Raising the bar of efficacy in cancer therapeutics
Alberto Sobrero
Ospedale San Martino Genova, Italy
Today’s topic: size of benefit in phase III clinical trials on advanced solid tumorsToday’s topic: size of benefit in phase III clinical trials on advanced solid tumors
• Clinically worthwhile Clinically relevant (efficacy-effectiveness)
Vs
• Statistically significant
• Clinically worthwhile Clinically relevant (efficacy-effectiveness)
Vs
• Statistically significant
NOT
• Adjuvant setting
• Type of endpoint
• Ways of summarizing benefit
• Cost , price, reimbursement
NOT
• Adjuvant setting
• Type of endpoint
• Ways of summarizing benefit
• Cost , price, reimbursement
median HR
PFS .57
OS .73
Sobrero and Bruzzi , JCO 2009
15 pivotal R phase III registration trials, 9 biologics , 8 cancer types
median absolute gain
2.7 months
2.0 months
Very good / f
antastic
…hmm…
1. HR vs absolute delta
2. low target HR in trial design
3. target HR in trial design vs p value in trial analysis and interpretation.
The 3 problems
PROBLEM 1: ABSOLUTE GAIN Increase in median OS for different
HR as a function of prognosis
MST Increase in median values as a function of HRIn control
0.9 0.8 0.7 0.6 0.5 0.4
6 .6 1.5 2 4 6 9
worthless worthwhile Unrealistic
24 2.6 6 10 16 24 36
Clinically worthwhile relative delta is a function of prognosis
Both HR AND absolute gain must be considered
PROBLEM 2. ‘ LOW PROFILE’
Typical phase III trial design in advanced cancer (PFS 6 mo)
• Delta 25% i.e. HR = .75
• Median delta = 1.8 mo
• Power 90%
• N = 800
• Cost = 100 MIf w
e get this , is
this really clinically worthwhile?
Be more corageous : raise the bar
PROBLEM 3: INCONSISTENCY
DESIGN CONDUCT ANALYSIS REPORT INTERPRET.
Define target delta…………....target delta is ignored and... p value becomes the focus…
Problem 3 : INCONSISTENCY
HR 0.4 0.5 0.6 0.7 0.8 0.9 1.0
H1 H0
NEG
POSITIVE ( median gain 25 days)
POS
POS
‘Statistically positive’ trials with deltas lower than those pre-specified
in the protocol
AUTHOR DRUG TUMOR predefined reported p HR HR value
Johnstone 09 lapatinib breast 0.64 0.71 0.019Jonker 07 cetuximab colon 0.74 0.77 0.001Moore 07 erlotinib pancreas 0.75 0.82 0.038Llovet 08 sorafenib liver 0.6 0.69 0.001Escudier 07 sorafenib renal 0.67 0.72 0.02
modified from Ocana A. JNCI,2011
The solutions: raising the bar above the minimum clinically
worthwhile effect
•Maintaining today’s statistical thinking• Change H1: Shoot at larger, clinically worthwhile effect
Proposal maintaining today’s classical stat thinking: raise the
bar, change H1
HR 0.4 0.5 0.6 0.7 0.8 0.9 1.0
New H1
H1 H0
NEG
POS
POS
? LIMBO
• Co-development• Predictive markers• Adjuvant setting
The pros of raising the bar
1. POP agents off market credibility / uniformity
2. Smaller trials reduced costs, more rapid clinical devel.
3. Trials on selected patients selective approval
The contras of raising the bar
1. Increased statistical uncertainty
2. Missing cumulative effect of incrementalists
3. Cost and devel. time vs RISK fewer agents
4. Less funding to clinical and translational research
The solutions: the two ways of raising the bar above the
minimum clinically worthwhile effect
•Maintaining today’s statistical thinking• Change H1: Shoot at larger, clinically worthwhile effect
•Changing today’s statistical thinking • Change H0: shoot at rejecting anything inferior to a
minimum clinically worthwhile effect
HR 0.4 0.5 0.6 0.7 0.8 0.9 1.0
New H1
H1
New H0, MCWE
H0
Proposal changing today’s classical statistical thinking:
change H0
NEG
LIMBO
POS
NEG NEG
HR 0.4 0.5 0.6 0.7 0.8 0.9 1.0
MCWE, new H0
The limbo level
APPROVE
LIMBO
Further studies only if non toxic low cost
Consider increasingSample size
APPROVE
LIMBO
• Co-development• Predictive markers• Adjuvant setting
H0
Pros and cons of changing H0
PROS
• Forces to reason in terms of relevance, not stat. significance
• Statistical uncertainty not increased
• Promotes adaptive designs
CONS
• Identification of MCWE difficult
• Size of trials
( if effect close to MCWE)