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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
EXAMPLE• NDA - Ab-X
– 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
Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections
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
Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections
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
Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections
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
Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections
• 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
EXAMPLE• NDA - Ab-X
– 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
Ab-X: Regression Analyses of QTcRegression 1:
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
Ab-X: Regression Analyses of QTcRegression 2:
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
Future of Clinical Trials:Key Considerations (cont.)
• 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
Future of Clinical Trials:Key Considerations (cont.)
• 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
Future of Clinical Trials: Other Considerations/Tools
• 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
Future of Clinical Trials: Other Considerations/Tools
• 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)