51 (-3.29, 14.32)

2X – Placebo 1(8 / 8)

16.12 (3.62, 28.61)

July 2001 27

Ab-X: Regression Analyses of QTcRegression 1:

Delta QTc from Baseline vs. Observed CmaxAll Single Doses (0.5X, 1X, 1.5X, 2X)

y = 0.2594x - 0.9688

R2 = 0.0002

-80.0

-60.0

-40.0

-20.0

0.0

20.0

40.0

60.0

0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00

Cmax (ug/mL)

Del

ta Q

Tc fr

om B

asel

ine

(mse

c)

All Doses

Linear (All Doses)

July 2001 28


Delta QTc from Baseline vs. Observed CmaxAll Repeat Doses (1X, 1.5X, 2X)

y = 0.8359x + 0.0511

R2 = 0.0012

-60.0-50.0-40.0-30.0-20.0-10.0

0.010.020.030.040.050.0

0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00

Cmax (ug/mL)

Del

ta Q

Tc fr

om B

asel

ine

(mse

c)

All Doses

Linear (All Doses)

July 2001 29


Maximal Change in QTc from Baseline vs. Corresponding Plasma Conc.All Single Doses (0.5X, 1X, 1.5X, 2X)

y = 1.1112x + 13.468

R2 = 0.0029

-40.0

-20.0

0.0

20.0

40.0

60.0

80.0

100.0

0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00

Conc (ug/mL)

Max

imal

Del

ta in

QTc

(mse

c)

All Doses

Linear (All Doses)

July 2001 30

Ab-X: Exposure-QTc Response• Conclusions

– Meta Analysis of Dose-Response• No clear trend with single doses

• Some trend with repeat doses

– Regression Analyses of Cp-Response• Weak (if any) relationship for QTc vs. Cmax or for

MaxQTc vs. corresponding Cp with either single or repeat doses

• MaxQTc occurred, on average, between 5 to 10 hrs postdose in the majority of subjects after both single and repeated doses – substantially longer than the Tmax (i.e., ~1.0 hr); suggesting lag-time for the occurrence of maximum QTc changes

July 2001 31

Ab-X: Exposure-QTc Response• Limitations

– Studies not designed to specifically evaluate QT effects

– Relatively sparse data for repeated dosing vs. single dosing

– Sparse data in elderly

– Timing of ECG’s varied with study; did not always correspond with actual observance of Cmax

– Lack of evaluation of exposure-response at higher doses (up to 3X clinical dose)

– Lack of comparison with other FQ

July 2001 32

Future of Clinical Trials:Key Considerations

• Challenge the drug development program by asking the “tough” questions

• Does the drug fill a current (or future) unmet medical need? (e.g., treatment of infection(s) due to resistant pathogen(s); serious/life-threatening infection)

• Is there enough evidence to demonstrate that the drug fills this need?

• What are the safety issues and can they be adequately managed?

July 2001 33

Future of Clinical Trials:Key Considerations (cont.)

• What are important PK and PK/PD issues?

• Variability in Systemic Exposure (PK) and MIC (PD)

• Exposure-Therapeutic Response Relationships

• Exposure-Toxicity/Safety Relationships

• Drug-Drug / Drug-Food Interaction Potential

• Other Intrinsic and Extrinsic Factors

July 2001 34


• Greater integration and use of information obtained from in vitro/pre clinical evaluations and early phase clinical trials

• Continuum of learning and confirming throughout all phases of drug development

• Knowledge Based Development

July 2001 35


• In the End: What is the Benefit vs. Risk?• Proven Benefit for indication(s) for which there is

an unmet medical need?

• Proven Benefit for indication(s) for which acceptable therapeutic agents already exist?

• Is there less Risk over existing therapies?

• Risk Management Strategy?

July 2001 36

Future of Clinical Trials: Other Considerations/Tools

• Develop labeling at the outset of development; Targeted Product Information (TPI) document

• Pilot in ODE IV (FDA & PhRMA)

• Evolving version of proposed labeling that can be used throughout all phases of development

• Embodies the notion of beginning development with the end in mind (approval and final labeling)

• Can be used by sponsor to:– guide design, conduct, and analysis of clinical trials

– facilitate communication between FDA and sponsor

– promote shared understanding of the development program

• http://www.fda.gov/cder/tpi

July 2001 37


• Pop PK & PK/PD Approaches/Analyses• Prospectively designed into Phase 3 trials (vs. after

thought)

• Exploration of other PK/PD Indices

• How important are unbound drug concentrations?

• Computer Assisted Trial Design (CATD) and Simulation

• Monte Carlo Simulation

• Probability Functions for PK and MIC Values

• Estimating Susceptibility Breakpoints - Maybe?

July 2001 38


• Present and Future Initiatives at FDA• Resistant Pathogens Guidance (Draft)

• Exposure-Response Guidance (Draft)

• CATD/Modeling & Simulation Research (OCPB/Biostats)

• PK/PD Database for Anti-Infective Classes (Clin Pharm, Micro, Medical)

FUTURE of PHASE 1, 2, and 3 TRIALS

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