Download week9-clinical trials-Presentation_2014_11_06

Early Phase Clinical Trials
Greg Pond
Ph.D., P.Stat.
Escarpment Cancer Research Institute
Department of Oncology
Department of Clinical Epidemiology and Biostatistics
6 November 2014
Learning Objectives
1.
Understand clinical questions of interest
2.
Understand statistical questions of interest
3.
Understand different phases (1/2/others)
4.
Able to discuss designs for early phase clinical
trials
My Background (biases)
•Department of Oncology (associate appointment
with Clin Epi & Biostats)
•13+ years in cancer clinical trials
•Minimal involvement with other diseases
•Interaction (questions) are good 
Your Background
•Does anyone have experience designing an early
phase trial?
•How many have clinical trials experience? What
sort?
•Who is clinician / statistician / researcher /
other?
Thought Experiment
•You (or collaborator) has new drug which showed
astonishing activity in animals / lab experiments.
Ultimately, you want to apply for regulatory
approval.
•You need to convince financier to fund you to get
to regulatory approval. What processes will you
use?
Standard Drug Development
Paradigm
•Phase I – safety. Find safe dose.
•Phase II – preliminary efficacy. Is it active?
•Phase III – efficacy. Is it superior to standard?
•Phase IV – effectiveness. Is it beneficial in the
real-world?
Phase I
•FDA Definition:
Phase 1 includes the initial introduction of an
investigational new drug into humans. These studies are closely monitored and may
be conducted in patients, but are usually conducted in healthy volunteer subjects.
These studies are designed to determine the metabolic and pharmacologic actions
of the drug in humans, the side effects associated with increasing doses, and, if
possible, to gain early evidence on effectiveness. During Phase 1, sufficient
information about the drug's pharmacokinetics and pharmacological effects should
be obtained to permit the design of well-controlled, scientifically valid, Phase 2
studies
Phase II
•FDA Definition:
Phase 2 includes the early controlled clinical studies
conducted to obtain some preliminary data on the effectiveness of the drug for a
particular indication or indications in patients with the disease or condition. This
phase of testing also helps determine the common short-term side effects and risks
associated with the drug. Phase 2 studies are typically well-controlled, closely
monitored, and conducted in a relatively small number of patients, usually involving
several hundred people.
Clinical Trial Phases
•NIH Definition:
PHASE I TRIALS: Initial studies to determine the metabolism and pharmacologic
actions of drugs in humans, the side effects associated with increasing doses, and
to gain early evidence of effectiveness; may include healthy participants and/or
patients.
PHASE II TRIALS: Controlled clinical studies conducted to evaluate the
effectiveness of the drug for a particular indication or indications in patients with the
disease or condition under study and to determine the common short-term side
effects and risks.
PHASE III TRIALS: Expanded controlled and uncontrolled trials after preliminary
evidence suggesting effectiveness of the drug has been obtained, and are intended
to gather additional information to evaluate the overall benefit-risk relationship of the
drug and provide and adequate basis for physician labeling.
Clinical Trial 1
• What question should be answered in first
clinical trial?
• Is it safe to administer? Is there any biological
activity? How much should we give?
• Give to small number of humans in a controlled
environment (why?) and check (side) effects
TGN1412 for RA
• Injected to six volunteers at sub-clinical dose on
13 March 2006, 10 min apart in London, UK
• All ‘immediately’ hospitalised, six with multiorgan failure due to ‘cytokine storm’. 1 ballooned
up like ‘the elephant man’.
• Volunteers given ₤2000. All survived, but may
have long-term immune system issues.
• The company, TeGenero, went bankrupt within
the year.
Dose Levels
• DL1 usually based on animal data (e.g. 1/10th
LD50 in mice)
• Escalation of doses uses Fibonacci sequence
(x2, x1.67, x1.5, x1.33, x1.33, …)
• Oral medications: based on availability of doses
(i.e. if only come in 50 mg pills)
Penel N and Kramar A. BMC Med Res Meth 12:103, 2012
Phase I: Cancer (3+3)
• Give to 3 patients
• If 0/3 have dose limiting toxicity - escalate
• If 1/3 has DLT, expand to 3 more patients
• If 1/6 has DLT – escalate
• If ≥2/3 or ≥2/6 – reached maximum tolerated
dose (MTD)
• DLT: serious or life-threatening AE occurring in
first cycle – not standard
Hansen, Graham, Pond, Siu, Phase I Trial Design: Is 3+3 the Best? Cancer Control. 21(3): 2014
DLTs
• Serious or life-threatening AE occurring in first
cycle – not standard
• Grade of AE (1=mild, 2, 3, 4, 5=death). Grade 3+
• Leukemia patients almost all have grade 4
hematological AE
• Attributable to drug?
• Chronic grade 2 AE (fatigue, nausea, etc)
Phase I: Cancer (3+3)
• Recommended phase II dose is the dose below
MTD
• Europe: MTD=RP2D
• DEFINE!!!!!!
Phase I: Non-cancer
• Give drug to paid volunteers
• How much would you need to be paid to take a
drug with a 33% chance of giving you a
serious/life-threatening AE?
• What is compensation if 33% of volunteers get
SAE?
• Luckily, most treatments expected to have
few/none AE
Phase I: Non-cancer
• How do you measure safety/outcomes?
• Measure the effects on body (pharmacokinetics,
pharmacodynamics)
• Ensure it is within acceptable limits
Phase I: Non-cancer
• Statistical tests on differences in variability
• Differences in mean less important (why?)
• How do you define sample size?
• Often want to ensure biodistribution
Cancer Phase I Ethics
• Often start ‘too low’ for safety reasons
• Suboptimal dose reduces chance of response
• Phase I response rates quoted as ~5%
• Patients do not enter these trials altruistically
Ethics
• Should you allow intrapatient dose escalation?
• Chance of response for patient
• How to evaluate late AE?
• How likely is it for a patient with worsening
disease to stay on treatment for >2 cycles?
• Generally No.
Ethics
• Average patient survival may be a few months
• What if drug requires weekly IV injections?
• How to assess long-term toxicities?
Correct RP2D
• Too low  reduced chance of efficacy in later
trials
• Too high  excess toxicity / dose reductions
• Based on 3+3=6 patients
Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms
by pharmaceutical sales (2005) by period during which compound first entered clinical testing.
DiMasi J A , and Grabowski H G JCO 2007;25:209-216
©2007 by American Society of Clinical Oncology
http://joneslab.chem.wsu.edu/
Modified Designs
• Rapid early escalation and intra-patient
escalation permitted
• 1 pt / dose level until grade 2 AE, then 3+3
• Reduce # of patients in trial (slightly), # at
suboptimal dose. More likely to give patients too
toxic dose
Model-Based Designs
• ‘Recent’ innovation
• Specify dose-toxicity relationship
• Update based on data
Example dose-toxicity curve
Garrett-Mayer, E, "Understanding the Continual Reassessment Method for Dose Finding Studies: An Overview for Non-Statisticians"
(March 2005). Johns Hopkins University, Dept. of Biostatistics Working Papers. Working Paper 74.
Others
• EWOC – curve based on probability of observing
a SAE
• TITE-CRM – time to event CRM
• Mixed effects proportional odds model – odds of
severe toxicity per cycle
• Some gain in assessing accurate dose. May use
more patients (pre-define limit on sample size)
Hansen AR1, Graham DM, Pond GR, Siu LL. Phase 1 trial design: is 3 + 3 the best? Cancer Control. 2014 Jul;21(3):200-8.
Secondary Outcomes
• Small numbers of patients
• Want correlative (pK/pD/biological effects)
• Patients receive different doses
• Many correlative outcomes are binary/ordinal
• Consider cost/benefit
Secondary Outcomes
• Does biology change pre- to post-treatment?
• Is patient healthy enough post-treatment?
• Ethics of paired biopsies
• What is accuracy of assay?
However…
• Some argue no reason to pursue development of
new drug if no marker of target
• Molecularly targeted agents
• Drug A targets marker X, highly prevalent in
cancer
• If patient does not express X, then drug useless
Targeted Agents
• If 80% of patients with X respond, but only 10%
of patients have X, and 0% of patients without X
respond. SOC is 5% response.
• Phase III RCT needs >2250 patients without
accurate assay
• Phase III RCT needs 16 ‘enriched’ patients with
accurate assay
• Regulatory bodies asking for proof of
mechanisms of action
Phase II
• Is there any evidence of activity?
• Might this agent be potentially useful?
• Do not want to test if drug is ‘better’ than
standard treatment (why not?)
• Proof of principle
Clinical phase transition probabilities for investigational oncology compounds for the 20 largest firms
by pharmaceutical sales (2005) by period during which compound first entered clinical testing.
DiMasi J A , and Grabowski H G JCO 2007;25:209-216
©2007 by American Society of Clinical Oncology
Phase II: non-cancer
• Compare efficacy – often of a surrogate outcome
• Small, randomised trial
• Does blood pressure go down – surrogate for MI
• Do MS patients improve activity levels, walk? –
long-term abilities
Placebo
5 mg
R.
10 mg
20 mg
50 mg
Phase II: non-cancer
• Size – few hundred
• Multiple comparison adjustments
• α=0.05, β=0.80
Phase II: non-cancer
• Select optimal dose / regimen
• Highest dose may be unsafe / not tolerable
• Ideally want dose-response relationship
Phase II: non-cancer
• Trial design: standard statistical analyses
• T-tests, χ2 tests, Wilcoxon rank-sum, Fisher’s
exact tests
• Estimation of differences also important
• Some subgroup analyses performed, though
power is small – pre-define
Phase II: non-cancer
• Secondary outcomes: safety, tolerability,
treatment completion rate
• Preliminary evidence of OS (or phase III
outcome)
• Use for designing phase III trial
Phase II: Cancer
• Placebo generally considered unethical
• Any disease which is terminal, or requires
intervention of some sort (schizophrenia, HIV)
• Best supportive care may be given for palliation
Phase II: Cancer
• How would you measure if there is ‘any evidence
of activity’?
• Most cancer drugs historically fail and have
substantial side effects
• Remember: 33% have serious/life-threatening
AE in 1st 28 days alone and ~5% respond at all
• Thoughts?
Phase II: Cancer
• Give to small numbers of patients (single-arm)
• If anyone responds => evidence of activity
• Add a few more patients and estimate RR
• Gehan - 1960
Phase II: Cancer
• Two stages, formalize based on α and β
(Fleming, 1982)
• Optimal designs (Simon, 1989)
• Assuming drug is ineffective, what is minimum
number of patients needed
• Reduces total sample size across all trials
Design Issues
• Some advances – some patients respond to std
• Ethically can not give novel therapy with less
chance of response
• Novel therapies designed not to shrink tumour,
but only prevent it from growing
• How to proceed?
Questions
• Often novel therapies are given in addition to
standard of care
• Outcome of response changed to time to
progression
• Randomization
Histogram of number of randomized phase II cancer studies
published from 1986 to 2002.
Lee J J , and Feng L JCO 2005;23:4450-4457
Randomized Phase II designs
• >4x number of patients needed
• Solutions: look for massive effects, inflate α and
β
• One suggestion is α=0.20, β=0.20, HR=0.6 –
unrealistic
Randomized Phase II Outcomes
• PFS instead of OS
• PFS often a poor surrogate
• May be difficult to run phase III if large
differences observed
Other designs
• ‘Pick-the-winner’
• 2:1 allocation, with control only to ‘ensure H0 is
accurate’
• No formal comparison, different regimens
• None widely accepted
Type of Statistical Design Used in Randomized Phase II Trials Among the Studies With Reported Statistical Designs (N = 123)
Statistical Design
Design categories
SWE randomized phase II
1-stage design
No.
%
13
10.6
48
39.0
1-sample binomial
14
2-sample binomial
15
2-sample continuous
12
2-sample survival
7
2-stage design
55
Gehan’s
14
Simon’s optimal
14
Simon’s minimax
11
Ad-hoc binomial
10
Fleming’s
3
Multinomial
2
Logistic
1
3-stage design
4
EORTC binomial
3
Ensign’s binomial
1
Bayesian binomial
3
2
Group sequential binomial
1
Others
44.7
3.3
2.4
Design by type of primary end points
Binomial
Continuous
Survival
Multinomial
Total
Lee J J , and Feng L JCO 2005;23:4450-4457
102
12
7
2
123
82.9
9.8
5.7
1.6
100.0
‘Novel’ designs
• Randomised discontinuation trials
• Treat all patients with agent for 1 cycle
• Keep treating patients with a response
• Stop treating patients who are progressing
• Randomize patients with stable disease to
treatment versus placebo
Summary of phase II trial designs.
Rubinstein L et al. Clin Cancer Res 2009;15:1883-1890
RDT Trials
• Primary analysis is comparison of randomized
patients
• Re-challenge placebo patients who progress
• Ethics?
• Can fail miserably if # of patients with SD is
small
Crossover
• Trial is novel therapy versus BSC
• Patients who fail BSC ‘crossover’ to receive novel
therapy
• Ethically, all pts receive trt
Crossover
• Problem is study is really treat now, or treat
later
• All patients are progressing at start of study
• Tumour grows and becomes more resistant
• Cannot determine long-term OS advantage. If
trial is + and regulatory approval, difficult for
funders/insurance (OHIP)
Bayesian Response-Toxicity Curve
Genetic Marker Design
• NSCLC pts, primary outcome: 8-week SD
• Genetic profiling improved primary outcome
from 30% (expected) to 46% in BATTLE
Bayesian Adaptive Design
• BATTLE: randomize pts 1:1:1:1 initially
• As info increases, allocate patients preferentially
to treatment/marker combination with best
performance
• Outcome is Prob(8 week SD|marker &
treatment)
• Large, complex, need real-time data/histology
Marker Designs
• I-SPY2 underway in breast cancer
• Lots of information; essentially many single-arm
trials
• May reject treatment/marker combo with small
numbers
• Costs ~$27 million over 5 years for 800 patients
Combined Phase Trials
• Phase I/II trials
• Include phase I patients in phase II analysis
• Only pts treated at RP2D
• Population must be the same, thus, may reduce
#s evaluable for phase I
Combined Phase Trials
• Phase II/III
• Do randomised phase II study using a surrogate
endpoint
• Stop at analysis 1 if lack of efficacy
• Continue to phase III if some evidence
Combined Phase Trials
• Does not affect the α since interim analysis
based on different endpoint
• However, must be willing to commit resources
for phase III study
• Phase III tends to have large # of institutions; if
stop at IA, much work for little gain
• 3-6 months to get study started
Secondary Outcomes
• Safety / toxicity / cost / QOL / ease of
treatment
• Many not known after phase I
• May inform phase III design, but may be added
costs with no benefit if phase II fails
• Can add support for regulatory approval of
positive trials
Registration Information for US Food and Drug Administration (FDA) Oncology Drug Approvals for Solid Tumors 1998 Through
2008 Inclusive
Basis of All Initial
Approvals
Cytotoxic Drugs (n = 13 drugs in 34
indications)
Targeted Drugs (n = 11 drugs in 26
indications)
No.
%
No.
%
Phase III data*
30
88
20
77
Single-arm phase II
data only
4†
12
4‡
15
Randomized phase
II data only
0
0
2§
8
Hui K. Gan, Axel Grothey, Gregory R. Pond, Malcolm J. Moore, Lillian L. Siu⇓ and Daniel Sargent Randomized Phase II Trials: Inevitable or Inadvisable?
JCO 28(15): 2641-2647; 2010
Phase 0
• Looking for biological effects only
• Give agent as a single-agent for 1 week/day
• Evaluate biological markers only
• Some then combine agent with standard in full
trial
• No clinical benefit
Phase 0
• Preferentially given as part of phase I study (can
identify dose effect)
• Not necessarily given to all patients in study
• Occasionally given in isolation (give 1 month of
treatment to 5-10 patients)
• Recruitment is a major issue
Additional Considerations
• Benefit to patient is of concern
• Considerable risk of harm
• Small numbers of patients
• Benefit is that may identify assay / target
Additional Considerations
• Phase I and II are supposed to be ‘quick’
• Can take 2-3 years (or more) each
• What will landscape look like in 10 years (when
applying for regulatory approval)?
Additional Considerations
• Up to 1 year to get study activated after protocol
finalized
• Research Ethics Boards
• Legal contracts with all sites
• Database / data collection
• Site scientific and finance reviews
Data Collection
• Up to 1000 data items collected / trial
• Average of <20% used (<100 / trial)
• Massive wastage
O’Leary, Seow, Julian, Levine, Pond. Data collection in cancer clinical trials: Too much of a good thing? Clin Trials
10(4):624-632; Aug 2013
Data Collection
•
•
•
•
•
•
•
•
•
Clinical trials nurse collects data
Data manager enters data
Trial coordinator reviews data / finds issue
Coordinator sends DCF to data manager
Data manager reviews with nurse
Data manager sends revised data
Trial coordinator re-reviews data
Study investigator reviews and signs off
Database is locked
• All at >$50 / hour
Data Collection
• Is it critical to the study?
• How likely will it be for planning future study?
• Data clarification is important
Weight=110 (kg/lbs?)
What date is 11/6/14 ?
How important is family history if half patients
answer=UNK?
Privacy
• Large restrictions on data captured due to
privacy
• Date of birth / diagnosis – restricted to year?
• Genetic markers
• Want tissue sample sent to third party for QA
review – did you specify in the consent?
Consent Form
• Legal document describing procedures / goals /
information needed / options for patient
• Very detailed (I have seen >30 page consents)
• Sub-consents for biomarker research
• Signed by patient / personnel (not in position of
authority)
Regulatory Burden
• 296Comparison
distinct
processes
required
to byactivate
a
of Works Steps,
Decision Points, Loops,
and Stopping Points
Major Stage of Development
phase III trial
•
Area
Processing Step
Decision Point
Loop
Stopping Point
Concept (total)*
106
21
5
6
CRM
76
13
2
4
Task force
71
19
4
5
Protocol
88
17
8
4
PMB
10
6
2
1
CDE
20
4
1
0
CIRB
34
9
5
2
Final review
16
3
3
0
Total CRM
244
52
21
11
Total task force
239
58
23
12
Dilts DM, Sandler AB, Cheng S, et al. (2009) Steps and time to process clinical trials at the Cancer Therapy Evaluation Program. J Clin
Oncol 27:1761–1766
Median of >600 days from concept to activation
Dilts D M et al. JCO 2009;27:1761-1766
Costs per Year of Life Gained by Selected Interventions
Procedure
Clinical trials regulations
Cost/Life-Year Saved*
$2,700,000
Hemodialysis29
$43,000-$104,000
Statins for heart disease
(moderate- to high-risk patients)30
$19,000-$25,000
Colorectal cancer screening by
colonoscopy32
$14,000
Adjuvant trastuzumab breast
cancer31
$20,000
Bevacizumab advanced non–
small-cell lung cancer33
$380,000
Paclitaxel/cisplatin for advanced
ovarian cancer34
$26,000
David J. Stewart, Simon N. Whitney, Razelle Kurzrock Equipoise Lost: Ethics, Costs, and the Regulation of Cancer Clinical Research. JCO, 28(17):
2925-2935; 2010
DSMB
• Debate about if they are needed
• Phase I probably not
• Cancer phase II – depends on design
(randomized or single-arm, # of patients)
• Non-cancer phase II - probably
DSMB
• 1-2 sites: investigators know each patient
• DSMB knows just numbers
• Steering committee should meet before every
stage/dose escalation decision, etc
• Larger studies/more sites may need
independent review
Final thoughts
• Early phase studies often have ‘simple’ designs
• More complex logistical / practical issues than
late stage designs
• These must be incorporated in analysis, design,
interpretation, inference
Final thoughts
• Must, as a biostatistician, have understanding
of non-statistical aspects, and
• Must be able to communicate effectively with
non-statisticians (clinicians, nurses, CRA,
ethics, regulatory, pathologists, radiologists, lab
technicians, scientists, IT, geneticists, …)