1. Session 8: Accelerating the Development and Approval of New Drugs: FDA OHOP perspective
Gideon Blumenthal, MD
Office of Hematology Oncology Products
Center for Drug Evaluation and Research, US FDA

2. Key Questions (from Dr Flaherty, session chair)
Is there a need for centralized infrastructure for diagnostic testing, IRB, or umbrella protocols?
Is cross validation of tumor-based testing or blood-based testing pre-competitive?
What is the threshold of rarity that defines the need for national scale investigation (NCTN or private sector)?

3. FDA Expedited Programs
Breakthrough Therapy
Priority Review
Accelerated Approval
Fast Track
Non-Clinical
Early
Clinical
Registration Trial(s)
NDA/BLA
Submission
APPROVAL
IND
Submission
Dose Exploration / Prelim Activity
SPA
FDA Review
Efficacy and Safety Data
If considering accelerated approval, post-marketing clinical trials should be underway at the time of approval.

4. Breakthrough therapy designation
Inception 2012
Since June 8, 2016: FDA approved 49 breakthrough-designated products, 25 in oncology
~40% of requests across center for drugs have been in oncology
~1/3 granted
Source:

5. Examples of Breakthrough therapies granted and subsequently approved in NSCLC
Ceritinib for crizotinib-refractory ALK+ NSCLC based on expansion cohort in Phase 1
First in human to Accelerated approval 3.25 years
Expeditious resolution of “late” in cycle cGMP issue
<5 month review
Osimertinib in T790M mNSCLC
First in human to accelerated approval ~2.8 years

6. Example of two accelerated approvals based on expansion cohorts in a “phase 1” trial: Keynote-01
Source: AAADV 2015

8. Original Lung-MAP Design
PD-L1 mAb
MEDI4736
Broad Biomarker Profiling: NGS,IHC
Non-Match
Docetaxel
PIK3CA
mut
cdk4/6 CCND1 mut, del, amp
FGFR
mut, amp, fusi
HGF
Met amplific. By IHC
PI3K TKI
GDC-0032
Doce-taxel
CDK4/6 TKI
Palbo-ciclib
Doce-taxel
FGFR
TKI
AZD-4547
Doce-taxel
HGF mAb
Rilotumumab +
erlotinib
Erlotinib
PFS/
PFS/
Interim Analysis (Phase 2 part): IRR PFS; futility/efficacy
Final Analysis (Phase 3 part): Co-primary OS (powered) and PFS

9. Revised Lung MAP after nivolumab approval March 2015 2nd line NSCLC (docetaxel no longer SOC)
Biomarker–Driven
Sub-Studies
Non-match
Sub-Studies
S1400B
PI3K+
S1400C
CCGA+*
S1400D
FGFR+
S1400G
HRRD+*
S1400I
Checkpoint
Naive
S1400F
Checkpoint
Refractory
Single Arm
Phase II
GDC-0032
Palbociclib
AZD4547
PARP
Nivolumab/Ipilimumab
vs. Nivolumab
PD-L1 / CTLA-4 Combination
GDC-0032
vs. TBD
Palbociclib
vs. TBD
AZD4547
vs. TBD
PARP
vs. TBD
Two new sub-studies – S1400G and S1400F – added within 6 months; Additional Sub-studies expected within 6-9 month period
*CCGA = Cell Cycle Gene Alternation, HRRD = Homologous Recombinant Repair Deficiency

10. Real World Evidence for rare indications?
Example MSI-high rare tumor types: gallbladder, endometrial, etc.
Collect ORR/ DoR data of PD1/PDL1 in real world settings?
Leverage existing safety/efficacy data

11. Key Questions (from Dr Flaherty, session chair)
Is there a need for centralized infrastructure for diagnostic testing, IRB, or umbrella protocols?
Is cross validation of tumor-based testing or blood-based testing pre-competitive?
What is the threshold of rarity that defines the need for national scale investigation (NCTN or private sector)?

12. Recommendations
Establish trials of multiple novel agents against a common control
Investment in centralized diagnostic testing platforms, cross-validation to credential multiple drugs, multiple platforms
Investment in federated registries to understand predictive/prognostic implications of rare biomarker subsets, link ‘omics data to clinical outcome data