This is the final report of the ODAC meeting held on
http://www.fda.gov/ohrms/dockets/ac/cder03.html#OncologicDrugs
All external requests should be submitted to the Freedom
of Information office.
The
75th meeting of the Oncologic Drugs Advisory Committee was held in the CDER
Conference Room
Open Public Hearing
Mark Scott – Astra Zeneca Oncology
The Agenda proceeded as
follows:
Call
to Order Donna
Przepiorka, M.D., Ph.D.
Chair, Oncologic Drugs
Advisory Committee
Introduction
of Committee
Conflict
of Interest Statement Johanna
Clifford, M.S., RN, BSN
Executive Secretary,
Oncologic Drugs Advisory Committee
Opening Remarks Grant Williams, M.D., Deputy Director
General Regulatory
Background Ann Farrell, M.D., Medical
Team Leader
Division of Oncology Drug
Products
Center for Drug Evaluation and Research, FDA
Endpoints
for Past Approvals Ramzi
Dagher, M.D., Medical Team Leader
Division of Oncology Drug
Products
Center for Drug Evaluation
and Research, FDA
Selected
Issues in Oncology Grant
Williams, M.D., Deputy Director
Trial Design Division of Oncology Drug Products
Center
for Drug Evaluation and Research, FDA
Clarification Questions to
Presenters
Break
Open Public Hearing
Questions
for Discussion
Lunch
Non
Small Cell Lung Cancer Martin
Cohen, M.D., Medical Officer
Regulatory Background Division of Oncology Drug Products
Center for Drug Evaluation
and Research, FDA
FDA/ASCO Non Small Cell Lung Paul Bunn, M.D.
Cancer
Workshop Summary Professor
and Director
University of
Quality
of Life and Patient Reported Richard
Gralla, M.D.
Outcomes
as Endpoints in Clinical President,
Multinational Association of
Cancer
Trials Supportive
Care in Cancer
Clarification
Questions to Presenters
Break
Open Public Hearing
Questions
for Discussion
Adjourn
Meeting Questions– Session I
Background
Sponsors
must demonstrate that drugs are safe and must provide substantial evidence of
effectiveness from "adequate and well-controlled clinical
investigations." Such effects could
include important clinical outcomes (e.g., survival), symptomatic improvement,
or effects on established surrogate endpoints, such as blood sugar, blood
pressure, or blood cholesterol, and all of these endpoints have often been used
as a basis for approval.
In oncology, survival is the gold standard for clinical
benefit, but the FDA has accepted other endpoints for cancer drug
approval. Given the toxicity of cancer
drugs, approval required evidence of improvement in survival or in a patient's
quality of life, e.g., improved physical functioning or improved tumor-related
symptoms. Other endpoints have been
accepted in specific clinical situations.
Disease-free
survival has been accepted as an adequate endpoint for adjuvant cancer
treatment when a large proportion of patients with recurrence was symptomatic.
Durable complete response was considered an acceptable endpoint in
testicular cancer and acute leukemia because the untreated conditions were
quickly lethal or even in some chronic leukemias and lymphomas, where it was
clear that remission would lead to less infection, bleeding, and blood product
support. Response rates have been
considered as endpoints for regular approval in specific settings when other
factors were taken into consideration, such as response duration, relief of
tumor-related symptoms, and drug toxicity
With
this background in mind, please discuss issues relating to the following
endpoints:
Survival
1. Discuss the role of survival as an
endpoint. Consider in your discussion 1)
the importance of whether existing therapies prolong survival and 2) the
potential confounding of survival results by patient crossover or where several
subsequent therapies may also affect survival.
The committee felt that survival should always be assessed but need not
always be the primary endpoint. The committee acknowledged that in some cases,
crossover could obscure detection of a potential survival benefit.
Time to tumor progression
(TTP)
TTP
has been proposed as an endpoint for regular approval, but has not been
rigorously validated as a surrogate for survival. As noted below TTP has important attributes,
yet difficulties exist with its use.
Pros
·
TTP is a measure of tumor effect in all patients, rather than measuring
effect in a subset of patients.
·
Progression is widely viewed by oncologists and patients as an
indicator of worsening necessitating a change in therapy.
·
Tumor progression is in the direct causal path of morbidity and death.
Cons
·
TTP is an indirect measure of patient
benefit.
·
The clinical meaning of small TTP
difference is unclear.
·
Reliability in an unblinded setting
has been questioned.
·
TTP findings are difficult for
independent review groups and for FDA to verify.
2. Discuss whether clinical settings exist where TTP improvement should be
considered
an established surrogate for
clinical benefit and should support regular drug approval. Identify the factors that determine when TTP
is an adequate endpoint for drug approval.
Factors to be considered in your discussion include
reliability in measuring the endpoint, relationship of disease progression to
death, established benefit of available therapy, drug toxicity, and whether
progressing patients are symptomatic.
(Clinical scenarios highlighting these factors are listed in the
appendix).
First, all committee members
preferred inclusion of deaths in the TTP endpoint, i.e., they preferred progression
free survival (PFS) to TTP. Most
committee members felt that an improvement in PFS was clinical benefit, but
that whether to TTP as a regulatory endpoint depended upon many factors, such
as treatment toxicity, the ability to measure TTP without bias, the size of
theTTP benefit, the toxicity of treatment, and the effectiveness of other
available therapy. The committee did not feel that
measurement of TTP at a single time point was an attractive option until the
concept had been studied further.
Disease-free survival
FDA has stated that
disease-free survival (DFS) can support regular drug approval in cancers where
the majority of recurrences are symptomatic.
Others propose that prolongation of DFS should support regular approval
in all clinical settings because a delay in cancer detection or a delay in the
need for toxic cancer treatment is of clinical benefit.
3. Discuss whether DFS is generally an adequate endpoint for approval of
cancer drugs or whether additional evidence is needed, such as data
demonstrating (or suggesting) that DFS is a survival surrogate.
4. Consider whether the adequacy
of DFS varies with the clinical setting.
For instance, consider the following clinical scenarios:
A. No standard adjuvant therapy exists.
Treatment with investigational drug shows superior DFS compared to an
unproven control regimen.
B. Treatment with investigational drug shows prolongation of DFS compared
to highly effective standard therapy (that imparts a survival benefit).
C. Treatment with investigational drug shows non-inferior DFS compared to
highly effective standard therapy (that imparts a survival benefit).
The committee felt that prolongation of DFS is a clinical benefit, not
just a surrogate for survival. Even so, when deciding whether to accept DFS as
a primary endpoint, the FDA should weigh the benefit from delay in tumor
detection versus the toxicity of treatment.
In evaluating treatment toxicity, effects on functionality are of most
interest, not minor toxicities or minor changes in QOL scales. Whether DFS would be an appropriate primary
endpoint for a particular setting should be made on a case-by-case basis. Survival should be assessed in all studies.
First-line NSCLC treatment
setting: approval based on demonstrating superior TTP
Considering
the pros and cons of TTP discussed in the morning session:
1. For approval of drugs for first-line
treatment of advanced lung cancer, could a TTP benefit of a new drug compared
to a standard first-line regimen justify regular drug approval? (Assume the
standard control arm has a known small [2-month] survival benefit.)
The question was rephrased to address locally advanced and metastatic
disease as separate entities. As such,
the
question to the
committee read, would you consider progression free survival as an appropriate
endpoint for full
approval for the
patient with metastatic NSCLC?
Yes – 11 No
– 08
Please note that all but one of the lung cancer consultants voted no on
this issue. Dr. Temple suggested that
data should be examined to assess whether patients are symptomatic at the time
of recurrence. If they were, this would
strengthen the case that PFS is a clinical benefit measure in this setting.
The committee then addressed the question with
respect to the inoperable, locally advanced setting, asking the committee to
vote on whether they would use progression-free survival as a primary endpoint
for approval.
Yes – 4 No - 15
2. If the answer to question 1 is yes, describe
the TTP evidence that would suffice:
a.
Discuss the magnitude of TTP improvement that would be clinically
relevant.
b. Given the difficulties with measuring TTP, should
FDA's evidentiary requirements (number of trials, required significance level)
be greater for TTP than for survival?
c. If TTP is the primary endpoint should trials be blinded? If not, should progression be verified by
blinded central reading of scans?
3. In addition to the TTP finding what, if
any, survival evidence would be needed?
a. Should
trials rule out a survival decrement of some size?
b. Should trials be powered to detect a realistic improvement in
survival even if survival improvement is not an approval requirement?
4. If an improvement in TTP
would not support regular approval, could it support accelerated approval?
The committee felt that
under the considerations discussed, they would support AA, if a clinically
significant effect on TPP were documented.
Yes – 18
No - 0 Abstain
– 1
First-line NSCLC treatment
setting: approval based on demonstrating non-inferiority in survival
5. When designing a non-inferiority (NI) trial,
the active control treatment should have demonstrated a consistent treatment
effect in numerous trials. The effect should be reasonably large and precisely
defined. A critical assumption (the
constancy assumption) is that the treatment effect of the active control will
also exist in the planned NI trial setting.
a. FDA believes that data from existing active control
regimens for NSCLC are insufficient to support the design of NI trials based on
survival. Do you agree?
First-line NSCLC treatment setting:
approval based on non-inferiority (NI) analyses of TTP and/or RR
6. Could approval be based
on NI analyses of RR and/or TTP in situations where a NI analysis of survival
cannot be performed? Examples would be
when there are insufficient patient numbers to allow a survival NI analysis or
when there is confounding of the survival analysis by crossover.
Specifically, address the following situation:
A less toxic experimental drug demonstrates
non-inferiority of both RR and TTP
compared to the standard toxic
regimen. The standard toxic regimen has
previously demonstrated an estimated 2-month survival benefit in one trial
comparing it to best supportive care. In
the current trial data 95% confidence intervals cannot establish whether the
experimental therapy retains the survival benefit of the standard regimen.
The committee felt that it
is very complicated to perform a NI on a surrogate endpoint as described in
this question. Further information would be required to respond adequately, in
terms of functional relationships with respect to the fractions of the benefit
in TTP that translates into the fraction of the survival benefit.
The surgical adjuvant setting
7. FDA has stated that disease-free survival (DFS) can support regular
drug approval in cancers where the majority of recurrences are
symptomatic. Others propose that
prolongation of DFS should support regular approval in all clinical settings
because a delay in cancer detection or a delay in the need for toxic cancer
treatment is of clinical benefit.
a. In NSLC, should a DFS improvement from
adjuvant chemotherapy support regular drug approval? If so, clarify why you
consider DFS an established surrogate for clinical benefit in this setting:
·
Because it delays the detection of cancer and
treatment?
·
Because it delays symptoms?
·
Because it delays death?
b. If not, could a DFS improvement support accelerated
approval? Would a survival advantage ultimately be required for conversion to
regular approval?
The experts on the panel suggested that adjuvant therapy has yet to play a role in lung cancer. However, the committee agreed that DFS can be used as a primary endpoint. There are currently 2 studies underway.
Symptoms and QOL in lung cancer studies
Symptom-based endpoints have
served as the basis of approval for several drugs including drugs for local
treatment of obstructing endobronchial cancer.
However, difficulties exist with using such endpoints in cancer
treatment, including lack of blinding and missing data.
7. Do lung cancer settings exist where symptom-based endpoints can serve
as the primary endpoint for approval? If
so, discuss suitable symptom-based endpoints.
The committee had concerns about the length of
the QOL instruments (21+ questions).
They emphasized the merits of using very
targeted symptoms scales such as the Lung Cancer Symptom Scale (LCSS).
8. Discuss the role of HRQOL as a drug approval
endpoint.
a. In
the NSCLC setting, are HRQOL results meaningful in single arm studies?
b. In randomized studies are HRQOL results meaningful without blinding?
c. Should HRQOL instruments be routinely included in lung cancer
studies? If so, which instruments?
The committee felt that long
HRQOL instruments should be used sparingly in lung cancer patients who are
often experiencing lung cancer symptoms.
They recommended shorter targeted scales.