Transcript Key Questions (from Dr Mansfield, session chair)

Session 2: Regulation of Genetic Testingview from FDA OHOP
Gideon Blumenthal, MD
Office of Hematology Oncology Products
Center for Drug Evaluation and Research, US FDA
Key Questions (from Dr Mansfield, session chair)
• Should FDA be encouraging broad NGS tests or keep focusing on
panels which are limited to known mutations/genes?
• What kind of test should FDA be looking for in terms of actionability
particularly with regard to hematologic cancers? What is the
clinical utility of these tests?
• What should we do about differences between tests that are
supposed to be measuring the same thing? How do we set the
parameters?
• Are there labeling questions that we should be asking (appropriated
labeling of drugs and devices) so that physicians know how to use
them?
Companion Diagnostics (July 2016)
Target
Site
Drugs
Technique
Diagnostic Co
EGFR mutation
NSCLC
erlotinib, afatinib, gefitinib,
osimertinib
RT-PCR
Roche, qiagen
P53
CLL
venetoclax
FISH
abbott
KIT D816V
ASM
imatinib
RT-PCR
ARUP
PDGFRB
MDS/MPD
imatinib
FISH
ARUP
PDL1
NSCLC
pembrolizumab
IHC
Dako
ALK
NSCLC
crizotinib
FISH, ALK
Abbott, ventana
KRAS
CRC
cetuximab, panitumumab
RT-PCR
Roche, qiagen
BRCA
Ovarian
olaparib
PCR, sanger
Myriad
EGFR protein
CRC
cetuximab, panitumumab
IHC
Dako
C-Kit protein
GIST
imatinib
IHC
Dako
Evolving companion diagnostic paradigm
• Single analyte/single gene/single drug
multiplex platform/multiple drugs
• Tissue only blood + tissue
Oncologist, June 2016
“The primary uncertainty is the lack of an approved companion diagnostic to
reliably select patients with tumors that contain the ROS1 alterations… This
uncertainty will be mitigated by a postmarketing commitment… to support the
availability of an in vitro diagnostic device for the detection of ROS1-positive
mNSCLC… Per the guidance for industry, FDA may decide to approve a drug, even
if a companion diagnostic device is not yet approved, when the drug is intended
to treat a serious or life-threatening condition for which no satisfactory alternative
treatment exists and the benefits of the drug are so pronounced as to outweigh
the risks from the lack of an approved device.”
In vitro companion diagnostic guidance for industry and FDA staff. http://www.fda.gov/downloads/medicaldevices/deviceregulationand
gudance/guidancedocuments/ucm262327
Companion diagnostics versus “complementary
diagnostics”
• Companion diagnostic- well established (>22 drug/ co-dx
pairs)
essential for safe and effective use of a drug
• Complementary diagnostic- draft guidance pending
Useful to identify patients more/less likely to derive benefit
from a drug?
PD-L1- nivolumab (NSCLC, melanoma)
PD-L1- atezolizumab (bladder)
6
Example of pre-post competitive harmonization
Drug
BMS
Merck
GTECH
Medi/AZ
Diagnostic
Dako
Dako
Ventana
Ventana
Cell Type
Tumor
Tumor
Tumor or Immune Cell
Tumor
Cut-offs
>1%,>5%
>1%,>50%
IHC 0-3
>25%
clone
28-8
22C3
SP142
SP263
FDA-AACR-ASCO Public Workshop
Complexities in Personalized Medicine:
Harmonizing Companion Diagnostics Across a Class of Targeted Therapies
March 24, 2015, Washington DC
IASLC-AACR-Industry PDL1 cross-validation consortium
Preliminary data from 37 NSCLC specimens presented at AACR 2016
7
FDA Public Workshop on NGS-based Oncology Panels: February 2016
Intended use of NGS-based Oncology Panels
“X is a qualitative IVD that uses high throughput parallel sequencing technology intended to detect
sequence variations using the [instrument name]. The XX is indicated as an aid in characterizing
sequence variations in [xx genes] on [DNA and/or RNA] isolated from [YY] specimens. The device is also
indicated as a CoDx to aid in selecting oncology patients for treatment with the targeted therapies listed
in Table 1 in accordance with approved therapeutic product labeling”
Table 1
Gene
Variant Status
Tissue Type
Targeted Therapies
Results other than those listed in Table 1 are only indicated for use in patients who have
already been considered for all appropriate therapies… safe and effective use has not been
established for selecting therapy using this device for the variants in the associated tissue
types not listed in Table 1. Analytical performance has been established for the variants in
table 2.
Table 2
Gene
Variants
Sample Type
Tissue Type
LoD
Rare variant information in drug labeling:
afatinib for EGFRm mNSCLC- example #1
Rare variant information in drug label: ivacaftor for Cystic
Fibrosis- example #2
A challenge moving forward: PARP inhibitors for DNA repair
defects in mCRPC (as an example)
Many genes, even
more variants
What if spectrum of
genes/variants not
captured in the
pivotal studies?
Mateo J, Carreira S, Sandhu S et al. NEJM Oct 29, 2015
Key Questions
• Should FDA be encouraging broad NGS tests or keep focusing on
panels which are limited to known mutations/genes?
• What kind of test should FDA be looking for in terms of actionability
particularly with regard to hematologic cancers? What is the
clinical utility of these tests?
• What should we do about differences between tests that are
supposed to be measuring the same thing? How do we set the
parameters?
• Are there labeling questions that we should be asking (appropriate
labeling of drugs and devices) so that physicians know how to use
them?
Recommendations
• Concordance across platforms
• Consider tiered levels of evidence to determine
actionability of rare variants in product labeling
• Consider establishing in-house expertise and
external advisors to interpret diverse pipelines of
data (non-clinical, registry, EMR, clinical trial) on
actionability