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1st draft of Colon Cancer Workshop Agenda (to begin the discussion)
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1st draft of Colon Cancer Workshop Agenda (to begin the discussion)
Colon
Cancer Workshop Questions
November
12, 2003
Topic Presenter1/
Discussion Leader2 Time
Introduction Richard
Pazdur (FDA) 1 8:00 AM
1. Regulatory background
-Regulations and endpoints Grant
Williams (FDA) 1 (15 min)
-Past approvals for colorectal
Amna Ibrahim (FDA) 1 (15 min)
cancer drugs
2. First-line therapy of
advanced colon cancer 8:40 AM
-TTP discussion Langdon Miller1 (30
min)
-Non-inferiority/surrogates Tom
Fleming1 (20 min)
-Questions to speakers (15 min)
-Break
Questions: First-line
treatment setting: regular drug approval (10:00-12:00)
A. Survival in the first-line treatment setting
(Discussion
Leader: James Krook)
Background:
Most approved first-line
treatments have a small documented survival benefit.
Crossover or change
to other available drugs may obscure an effect on survival.
Demonstration of
a survival effect by showing non-inferiority to standard therapy is
very difficult because standard therapies are associated with small
and imprecisely defined survival benefits.
For initial approval
of a drug in a combination regimen, FDA needs evidence that the new
drug is contributing to the efficacy of the combination. This
may be difficult to do with trials designed to show non-inferiority.
Questions:
1. Is survival
the only acceptable endpoint for supporting the approval of drugs for
first-line treatment of colon cancer?
2. Is demonstration
of non-inferiority with respect to survival a viable approach for drug
approval in this setting, or are the difficulties too great (e.g., the
small and imprecisely defined survival benefits associated with standard
therapy)? If this is a viable approach, suggest active control
treatments for these studies.
3. For a superiority
design (Drug B beats Drug A), what control arms are ethically and practically
acceptable for evaluating survival in the first-line treatment setting?
4. Although evidence
from more than one trial is generally needed for drug approval, in some
cases FDA has accepted a single well-conducted well-controlled study.
As noted in an FDA Guidance*,"reliance on only a single study is
generally limited to situations in which a trial has demonstrated a
clinically meaningful effect on mortality, irreversible morbidity, or
prevention of a disease with potentially serious outcome and confirmation
of the result in a second trial would be practically or ethically impossible."
This issue is also addressed in the FDA Modernization Act of 1997 (FDAMA).
FDAMA states that FDA may approve a study with only one adequate and
well-controlled study if "the FDA, based on relevant science, determines
that data from one adequate and well controlled clinical investigation
and confirmatory evidence (obtained prior to or after such investigation)
are sufficient to establish effectiveness."
Question:
Discuss settings where only a single trial might be acceptable for approval
of drugs for first-line treatment of advanced colorectal cancer.
B.
TTP in the first-line treatment setting
(Discussion
leaders: John Marshall and Mike O'Connell)
Background:
Drugs associated
with survival benefit may fail to demonstrate this benefit in clinical
trials due to inadequate power or crossover. TTP is generally
less affected by these problems.
Ascertainment of
the progression time may be biased because cancer trials are seldom
blinded.
The progression
time could be remote from the time of first morbidity, so TTP may not
be a direct measurement of patient benefit.
Questions:
1. Drug A has
previously demonstrated a survival benefit. Drug B shows a superior
TTP to Drug A. In this setting, is TTP an adequate endpoint for
full approval (Is it a reliable surrogate for benefit)? If so,
is it a surrogate based on its prediction of delayed morbidity or delayed
death?
In your answer address
the following points:
Consider the magnitude
of TTP benefit and precision of the estimate of the TTP benefit.
Consider whether
there is one or more than one trial showing a TTP benefit.
Consider whether
other endpoint analyses are supportive (e.g., response rate, survival
trend).
Consider issues
related to reliability such as patient and investigator blinding, blinded
reading of scans, etc.
Consider whether
deaths without prior documentation of tumor progression should be counted
as progression events in the TTP analysis.
Consider how much
survival data would be needed comparing Drug A to Drug B before accepting
the TTP benefit as the basis of approval.
2. Non-inferior
TTP: Assume that standard Drug A, in addition to having a known survival
benefit, has a well-documented effect on TTP. If drug B has a
non-inferior effect on TTP compared to drug A, should drug B receive
regular approval?
a.
Consider this question if Drug B is equitoxic to Drug A.
b.
Consider this question if Drug B is less toxic than Drug A.
c. At the time of the
approval decision based on non-inferior TTP, are data on survival also
needed?
3. If FDA allows
drug approval based on a TTP advantage, should these trials also be
powered to detect a survival advantage?
C.
Accelerated approval in the first-line
treatment setting
Background:
AA may be based on a surrogate
endpoint reasonably likely to predict clinical benefit in settings where
the new drug demonstrates an advantage over available therapy.
Questions: Drug
B is compared to Standard Drug A (which has a small documented survival
benefit):
1. Drug B has
a superior response rate and/or superior TTP compared to Drug A. Should
accelerated approval be considered?
2. Drug B has
a response rate and/or TTP that is "non-inferior" to Drug
A, and Drug B is less toxic than Drug A. Should accelerated approval
be considered?
3. Consider whether
comparative data on survival are needed before AA in either circumstance.
Lunch 12:00-1:00 PM
3. Second-line and subsequent therapy setting 1:00-2:15
PM
(Discussion
leader: Jordan Berlin)
A. In the second line setting:
1. Could prolongation of
TTP in a randomized study be sufficient for regular approval?
2. If not, could prolongation
of TTP in a randomized study be sufficient for accelerated approval?
Note that this study will have failed to (or was underpowered to) show
a significant difference survival difference (e.g., the recent oxaliplatin
AA for treatment of refractory colon cancer).
3. Could a superior response
rate in a randomized study support accelerated approval?
4. Could non-inferior TTP
and/or response rate in a randomized study support approval for a less
toxic drug? If so, would this approval be a regular approval or
accelerated approval?
B. In the refractory setting
(no available therapy):
Could response rate
(with an adequate response duration) demonstrated in one or more single
arm studies support accelerated approval in patients with no available
therapy? If so, discuss the response rate and response duration
that could suffice.
4. Other endpoints in advanced
disease Charles Blanke2 2:15 PM
(Discussion leader Charles
Blanke) (30 min)
What is the role of other
endpoints (e.g., biomarkers, symptom assessment, HRQOL) in clinical
trials of drugs for advanced colorectal cancer?
5. Adjuvant setting 2:45 PM
DFS versus
Survival Dan Sargent (15 min)
Question-centered
discussion (60 minutes)
(Discussion
leaders Mike O'Connell and Dan Sargent)
Background:
FDA has previously
stated that disease-free survival (DFS) can support regular approval
in cancers where the majority of recurrences are symptomatic.
DFS has supported
regular drug approval for the adjuvant treatment of breast cancer.
Questions:
A. For colon
cancer drugs, does an increase in DFS compared to standard therapy represent
clinical benefit and support regular drug approval?
1. If so, what
duration of DFS follow-up is needed for regular approval? (3 years,
5 years?)
2. If so, could
accelerated approval be granted based on a shorter follow-up (e.g.,
accelerated approval based on 3-year DFS and regular approval based
on 5-year DFS)?
3. If not, could
a DFS improvement compared to standard therapy support accelerated approval?
Would a survival advantage ultimately be required for conversion to
regular approval?
B. Drug A is
associated with a modest survival benefit. Drug B is compared
to Drug A and shows a non-inferior DFS, but the data are insufficient
for a formal non-inferiority comparison of survival. Could
Drug B be approved based on non-inferior DFS?
1.
Consider this question if Drug B is equitoxic to Drug A.
2.
Consider this question if Drug B is less toxic than Drug A.
6. Rectal cancer endpoints 4:00 PM
-Neoadjuvant therapy presentation Meg
Mooney (15 min)
-Questions
(45 min)
(Discussion leader Meg Mooney)
A. In selected drugs
for local therapy (e.g., radiation sensitizers), is local control of
rectal cancer a suitable endpoint for either full or accelerated approval?
B. Discuss the role
of pathological complete response rate as an endpoint for accelerated
approval or full approval in neoadjuvant therapy of rectal cancer.
Reference:
*FDA Guidance for Industry:
Providing Clinical Evidence of Effectiveness for Human Drugs and Biological
Products, 1998
1st draft of Colon Cancer Workshop Agenda (to begin the discussion)
Colon
Cancer Workshop Questions
November
12, 2003
Topic Presenter1/
Discussion Leader2 Time
Introduction Richard
Pazdur (FDA) 1 8:00 AM
1. Regulatory background
-Regulations and endpoints Grant
Williams (FDA) 1 (15 min)
-Past approvals for colorectal
Amna Ibrahim (FDA) 1 (15 min)
cancer drugs
2. First-line therapy of
advanced colon cancer 8:40 AM
-TTP discussion Langdon Miller1 (30
min)
-Non-inferiority/surrogates Tom
Fleming1 (20 min)
-Questions to speakers (15 min)
-Break
Questions: First-line
treatment setting: regular drug approval (10:00-12:00)
A. Survival in the first-line treatment setting
(Discussion
Leader: James Krook)
Background:
Most approved first-line
treatments have a small documented survival benefit.
Crossover or change
to other available drugs may obscure an effect on survival.
Demonstration of
a survival effect by showing non-inferiority to standard therapy is
very difficult because standard therapies are associated with small
and imprecisely defined survival benefits.
For initial approval
of a drug in a combination regimen, FDA needs evidence that the new
drug is contributing to the efficacy of the combination. This
may be difficult to do with trials designed to show non-inferiority.
Questions:
1. Is survival
the only acceptable endpoint for supporting the approval of drugs for
first-line treatment of colon cancer?
2. Is demonstration
of non-inferiority with respect to survival a viable approach for drug
approval in this setting, or are the difficulties too great (e.g., the
small and imprecisely defined survival benefits associated with standard
therapy)? If this is a viable approach, suggest active control
treatments for these studies.
3. For a superiority
design (Drug B beats Drug A), what control arms are ethically and practically
acceptable for evaluating survival in the first-line treatment setting?
4. Although evidence
from more than one trial is generally needed for drug approval, in some
cases FDA has accepted a single well-conducted well-controlled study.
As noted in an FDA Guidance*,"reliance on only a single study is
generally limited to situations in which a trial has demonstrated a
clinically meaningful effect on mortality, irreversible morbidity, or
prevention of a disease with potentially serious outcome and confirmation
of the result in a second trial would be practically or ethically impossible."
This issue is also addressed in the FDA Modernization Act of 1997 (FDAMA).
FDAMA states that FDA may approve a study with only one adequate and
well-controlled study if "the FDA, based on relevant science, determines
that data from one adequate and well controlled clinical investigation
and confirmatory evidence (obtained prior to or after such investigation)
are sufficient to establish effectiveness."
Question:
Discuss settings where only a single trial might be acceptable for approval
of drugs for first-line treatment of advanced colorectal cancer.
B.
TTP in the first-line treatment setting
(Discussion
leaders: John Marshall and Mike O'Connell)
Background:
Drugs associated
with survival benefit may fail to demonstrate this benefit in clinical
trials due to inadequate power or crossover. TTP is generally
less affected by these problems.
Ascertainment of
the progression time may be biased because cancer trials are seldom
blinded.
The progression
time could be remote from the time of first morbidity, so TTP may not
be a direct measurement of patient benefit.
Questions:
1. Drug A has
previously demonstrated a survival benefit. Drug B shows a superior
TTP to Drug A. In this setting, is TTP an adequate endpoint for
full approval (Is it a reliable surrogate for benefit)? If so,
is it a surrogate based on its prediction of delayed morbidity or delayed
death?
In your answer address
the following points:
Consider the magnitude
of TTP benefit and precision of the estimate of the TTP benefit.
Consider whether
there is one or more than one trial showing a TTP benefit.
Consider whether
other endpoint analyses are supportive (e.g., response rate, survival
trend).
Consider issues
related to reliability such as patient and investigator blinding, blinded
reading of scans, etc.
Consider whether
deaths without prior documentation of tumor progression should be counted
as progression events in the TTP analysis.
Consider how much
survival data would be needed comparing Drug A to Drug B before accepting
the TTP benefit as the basis of approval.
2. Non-inferior
TTP: Assume that standard Drug A, in addition to having a known survival
benefit, has a well-documented effect on TTP. If drug B has a
non-inferior effect on TTP compared to drug A, should drug B receive
regular approval?
a.
Consider this question if Drug B is equitoxic to Drug A.
b.
Consider this question if Drug B is less toxic than Drug A.
c. At the time of the
approval decision based on non-inferior TTP, are data on survival also
needed?
3. If FDA allows
drug approval based on a TTP advantage, should these trials also be
powered to detect a survival advantage?
C.
Accelerated approval in the first-line
treatment setting
Background:
AA may be based on a surrogate
endpoint reasonably likely to predict clinical benefit in settings where
the new drug demonstrates an advantage over available therapy.
Questions: Drug
B is compared to Standard Drug A (which has a small documented survival
benefit):
1. Drug B has
a superior response rate and/or superior TTP compared to Drug A. Should
accelerated approval be considered?
2. Drug B has
a response rate and/or TTP that is "non-inferior" to Drug
A, and Drug B is less toxic than Drug A. Should accelerated approval
be considered?
3. Consider whether
comparative data on survival are needed before AA in either circumstance.
Lunch 12:00-1:00 PM
3. Second-line and subsequent therapy setting 1:00-2:15
PM
(Discussion
leader: Jordan Berlin)
A. In the second line setting:
1. Could prolongation of
TTP in a randomized study be sufficient for regular approval?
2. If not, could prolongation
of TTP in a randomized study be sufficient for accelerated approval?
Note that this study will have failed to (or was underpowered to) show
a significant difference survival difference (e.g., the recent oxaliplatin
AA for treatment of refractory colon cancer).
3. Could a superior response
rate in a randomized study support accelerated approval?
4. Could non-inferior TTP
and/or response rate in a randomized study support approval for a less
toxic drug? If so, would this approval be a regular approval or
accelerated approval?
B. In the refractory setting
(no available therapy):
Could response rate
(with an adequate response duration) demonstrated in one or more single
arm studies support accelerated approval in patients with no available
therapy? If so, discuss the response rate and response duration
that could suffice.
4. Other endpoints in advanced
disease Charles Blanke2 2:15 PM
(Discussion leader Charles
Blanke) (30 min)
What is the role of other
endpoints (e.g., biomarkers, symptom assessment, HRQOL) in clinical
trials of drugs for advanced colorectal cancer?
5. Adjuvant setting 2:45 PM
DFS versus
Survival Dan Sargent (15 min)
Question-centered
discussion (60 minutes)
(Discussion
leaders Mike O'Connell and Dan Sargent)
Background:
FDA has previously
stated that disease-free survival (DFS) can support regular approval
in cancers where the majority of recurrences are symptomatic.
DFS has supported
regular drug approval for the adjuvant treatment of breast cancer.
Questions:
A. For colon
cancer drugs, does an increase in DFS compared to standard therapy represent
clinical benefit and support regular drug approval?
1. If so, what
duration of DFS follow-up is needed for regular approval? (3 years,
5 years?)
2. If so, could
accelerated approval be granted based on a shorter follow-up (e.g.,
accelerated approval based on 3-year DFS and regular approval based
on 5-year DFS)?
3. If not, could
a DFS improvement compared to standard therapy support accelerated approval?
Would a survival advantage ultimately be required for conversion to
regular approval?
B. Drug A is
associated with a modest survival benefit. Drug B is compared
to Drug A and shows a non-inferior DFS, but the data are insufficient
for a formal non-inferiority comparison of survival. Could
Drug B be approved based on non-inferior DFS?
1.
Consider this question if Drug B is equitoxic to Drug A.
2.
Consider this question if Drug B is less toxic than Drug A.
6. Rectal cancer endpoints 4:00 PM
-Neoadjuvant therapy presentation Meg
Mooney (15 min)
-Questions
(45 min)
(Discussion leader Meg Mooney)
A. In selected drugs
for local therapy (e.g., radiation sensitizers), is local control of
rectal cancer a suitable endpoint for either full or accelerated approval?
B. Discuss the role
of pathological complete response rate as an endpoint for accelerated
approval or full approval in neoadjuvant therapy of rectal cancer.
Reference:
*FDA Guidance for Industry:
Providing Clinical Evidence of Effectiveness for Human Drugs and Biological
Products, 1998