1. Session 2: Regulation of Genetic Testing- view from FDA OHOP
Gideon Blumenthal, MD
Office of Hematology Oncology Products
Center for Drug Evaluation and Research, US FDA

2. 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?

3. 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
ARUP
PDGFRB
MDS/MPD
PDL1
pembrolizumab
IHC
Dako
ALK
crizotinib
FISH, ALK
Abbott, ventana
KRAS
CRC
cetuximab, panitumumab
BRCA
Ovarian
olaparib
PCR, sanger
Myriad
EGFR protein
C-Kit protein
GIST
HER2
Breast, GEJ
trastuzumab, pertuzumab,
ado-trastuzumab-emtansine
IHC, FISH, CISH
Dako, Ventana, Abbott, biogenex, Life, Leica
BRAF V600
Melanoma
vemurafenib, dabrafenib, trametinib, cobimetinib
Bio-merieux, roche

4. Evolving companion diagnostic paradigm
Single analyte/single gene/single drug multiplex platform/multiple drugs
Tissue only blood + tissue

5. 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. gudance/guidancedocuments/ucm262327

6. 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)

7. Example of pre-post competitive harmonization
Drug
BMS
Merck
GTECH
Medi/AZ
Diagnostic
Dako
Ventana
Cell Type
Tumor
Tumor or Immune Cell
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

8. 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

9. Rare variant information in drug labeling: afatinib for EGFRm mNSCLC- example #1

10. Rare variant information in drug label: ivacaftor for Cystic Fibrosis- example #2

11. Many genes, even more variants
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

12. 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?

13. 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