Regulatory Evaluation of
Radiation Therapy
Tumor Imaging and
Evaluation
Gerald Sokol MD, MSc, FCP
CDER/DODP/FDA
USUHS
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This presentation does not
reflect the opinions of the FDA or
any other government
organization
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FDA Campus @ White Oak,
Silver Spring, Maryland
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 The most terrifying words in the English language are:
I'm from the government and I'm here to help."
Ronald Reagan
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Summary
 Regulatory background of drugs and
devices
 Use of surrogate markers
 Why and why not Radiation therapy
devices and protocols should be
reviewed.
 Regulatory experiential pitfalls in the
review process.
 Regulatory Process Admonitions
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Jerry if you keep playing around with drugs,
medical oncology and radiation oncology you
will amount to nothing”
“
Juan Del Regato
1980
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FDA TODAY
21 U.S.C. § 393
***
“(b) MISSION.—The Administration shall—
“(1) promote the public health by promptly and
efficiently reviewing clinical research and
taking appropriate action on the marketing of
regulated products in a timely manner;
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FDA Oncology Drug Approval
 FDA – U.S. Food and Drug Administration

Dept of HHS – Executive Branch
 Created by Congress because of prior unsafe
drugs being marketed
 FDA charged by Congress to evaluate all new
prescription drugs seeking marketing in the
U.S.
 Federal Laws govern these activities
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Drug Development Focal Points FDA Meetings
Phase
Format
Intent (FDA concerns)
Pre-IND / IND T-con, FTF, none
Ph 1 design – FDA safety population and dosing
EOP1
Tcon, FTF
Ph 2 design – FDA safety population and dosing
EOP2
FTF
Ph 3 design – FDA safety, study
design & analysis
Pre-NDA
FTF
(face to face)
Results; format & content of
reports; time frame of submission;
priority?
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Communication is the Key
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Statutory Definitions
DRUG--Articles recognized in the United States
Pharmacopeia, Homeopathic Pharmacopeia of
the United States, or National Formulary,
intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease
in man or other animals, (other than food)
intended to affect the structure or any function
of the body of man or other animals...
21 U.S.C. § 321(g)(1)
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Statutory Definition - New Drug
NEW DRUG -Any drug (except a new animal drug or
an animal feed bearing or containing a new animal
drug) the composition of which is such that such
drug is not generally recognized, among experts
qualified by scientific training and experience to
evaluate the safety and effectiveness of drugs, as
safe and effective for use under the conditions
prescribed, recommended, or suggested in the
labeling thereof...
21 U.S.C. § 201(p)
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Device
 “…an instrument, apparatus, implement, machine, contrivance,,
implant, in vitro reagent, other similar or related article,
including any component, part, or accessory, which isrecognized in the official National Formulary, of the US
Pharmacopeia, or any supplement to them, intended for the use
in the diagnosis of disease or other conditions, or in the cure,
mitigation, treatment, or prevention of disease, in man or other
animals, or intended to affect the structure, function or the body
of man or other animals and which does not achieve its primary
intended purposes through chemical action within or on the
body of man or other animals and which is not dependent upon
being metabolized for the achievement of its primary intended
purposes”
 1998-FFDC Act, Section 201 (321)
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FDA - Oncology Drugs
 Office of Oncology Drug Products – OODP
 Three
FDA - Oncology Drugs divisions
DDOP- Chemotherapy drugs for Cancer
DBOP- Biologic oncology therapies BLAs
DHDP-Hematology
DMIP- Medical Imaging
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The IND Process

FDA determination that:
Human subject exposure to an unreasonable
and significant risk of illness or injury;
 Unqualified clinical investigators;
 Misleading, erroneous, or materially
incomplete investigator brochure;
 Incomplete information to assess the risk to
subjects; or
 Deficient plan or protocol

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Basis for New Drug Approval
 Demonstration of efficacy with acceptable
safety in adequate and well-controlled studies
CFR 314 - NDA Regulations
 Ability to generate product labeling that


Defines an appropriate patient population for
treatment with the drug
Provides adequate information to enable safe and
effective use – prescribing of the drug
 Analogous rules for Biologics - BLA
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FDA Oncology Drug Approval
 LIVE BETTER – Measure QOL - PRO
 LIVE LONGER – Measure Survival (OS)
 SAFER – Controlled study comparison
These are Clinical Benefit Endpoints
 LESS EXPENSIVE

NOT PURVIEW OF FDA
Demonstrate these endpoints
= Full Regular Approval
 Risk / Benefit Assessment (in context of the disease)
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Two Types of Drug Approval:
Regular or Accelerated
Endpoints Supporting Regular Approval
Regular Approval 
Demonstrate Clinical Benefit
Longer life
Better life (relief of tumor-related Sx) - PRO
Requires a valid measure of how a patient
feels or functions
Favorable effect on established surrogate
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Accelerated Approval (AA)
Only applies in the setting of a new drug
for a serious or life-threatening illness:
 Improvement over available therapy
 Study may use a surrogate endpoint,
reasonably likely to predict clinical
benefit
 Requires confirmation of benefit
Fed Register 1992
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Approval and tumor assessment endpoints (8
Regular Approval – RA


If Clinical Benefit shown (live longer, better, safer) - or Benefit on Established surrogate - (DFS, Heme CR)
Accelerated Approval - AA
For Serious or Life Threatening illnesses
 Show meaningful therapeutic benefit over existing therapy or
improved patient response over available therapy
 May be based on a surrogate endpoint which is reasonably likely
to predict clinical benefit - or
 a clinical endpoint other than survival or irreversible morbidity
• Confirmatory Trial commitment is required
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Devices
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510(K)
 Predominant type of submission
 Substantially equivalent to FDA cleared devices
currently on the market
 Traditional, Special and Abbreviated
 Analytical performance
 Might require clinical performance data
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PMA
 First of a kind
 Have to demonstrate safety and effectiveness
 Analytical and clinical performance
 Manufacturing inspection
 Bioresearch monitoring inspections
 Panel track and non-panel track
 Modular, real-time, expedited etc.
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Regulation of Radiotherapy Devices
Why radiotherapy trials and devices should be regulated
• In a way radiation is similar to a drug
• We must prove safety and efficacy with evidence based
methodology relative to a given treatment and to alternative
treatments
• We must define acute, subacute, and chronic toxicity and determine
ways to mitigate them (labeling as for a drug)
• Need to define how radiation interacts with other drugs, and
physiological processes over the appropriate time period
• Need to define the economic and cost benefits of new technology
(not the purview of the FDA)
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Evaluation of a Radiotherapy
Device
• Physics (beam quality, reliability, software, dose
distribution, scatter, neutron contamination, penumbra,
etc.)
• Patient interface-safety (table weight, immobilization,
emergency shut-offs, efficiency, accessibility, etc)
• For particle beams relevant pre-clinical radiobiology
likely to reflect biological effect.
• Follow-up for acute, subacute and long term toxicity
• Ultimately the safety and efficacy of combinations of
radiation, drugs or radiation of different biological
effectiveness, fractionation or geometric distribution.
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Why radiotherapy
device regulation is
difficult
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Evaluation of Radiotherapy Device
Trials-Issues
 Frequent incomparability of animal data
 Discerning the variable effects of fractionation, dose,
timing, breaks, field size, beam energy, device-cobalt vs
linac.
 Differing radiotherapy practice (which nodes, big pelvic
fields vs. little, CRT vs IMRT, beam energy effect
 Patient variation (previous rx, m/f, fat vs thin, old vs.
young, co-morbidities) etc
 Drug/drug interactions-protection, sensitization, barrier
disruption (BBB), biologics, cytotoxics, timing,
sequencing etc.
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Drugs vs Devices
Drug
 Specific indication-dose,
side effects
 Defined drug/drug
interactions
 Clear cut warning and
precautions
 Pharmacogenics
developing (personalized
medicine)
 Effect and side effects
are generally acute
 Organ effects well
described and reversible
Device
 No specific indications
 No specific dose
 Side effects dependent on
dose/fractionation
schema/site treated
 XRT/drug interactions less
well defined (drug effects
xrt-xrt effects drug
disposition)
 “Radiogenetics” in its
infancy
 Effects and side effects are
acute, subacute and chronic
 Organ effects evolve over
time
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Targeted Agents vs. Cytoxics
 The MTD may not be the optimal therapeutic dose
 Cytostatic vs. cytotoxic-may require life-time Rx
 Less toxic
 Unique endpoints required for targeted agents
 May require PD endpoints in pre-clinical and phase I studies
rather than response Epts
 May have more limited or heterogeneous molecular basis of
activity
 The mechanism of action may not effect the tumor as much
as the stroma or parenchyma.
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Targeted therapies vs. cytoxic
drugs
 Different toxicity profiles
 Chronic treatment
 Early use in combination
 Different benefits
 Blinding of trials, use of placebo
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To Target or Not
 Validated testing to define the target
population
 Treatment effect will be greater reducing
sample size
 Target population will be defined in
product label: “redfine disease” form
histopathological to molecular criteria
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To Target or Not
 May exclude patients who would benefit
due to an unrecognized mechanism of
action (such as BCR-abl, vs c-kit vs
PDGFR
 Targeting may limit the potential market
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Imaging
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Estimated Risks of Radiation-Induced Fatal Cancer from Pediatric CT:
David J Brenner, Carl Elliston, Eric Hall, and Walter E Berdon. American Journal of
Roentgenology AJR 2001; 176:289 – 296.
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and ITART
some
radiation
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exposure
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Chest x-ray
0.02 mSv (E) ~ 2.4 days of natural environmental radiation
1 in 1,000,000 risk of lifetime cancer mortality
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Ultrasound Imaging (US)
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Computed Tomography (CT)
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A new generation of dual scanners image a patient using a CT and nuclear
medicine scanner (either a PET scanner, or SPECT camera). These allow fused
images. Pictured is a dedicated CT/SPECT scanner.
PET = Positron emission tomography
SPECT = Single photon emission computed tomography
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The resulting fused image provides very accurate anatomical and
functional information.
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Magnetic Resonance Imaging (MRI) scanner.
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Nuclear medicine, where the radioactively labeled drug is detected and imaged
is playing a new role in molecular imaging and drug discovery. Nuclear
medicine includes conventional radionuclides such as technetium-99m and
iodine-131 and positron emitters such as carbon-11, oxygen-15 and fluorine18.
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Imaging Modalities for Tumor
Delineation and Response
 PET
 FLT
 Targeted Nanoparticles
 Optical Imaging
 Contrast enhancement
 MRI spectroscopy
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Why is imaging so important? (1)
 Monitoring an imaging metric, a biomarker, a surrogate
endpoint, may shorten the time necessary to conduct a
clinical trial.
 An early change in this imaging metric may provide
valuable information for patient management, e.g. FDG –
PET in days/weeks vs CT in months.
 Observing biomarkers may be more efficient than clinical
endpoints.
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Clinical endpoint*
Overall survival,
Symptom endpoints (patient defined),
Disease-Free Survival,
Objective Response Rate,
Complete response,
Progression-Free Survival,
Time to Progression
*Clinical Trial Endpoints for the Approval of Cancer Drugs and
Biologics (May 2007)
http://www.fda.gov/CBER/gdlns/clintrialend.htm
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Why is imaging so important?
(2)
 In clinical trials a change, statistically significant, in an image over
time can demonstrate efficacy, e.g. tumor size, tumor metabolism,
or vessel diameter. If these changes have been correlated with
true clinical endpoints!
 For radiation therapy, both efficacy and safety depend on the
accurate determination of radiation dose (energy/target mass), and
imaging is essential for the denominator. Radiotherapeutics such
as Bexxar®, Zevalin®, Y-90 microspheres, currently lack the level
of precision and accuracy associated with traditional external
beam and brachytherapy sources.
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Why are we here?
Imaging has been recognized as a potential tool
for drug development!
FDA’s Critical Path Initiative (2004)
Go to: www.fda.gov
Search on: The Critical Path
Imaging is not only a research tool when used
to monitor change in drug development, it is
essential for safety and efficacy as well.
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What will I discuss?
1. FDA wants good science in clinical trials!
2. FDA Rules
Regulations
Guidance
3. Other Activities (DIA, NCI, RSNA)
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Imaging Checklist (1a)
Select the imaging task and modality first, detection
or measurement.
Ho = There is no cancer observed
(detection
task),
Ho = There is no significant difference
(measurement task).
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Imaging Checklist (1b)
Detection involves multiple observers
(readers) and use of Receiver Operating
Characteristic (ROC) curves, (plots of
sensitivity vs specificity),
Measurement involves monitoring change
over time, with quality control essential.
Talk to a medical physicist!
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Imaging Checklist (2)
Train the qualified readers,
prospectively!
Use standard images to “calibrate”
readers, either physically together, or
with a detailed protocol. This should
minimize adjudication.
This protocol should specify data
collection, viewing conditions, image
scoring and other criteria.
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Imaging Checklist (4)
Technical Issues-Phantom
Select phantom that will be used to test
equipment relevant to the clinical metrics
being used.
Many phantoms exist, new ones always being
developed, a phantom can be designed for a
given trial and mass produced. (Make sure
phantoms are also tested and validated
collectively.)
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Imaging Checklist (5)
Technical Issues- Drug
Imaging metric requires knowledge of drug amount.
How can you assure that the drug quantity is accurate?
This is highly critical for SUV*studies and trials where
the patient is monitored over time. NIST** traceability
would add value and credibility to the trial.
* Standard uptake value
** National Institute of Standards and Technology
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Imaging Checklist (6)
Technical Issues
The Patient-Phantom Relationship
Quantitative Imaging is not only dependent on the
(1) imaging equipment, but on the
(2) quantity of the drug, (3) within the patient.
Phantoms provide a surrogate for the patient for standardization, but
anthropometric measurements need to be identified and made for each
patient.
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A few examples of phantoms:
Micro CT phantoms
Water- Calibration of Hounsfield Unit (HU)
Wire
Low contrast
High contrast
Fluoroscopy Dose phantom
CT Dose phantom
Mammography Phantom
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Phantoms are an essential quality
control (QC) Tool
Monitoring change in imaging equipment
performance is done with phantoms
because humans are neither standard
nor always available.
And its unethical to use humans for
repeated imaging.
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Variability in radiologist drawn boundaries
 Differences in reader’s criteria and display
settings will influence volume estimate
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History of Imaging Criteria
World Health Organization (1970’s)
Response Evaluation Criteria in Solid
Tumors – RECIST (2000)
3-dimensional volumetric analysis (current)
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Anatomy in 2D
8 Weeks
Baseline
WHO: Bi-linear Measurement (1970’s)
RECIST: Linear Measurement (2000)
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RECIST vs. Volumetrics
baseline
Volume = 886 mm3
Diameter = 17.7 mm
30 days
Diameter = 17.1 mm
Volume = 525 mm3
Percentage Change in the measurement
0
-10
% Change
-3%
-20
-30
-40
Bensheng Zhao, MSKCC
- 40 %
-50
1
RECIST
2
Volume
Measurement technique
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BONE
STD
Three different
reconstruction
algorithms
LUNG
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FDA Rules- Regulations
Center for Drug Evaluation and Research (CDER)
21 CFR* 312 Investigational New Drugs
21 CFR 314 New Drug Applications
21 CFR 315 Diagnostic Radiopharmaceuticals
21 CFR 361.1 Radioactive Drug Research
Committee
* Code of Federal Regulations
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FDA Rules- Imaging Guidance
(CDER)
Developing Medical Imaging Drug and Biological Products
Part 1: Conducting Safety Assessments (July 2004)
Developing Medical Imaging Drug and Biological Products Part 2: Clinical Indications
(July 2004)
Developing Medical Imaging Drug and Biological Products
Part 3: Design, Analysis, and Interpretation of Clinical Studies (July 2004)
Guidance for Industry, Investigators, and Reviewers
Exploratory IND Studies (January 2006)
Search on www.fda.gov
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FDA Rules- Regulations
Center for Biologic Evaluation and Research (CBER)
21 CFR 601 Biological Products, Licensing (BLA*)
21 CFR 601.3 (Biologics) Diagnostic Radiopharmaceuticals
Center for Devices and Radiological Health (CDRH)
21 CFR 800 Medical Devices (PMA)**
21 CFR 900 Mammography
21 CFR 1000 Radiological Health (Electronic Products)
* Biologics Licensing Application
**Premarket Approval
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FDA Rules- Medical Device and
Combination Product Information
In addition to drugs and biologics, medical devices have
there own set of rules and regulations.
Useful medical device information is available at:
http://www.fda.gov/cdrh/devadvice/
…and medical products that are combination products must
be registered with the Office of Combination Products. Their
website is http://www.fda.gov/oc/combination/faqs.html.
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Combination Products
 Radionuclide
 Immunotherapeutic
 Pharmaceutical
 Imaging agent
 Kit-packaging
 E.G; Zevalin, Bexar (radiolabeled CD20
Antibodies)
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Combination products
 PK/PD
 Radiation dosimetry
 Toxicology
 CMC (Stability, contaminants, etc)
 Imaging properties
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Combination Products
 Oncology
 Biologics
 Imaging
 CDRH
 Clin pharm
 Complex interactive product with a
“chosen lead division”
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Other Activities
Many other stakeholders and partners!
…such as, but not limited to, the
American Association of Physicists in Medicine (AAPM),
American College of Radiology (ACR),
Society of Nuclear Medicine (SNM), Radiological Society of
North America (RSNA), American Institute of Ultrasound in
Medicine (AIUM)…..
Too many overlapping, competing, uncoordinated efforts.
No single imaging modality is superior for all tasks, some
societies associate with one modality.
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Imaging Review Charters
Comprehensive checklist for use by clinical
research organizations (CRO’s)
Currently it is neither a regulation nor an FDA
guidance, although FDA supports this initiative.
http://www.diahome.org/DIAHOME/Education/F
indEducationalOffering.aspx?productID=14416
&eventType=Meeting
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National Institute of Standards
and Technology (NIST)
Imaging as a Biomarker: Standards for Change
Measurements in Therapy Workshop Summary
(September, 2006)
http://www.mel.nist.gov/msidlibrary/doc/NISTIR_74
34.pdf
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RECIST- Response Evaluation
Criteria in Solid Tumors
2000 guideline, replaced older WHO
criteria.
Widely criticized, but pioneering effort,
needs to be improved.
http://ctep.cancer.gov/guidelines/recist.html
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LIDC
 Lung Image Database Consortium
Focus is on CAD (Computer assisted
diagnosis)
 http://imaging.cancer.gov/programsandr
esources/InformationSystems/LIDC
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ACRIN
American College of Radiology Imaging
Network
http://www.acrin.org/
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IRAT
 Imaging Response Assessment Team

Nine funded imaging centers required to discuss
experiences periodically (monthly).

Subject to funding constraints.
http://www.aaci-cancer.org/irats/about_project.asp
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The Issue *******
 An imaging response must correlate with
a meaningful improvement in QOL, PFS,
Overall Survival i.e a meaningful
biological benefit
 Complete response may have superior
correlation to benefit than a partial
response-no matter how accurately
response is measured
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Drug evaluation admonitions
 Now is now, then was then
 Eminence is not evidence
 100,000 Frenchmen can’t be wrong
 For every ying theres a yang
 Mechanisms of action are not always
what they seem
 Law of unintended conseuences is at
play
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Regulatory Admonitions cont.
 Too much data may obuscate the issues
 Statistical significance does not mean
clinical significance
 PR, and even progression free survival
may or may not have clinical significance
 Bridge over the River Kwai effectinvestigators are enamored with their
work
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Regulatory admonitions cont
 Regulatory science is an evolving
practice and must grow with the
multitude of new agents and devices.
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Chaos, panic, & disorder-- my work here is done.
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