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Mario Tanguay, B.Pharm, Ph.D. Vice President, Scientific & Regulatory Affairs, Anapharm Guest Professor, Faculty of Pharmacy, University of Montreal April 12, 2010
The views expressed herein are solely those of the author and do not necessarily reflect the official policy, position or opinions of PharmaNet Development Group, Inc. and its affiliates
2010 PharmaNet Development Group, Inc. All rights reserved.
Agenda Introduction
Are you ready to go to Phase I Objectives of Phase I studies
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Less than proportional increase in AUC due to solubility issue No real conclusion can be drawn about safety data and MTD
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Neglecting those aspects can make the results from the FIH study useless
No clear demonstration of MTD if a plateau in bioavailability is reached May not reach systemic exposure required for the desired pharmacological effect
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In that context, calculation of MABEL (the minimal anticipated biological effect level) may be warranted Special attention to PK/PD data
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NOAEL: safety factor of 10 was applied about 40% of the time A more conservative safety factor was otherwise used (up to 300)
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Study Population
Trend to involve patients earlier in the clinical development, but healthy volunteers are still generally enrolled in single ascending dose (SAD) phase, unless unsafe or unethical Phase I studies may include cohorts of target populations, but more often in the multiple ascending dose (MAD) phase, when effects on clinical endpoints or biomarkers may be expected Recent examples we have seen during MAD: Overweight/obese subjects (diabetes drug) Elderly subjects (drugs used for cognitive disorders) HCV or HIV patients (antivirals) Type II diabetes subjects (hypoglycemia agent) Asthmatic subjects (bronchodilator)
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Study Population
Age limits - Recent trends observed for studies conducted at Anapharm
Uper age limit typically based on safety considerations Elderly subjects may be considered if this is the target population
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Study Population
Should Females Be Enrolled in FIH Trials Regulatory position Most regulatory agencies have encouraged the enrolment of female subjects earlier in clinical development Safety considerations Despite the use of appropriate method of contraception, it may not always be safe to include women of childbearing potential Potential issue for long T drugs that remain in the body following the period of confinement within the Phase I unit Trends in recent studies that we have conducted Only 11% of the studies enrolled males only Females of childbearing potential were enrolled in 63% of studies that included females
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AE incidence
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16
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Staggered dosing was widely used for biologics and for injectable products
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From: Zhou Y. Choice of designs and doses for early phase trials. Fundam Clin Pharmacol 18 (2004) 373-8
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2010 PharmaNet Development Group, Inc. All rights reserved.
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2010 PharmaNet Development Group, Inc. All rights reserved.
Phase B of the study planned to start after the 4th SAD cohort 1-2 weeks between each cohort
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Typical Time Course of a SAD-MAD Combo with IV arm and ISCV assessment arm
S, E-R 320 mg or Placebo Cohort 5 -D
SAD
S, E-R
-D
S, E-R
80 mg or Placebo Period 2
-D
-D
S, E-R
IV 20 mg or Placebo Period 2
S, E-R -D
-D
S, E-R
-D
MAD
S = Screening; E = Enrollment, R = Randomization; D = Study Discharge Cohorts in SAD (n = 6): 4 active drug : 2 placebo, in MAD (n=12): 8 active drug : 4 placebo
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Unique opportunity to study the effect on QT interval at doses higher than those that may eventually be studied in a formal TQT study If QT prolongation is observed, this may prompt the conduct of a TQT study earlier in the drug development process, or cessation of further development
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Many Guidance documents are available from the different regulatory agencies to assist sponsors and CROs in the design and analysis of BA/BE and clinical pharmacology studies
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Conclusion
Sponsors must assure that they have a drug product really suitable for Phase I trials Safety must always prevail when designing Phase I program There is a trend for more complex integrated FIH study protocols There is room for creativity in designing Phase I studies; but approach used must assure safety of study participants and must be scientifically sound The Phase I study represents a unique opportunity to gather information about the study drug within a large range of doses Growing interest for intensive QT evaluation in FIH studies
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Acknowledgements
Jean-Franois Gagn, M.Sc. Manager, Protocol Writing Sector, Anapharm Stphane Lamouche, Ph.D Ass. Director, Drug Development & Regulatory Affairs, Anapharm Richard Larouche, B.Pharm, MD Director, Medical Affairs, Anapharm Annie Ouimet, M.Sc. Senior Regulatory Affairs Associate, Anapharm Eric Shink, Ph.D Senior Biostatistician, Anapharm Fethi Trabelsi, Ph.D Director, Scientific & Regulatory Affairs, Anapharm
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2010 PharmaNet Development Group, Inc. All rights reserved.