Transcript Endpoints and Challenges in Oncology Drug Regulation

Defining Success in Oncology
Drug Development
Richard Pazdur, MD
CDER, FDA
The views expressed are the results of independent
work and do not necessarily represent the views or
findings of the United States Food and Drug
Administration or the United States
Basis for NDA Approval
• Demonstration of efficacy with acceptable
safety in adequate and well-controlled
studies
• Ability to generate product labeling that
– Defines an appropriate patient population
– Provides adequate information to enable safe
and effective use
– Approval for an indication, not drug
Regulatory Terms
• Accelerated Approval--serious or lifethreatening disease, benefit over available
therapy. Use of surrogate; mandated
phase IV trials
• Fast Track--life-threatening disease,
potential to address unmet medical need.
Rolling NDA, meetings
• Priority review--drug would be a significant
improvement compared to available drugs.
Review of NDA in 6 months
Activity vs. Benefit
• Biologic Activity--screening of a
compound, phase II trial endpoint, an
indication for further study
• Clinical benefit--what is meaningful to a
patient
• The approval process is not a screening
process for drug activity
Should Oncology Drug
Regulation Be Different?
• Life-threatening nature of diseases--patient
access vs necessary data for approval
• Drugs multiple action modes; combinations
• Risk/benefit ratio--different perspective on
serious adverse events; highly trained
specialists using drugs rather than GP
• Product label and off-label uses
Should Oncology Drug
Regulation Be Different?
• Investigational nature of discipline--Cancer
Centers, Cooperative Groups, NCI
• Wide variety of products used by
oncologists--chemotherapy, biotherapy,
devices, supportive care, diagnostics
• Multidisciplinary approaches
• Represents over 100 diseases/indications
Risks in Developing Oncology
Drugs
• Indication--lack of predictive models
• “Creative Indications”--progressively more
refractory patient, market share
• Two trials versus one trial
• Dose ranging studies--moving away from
MTD
Oncology Trial Concerns
• Minimize bias
– Blinding trials (few)
– Endpoints that minimize bias
– Internal consistency of subgroups, endpoints
• Magnitude of change of endpoint
– Clinical significance
– Underpowered trials--guessing treatment effect
• Isolating effect of drug
Endpoints for traditional
approval: Survival
• Defined as the time from randomization to
death
• Unambiguous endpoint that is not subject to
investigator interpretation or bias from
unblinded studies
• Assessed daily
Traditional Endpoints: Survival
• Drawbacks
– Requires large sample size and long follow-up
– Confounder--Cross-over therapy may “wash
out” a survival effect
Traditional Endpoints: Survival
• Non-inferior or improved survival
constitutes “patient benefit” after
consideration of toxicity and the magnitude
of the benefit
• Non-inferior outcome ensures that a
survival advantage associated with an
approved drug will not be lost with a new
agent
Time to Progression--Advantages
• Could use a smaller sample size and shorter
follow-up than trials that require a survival
endpoint
• Differences will not be obscured by
secondary therapy if cross-over effect exists
• “Time to symptomatic progression”
TTP: Problems
• Unblinded trials introduce bias
• Must evaluate all patients on a regular basis
– Must evaluate all sites of possible disease
– Complete ascertainment of all sites at baseline
and follow-up (i.e., look for new sites)
– Same type of assessment tool at each follow-up
– Should use same evaluation schedule
TTP: Problems
• How much improvement constitutes
benefit?
Response Rate
• Unique endpoint--treatment is “entirely”
responsible for tumor reduction
• In contrast, survival and TTP have an effect
of the natural history PLUS treatment effect
• Must consider duration of response
• Does not include stable disease
• Pick your criteria and stick with it
Complicated Picture of RR
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Number of CRs vs PRs?
Duration of responses?
Location of responses (e.g., liver vs skin)?
Association with symptom improvement?
Extent or bulk of metastatic disease?
Palliation and Patient Reported
Outcomes
• Blinding and associated antitumor effects
(response rates) lend credibility
– Use simple instruments
– Hypothesis-driven
– Avoid multiple endpoints
– Example: Photofrin PDT and dysphagia
scale
Potential palliative endpoint:
Health-related quality of life
• Pro: Patient’s perspective on treatment
• Con:
– Blinding is essential, but difficult to do
– Careful serial assessments
• Missing data makes interpretation problematic
• Multiple endpoints and comparisons to baseline must be
adjusted for in the statistical analysis plan
– Clinical significance of score changes may be unclear
– Is additional information gained, compared to a careful
recording of toxicity/symptom data?
Accelerated Approval- Subpart H
(21CFR 314)
• For serious or life-threatening diseases
• Where the drug appears to provide benefit
over available therapy
• Approval based on a surrogate that is
reasonably likely to predict clinical benefit
21CFR314 (continued)
• Subject to the requirement that the applicant
verify and describe benefit
• Post-marketing studies would usually be
underway
• The applicant shall carry out such studies
with due diligence
Accelerated Approval
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Docetaxel (Taxotere)
Irinotecan (Camptosar)
Doxorubicin HCl liposome (Doxil--2 indications)
Capecitabine (Xeloda)
Cytarabine liposomal injection (Depocyt)
Temozolomide (Temodar)
Amifostine (Ethyol)--sNDA
Celecoxib (Celebrex)
Gemtuzumab (Mylotarg)
Gleevec (imatinib mesylate) (STI 1571)
Issues Related to the AA
Program As a Whole
• The importance of confirmatory trials being
underway at the time of AA
• The approach of studying slightly different
populations in the confirmatory setting than
the AA population
• Relative merits of different trial designs
– single arm in refractory populations
– randomized trials in less refractory patients
Challenges for Oncology Drug
Regulations
• New “targeted therapies”
– Re-define definitions of diseases
– Greater efficacy in selected population may
result in smaller patient populations
– Novel surrogates to be validated
– Dosing aimed at target rather than MTD
– Dose studies, chronic administration
Challenges
• Greater number of candidate drugs
– Careful selection of agents to demonstrate
clinical benefit by oncology community
– Patient accrual to trials need to be increased
– Patients entering trials should reflect the patient
population which will eventually use the drug
– International studies, international agreement of
endpoints and study design and approval
criteria