© 2010 PharmaNet Development Group, Inc. All rights reserved.
Designing Safe and Efficient Phase I Studies to Expedite Clinical Development
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
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 2
Agenda
Study Design Issues
Attempts To Make Phase I Programs More Efficient
IntroductionAre you ready to go to Phase IObjectives of Phase I studies
Recent trends will be presented based on some FIH studies conducted at Anapharm over the last 2 ½ years (n=27)Determination of maximum recommended starting doseStudy population (age, inclusion of females)Sample size considerationsDose escalation scheme
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 3
Are You Ready to Move to Phase IThere is often a lot of pressure on the development teams to obtain data in humans (and proof of concept) as quickly as possible
For that reason, Phase I formulation development is often neglected (or simply delayed to a later date)
The challenge: ~60% of NCE in development are poorly soluble1 (poor solubility = dissolution problems, poor and/or erratic absorption …)
The risk: clinical testing may be initiated with a less than optimal formulation for which reliability, reproducibility and scalability are not fully understood
1) H. Dubin, Drug Del. Technol., 2006
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 4
Using a Non Optimal Formulation in FIH – Case Example
Less than proportional increase in AUC due to solubility issue
No real conclusion can be drawn about safety data and MTD
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 5
Formulations Used in Recent Studies Done at Anapharm
Powder in a bottle used in almost 50% of studies with oral administration
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Are You Ready to Move to Phase ISo poorly soluble and/or poorly permeable drugs should require more attention before moving quickly to Phase I
Biopharmaceutical properties must be taken in considerationBCS classification
Neglecting those aspects can make the results from the FIH study useless
No clear demonstration of MTD if a plateau in bioavailability is reachedMay not reach systemic exposure required for the desired pharmacological effect
Some possible advantages of a good Phase I formulation strategyEnhance the bioavailability of the compoundReduce the effect of floodDecrease PK variabilityEnsure scalability to manufacture batch size
Page 6
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Objectives of Phase I TrialsDetermination of safety and tolerability
To identify suitable dose or dose range for further studies
Pharmacokinetics of the drug
There is also a trend for adding various objectives in order to obtain more information earlier in drug development process:
Effect of foodDrug-drug interactionsAbsolute bioavailabilityEffect on biomarkersProof of concept in either healthy or patient populationsEtc.
Page 7
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Determination of Maximum Recommended Starting DoseFDA proposed a methodology (based on NOAEL) to be used to determine the maximum recommended starting dose (MRSD) in FIH
However, other factors should be considered, especially in the case of high risk compounds (EMEA Guidance, FIH trials), such as:
Drugs affecting immune systemDrugs with novel mode actionDrugs with steep dose-response relationshipWhen there is little knowledge about the nature of the targetWhen available animal models are of questionable relevance
In that context, calculation of MABEL (the minimal anticipated biological effect level) may be warranted
Special attention to PK/PD data
Page 8
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 9
Determination of Maximum Recommended Starting Dose
Recent trends observed for studies conducted at Anapharm
NOAEL: safety factor of 10 was applied about 40% of the time
A more conservative safety factor was otherwise used (up to 300)
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Study PopulationTrend 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)
Page 10
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 11
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
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 12
Study Population
Should Females Be Enrolled in FIH Trials
Regulatory positionMost regulatory agencies have encouraged the enrolment of female subjects earlier in clinical development
Safety considerationsDespite the use of appropriate method of contraception, it may not always be safe to include women of childbearing potentialPotential issue for long T ½ drugs that remain in the body following the period of confinement within the Phase I unit
Trends in recent studies that we have conductedOnly 11% of the studies enrolled males onlyFemales of childbearing potential were enrolled in 63% of studies that included females
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
How Many Subjects Are NeededNo clear requirements from regulatory agencies
Sample size rationale is most of the time not provided in protocols
General consensus is that a minimum of 6 subjects should receive the active drug at each dose level and some subjects should receive a placebo
Experience of Anapharm over the last two yearsIn 67% of studies, each cohort included 6 patients on active treatment and 2 subjects on placeboLowest number of subjects (on active treatment) per cohort was 3, while highest was 12Number of cohorts (1 cohort per dose tested) varied from 4 to 12, with a mean of 7 cohorts
Page 13
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 14
How Many Subjects Are NeededStatistical considerations
Minimum AE Incidence Needed to Observe at least one AE Occurrence (70%, 80% and 90% Probability) in a Treated
Subjects Cohort
00.10.20.30.40.50.60.70.80.9
1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Number of subjects on active treatment
AE
inci
denc
e
70%80%90%
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
What Should be the Dose Escalation ApproachCase-by-case approach based on safety profile of the drug and potential risk
Frequently used approaches:Classic approach using “doubling scheme”
N, 2N, 4N, 8N, 16N, etc.Fibonacci scheme
N, 2N, 3N, 5N, 8N, etc.Hybrid approach
N, 2N, 4N, 6N, 10N, etc.
Should be well justified to prevent questions from regulatory agencies or IRBs
Page 15
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 16
What Should be the Dose Escalation Approach
Experience of Anapharm over the last 2 ½ years
Lower dose rangesDoses increased in at least 2-fold icrement manner for 90% of the studies
Higher dose rangesMore conservative (e.g. Fibonacci) approach was used 63% of the time
Examples of dose escalation schemesMore conservative approach
100, 200, 300, 450, 600, 810, 100 mgMRSD was based on NOAEL with safety factor of 10
More aggressive approach1, 3, 10, 30, 100, 300, 600 mg
MRSD was based on MABEL (80 times < NOAEL/10)Interim blinded PK evaluation done before moving to the next cohort in about half the FIH studies
Strongly recommended
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Dosing Precautions Within A CohortCase-by-case approach based on safety profile of the drug, starting dose and potential risk
Staggered dosing clearly recommended for high-risk compounds
Approach often used: Dosing 2 subjects (e.g., 1 active and 1 placebo) at least 24 hours before remaining subjects of the cohort
This strategy should ideally be used for all cohorts but is sometimes used only for first cohort(s) (with proper justification)
Dosing may also be spread over the same day, e.g., first two subjects dosed 4 hours apart, on the same day
Again, the dosing strategy within a cohort should always be well justified in protocol
Page 17
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Dosing Precautions Within A Cohort
Page 18
Recent trends observed for studies conducted at Anapharm
Staggered dosing was widely used for biologics and for injectable products
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Should We Use Parallel or Cross-Over DesignParallel design is generally considered as a safer approach to SAD Phase I studies
Unknown PK in human (unknown T ½) Unknown PD properties in human (any possibility of prolonged or irreversible toxicitySafety population is larger (more subjects are exposed to the drug as compared to a cross-over approach)
Cross-over designLimit the number of subjects that need to be recruitedAllow a better assessment of PK linearityBut increased risk of losing subjects, thereby limiting safety evaluation
Page 19
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Should We Use Parallel or Cross-Over DesignMixed approach sometimes used
Example: 2 or 3 different cohorts of subjects who will receive more than one dose
Page 20
Parallel cohorts with cross-over dosing
From: Zhou Y. Choice of designs and doses for early phase trials. Fundam Clin Pharmacol 18 (2004) 373-8
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 21
Should We Use Parallel or Cross-Over Design
Recent trends observed for studies conducted at Anapharm
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
How Can We Make a Phase I Program More EfficientNew reality:
Increased pressure for reducing cost of clinical developmentNeed to obtain a proof-of-concept earlier in the drug development processPressure for obtaining more information from a single trial
More demands for “Integrated Phase I protocols”, such as:Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) within the same protocolFood effect armDrug-drug interaction armCohorts of patients (in addition to healthy volunteers)
Page 22
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 23
How Can We Make a Phase I Program More Efficient
Recent Trends Observed for Studies Conducted at Anapharm
44% of the FIH studies were integrated SAD/MAD studies
48% of the FIH studies included a PD evaluation
47% of the FIH studies performed with oral formulations included a food effect evaluation (usually in a cross-over)
Other additional objectives more occasionally seenEffect in CYP2D6 poor metabolizersDrug-drug interaction evaluation
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Example of an “Integrated” FIH Protocol (SAD/MAD)A Phase I, Single-Centre, Randomized, Double-Blind, Placebo-Controlled Study of YY-123 in Healthy Subjects and Patients
Page 24
Phase A: Single ascending doses (SAD): (Cohorts 1 to 5) 8 subjects (6 active/2 placebo) per cohort/dose5 cohorts plannedFood effect studies in 1 cohort in a cross-over fashion
Phase B: Multiple doses for 14 day (MAD): (Cohorts 7 to 11)8 subjects (6 active/2 placebo) per cohort/dose4 cohorts of healthy volunteers1 cohort of patients with targeted indication
Phase B of the study planned to start after the 4th SAD cohort
1-2 weeks between each cohort
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
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
S, E-R 40 mg or Placebo - D
Cohort MD1
S, E-R 80 mg or Placebo - D
Cohort MD2
S, E-R 160 mg or Placebo - D
Cohort MD3
S, E-R Oral 20 mg or Placebo
Cohort 1 Period 1
IV 20 mg or Placebo - D
Period 2
S, E-R 40 mg or Placebo
Cohort 2
S, E-R 80 mg or Placebo
Cohort 3 Period 1
S, E-R 160 mg or Placebo - D
Cohort 4
SAD
MAD
S, E-R 320 mg or Placebo - D
Cohort 5
80 mg or Placebo - D
Period 2
- D
Typical Time Course of a SAD-MAD Combo with IV arm and ISCV assessment arm
Page 25
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Pros and Cons of “Integrated” FIH ProtocolsPros:
Cost and time savingOnly one protocol to submit to regulatory agency and IRBOnly one study planningMaximize amount of information obtained from a single clinical trial
Cons (or challenges):Less experience from regulatory agencies and IRBsMore complex studies from a logistic standpointNot as much time for review process and decision making before MADNeed for flexible protocol and well defined safety measurements with clear stopping criteria according to the potential risksIncreased risk of amendments during the course of the studyConclusions drawn from non optimally designed study
Page 26
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 27
How Can We Make a Phase I Program More Efficient
Intensive QT Evaluation in Phase I Trial (SAD/MAD)
Early detection of a cardiac safety (QT) issue can potentially save enormous time and resources spent on development of an unsafe drug
ECG may be recorded and analyzed in Phase I with the same quality as in a thorough QT (TQT) study.
ECGs at multiple time points
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
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 28
How Can We Make a Phase I Program More Efficient
Example from Literature of Intensive QT Evaluation in FIH
Ref: Near-Thorough QT Study as Part of a First-In-Man Study.Malik et al, Journal of Clinical Pharmacology, 2008;48:1146-1157
SAD with 6 cohorts of 8 volunteers (6 active / 2 placebo)
In addition to standard screening and safety ECGs, each subject underwent 3 continuous 12-lead ECG recordings (13-hour duration each) on Day -1, Day 1 and Day 2
Automatic QT-interval measurements made at 63 time points (28 at baseline and 35 on treatment), with points most frequent between 2 and 3 hours (around expected Tmax)
Data points were synchronized to allow calculation of time-matched differences from Day -1 baseline
Placebo subjects of all cohorts were pooled
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.Page 29
How Can We Make a Phase I Program More Efficient
Intensive QT Evaluation in Phase I Trial (SAD/MAD)
We however must consider the following:No positive control (to establish assay sensitivity)Insufficient power to detect QTc prolongation of 5 ms, but data may allow PK-QTc modellingAbsence of QT prolongation in Phase I would generally not preclude the need for a TQT studyData may be supportive for drugs usually not requiring a TQT study (e.g., large molecules and cytotoxic drugs)
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Questions on FIH Studies Frequently Asked by IRB
Justification of the time allowed between cohorts
Justification of the time allowed between sentinels and main cohort
Justification for the non-use of sentinel subjects
Justification of the provision for starting the MAD before SAD cohorts are completed
Dose escalation criteria (should be included in the protocol)
Page 30
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Questions Frequently asked by Health Canada (TPD or BGT)
Clinical reviewClarification/justification of the upper age limitClarification regarding the selection of the starting doseClarification regarding selection of doses, dose escalation scheme and stopping criteriaRequest for allowing more time between each cohortRequest for allowing more time between dosing of each subject on the same dayClarification of the stopping rules
Page 31
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Phase I and Special PK Studies Often Performed
First time in human, single-and multiple dose
Pharmacokinetics
BA/BE studies
Dose proportionality studies
Drug-drug interactions
Mass balance/metabolism
Food effective study
Page 32
Effect of age
Effect of gender
Renal impairment study
Hepatic impairment
PK/PD studies
Effect on biomarkers
Proof of concept (included in FIH if possible
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
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
ConclusionSponsors 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
Page 33
Experience You Can Trust
© 2010 PharmaNet Development Group, Inc. All rights reserved.
Acknowledgements■ Jean-François Gagné, M.Sc.
Manager, Protocol Writing Sector, Anapharm
■ Stéphane Lamouche, Ph.DAss. Director, Drug Development & Regulatory Affairs, Anapharm
■ Richard Larouche, B.Pharm, MDDirector, Medical Affairs, Anapharm
■ Annie Ouimet, M.Sc.Senior Regulatory Affairs Associate, Anapharm
■ Eric Shink, Ph.DSenior Biostatistician, Anapharm
■ Fethi Trabelsi, Ph.DDirector, Scientific & Regulatory Affairs, Anapharm
Page 34