This video compares the content of the China’s CDE guidance with the U.S. FDA guidance. It will mainly provide an introduction of the similar considerations and differences between the two.

1. Molecular Imaging CRO Network
Comparison of the CDE Guidance and the FDA Guidance
for Antitumor Clinical Trials using Imaging Endpoints
Micron, Inc.
Imaging Service Department
1

2. Molecular Imaging CRO Network 2
Background
Center for Drug Evaluation, NMPA China
Published in Jan. 2021
(Guidance on Antitumor Clinical Trial Imaging
Assessment Process Standards)
U.S. Food and Drug Administration, HHS
Published in Apr. 2018

3. Molecular Imaging CRO Network
Similarities and Differences Between the
CDE Guidance and the FDA Guidance
– Recommended conditions of using an Independent Review Committee
– Key points of designing imaging assessment process
– Image reading process design
with issues
– Choosing the anti-tumor effect
assessment criteria
– Standardized management of FDG-
PET studies
– Analyzing discordance in
assessment results
Both Share Similar Considerations Of:
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The CDE Guidance Explained With More Detailed Examples Of:

4. Molecular Imaging CRO Network 4
1. Recommended Conditions for Using an
Independent Review Committee (IRC)
FDA Guidance CDE Guidance Same?
IRC is
recommended
Open-label clinical trials Single-arm trial, or other trial that cannot be blinded 〇
Some imaging modalities proved vulnerable to site-
specific image quality problems
When there tend to be variation on quality of image data, it is
necessary to conduct image quality control by setting a
centralized IRC.
〇
Trials using specialized imaging measures
The clinical trials using specialized assessment criteria may have
trouble standardizing among multiple sites. For example, special
quantitative measures such as the metaiodobenzylguanidine
(MIBG) scan used in neuroblastoma evaluation or PET study. In
some circumstances the image data may need specialized
software in order to process and evaluate.
〇
A centralized image interpretation may lead to a more
precise estimate of treatment effect.
The randomized controlled trial (RCT) when the estimated value
of treatment effect (the expected result) is near threshold. 〇
IRC is not
necessary
Centralized image interpretation is not always critical,
even for a phase 3 trial primary endpoint that uses some
aspects of quantitative imaging, if the quantitative
measures are widely performed and reported in clinical
medicine, little imaging acquisition or interpretation
variability is anticipated, and potential biases in image
interpretation are controlled by the trial design features.
If the image assessment data are proved to have good consistency
and reproducibility in existing medical practice, assessment by
IRC is not necessary. In phase 3 large-scale RCT, considering the
reproducibility/stability of result data, it is possible to test if the
concordance rate met the requirement by conducting blinded
independent central review of random sample. The test improves
the reliability of the result data.
△

5. Molecular Imaging CRO Network
Usefulness of IRC in quality control of image data acquisition and standardized assessment
Blinded management / image and clinical data provided to IRC
Frequency and timing of assessment
Choice of imaging modality
Standardizing image acquisition and assessment
Difference of trial-specific imaging process standards and medical practice
2. Design Points of the Image Evaluation Process
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6. Molecular Imaging CRO Network
3. Problems with Image Interpretation Design
✕ First a staff member chooses the target lesions, and then three readers conduct assessments
based on the chosen target lesions.
✕ The three readers are in the same room sharing one display. They cannot avoid discussing the
results and affect one another’s assessment.
✕ When an independent review is conducted retrospectively, and the reader is aware of the
assessment results of investigators at sites, including the results of one subject or the entire trial.
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CDE Guidance highly values the independency of the IRC
IRC should be independent from sponsor and investigator at site.
The reader of IRC should be independent from other readers when conducting
assessment.

7. Molecular Imaging CRO Network
4. Choosing Antitumor Response Criteria
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Choosing the Assessment Criteria for a Primary Endpoint
・Characteristic of the disease type and the mechanism of treatment
・Quantitative assessment or semi-quantitative assessment preferred
・Has been validated, is being used worldwide, and is widely
accepted
Lugano
Criteria
RECIST
1.1
mRECIST
for HCC Choi
PCWG3
RANO
Sargent DJ, Rubinstein L, Schwartz L, et al. Validation of novel imaging methodologies for use as cancer
clinical trial end-points. Eur J Cancer. 2009;45(2):290-299. doi:10.1016/j.ejca.2008.10.030
Criteria used for exploratory endpoints:
• Possible to use other not-yet-validated criteria
• Applicable for part of the disease and treatment
...

8. Molecular Imaging CRO Network
5. Standardized Management of FDG-PET Studies
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Quantitative assessment requires
periodic phantom studies.
An example of quantitative assessment:
Antitumor effect assessment based on
standard uptake value (SUV) changes
Regular inspection report is needed
when used as supporting information for
qualitative assessment.
An example of qualitative assessment:
Information on FDG-PET negativity or positivity
can be used as a reference when evaluating the
antitumor effect of RECIST 1.1.
Figure. An example of harmonization for preparation
of assessment based on PERCIST criteria
Tsutsui, Y., Daisaki, H., Akamatsu, G. et al. Multicentre analysis of PET
SUV using vendor-neutral software: the Japanese Harmonization
Technology (J-Hart) study. EJNMMI Res 8, 83 (2018).
https://doi.org/10.1186/s13550-018-0438-9

9. Molecular Imaging CRO Network 9
6. Analyzing Discordance in Assessment Results
Flow chart: An example of image assessment flow
Discordance Between Readers of the IRC
To define tolerance range for overall difference in the imaging
charter.
To analyze the intra and inner rater agreement.
Discordance Between the Clinical Site and the IRC
To compare the overall result of the invention group and control
group based on site and IRC’s assessment, respectively.
Does not require re-assessment only based on result differences.

10. Molecular Imaging CRO Network
Commonalities and Differences Between
the CDE Guidance and the FDA Guidance
10
– Recommended conditions of using independent review committee
– Key points of designing imaging assessment process
– Image reading process design
with issues
– Choosing the antitumor effect
assessment criteria
– Standardized management of FDG-
PET studies
– Analyzing discordance in
assessment results
Both Share Similar Considerations Of:
The CDE Guidance Explained With More Detailed Examples Of: