Download Breakthrough Therapy - OSU CCTS

FDA Tools to Accelerate Clinical
Development of Therapeutics Addressing
Unmet Medical Needs
Amy S. Rosenberg, M.D.
Division Director, Office of Biotechnology Products
CDER, FDA
FDA Regulated Research: Innovation & Compliance
March 3, 2017
The Ohio State University and Nationwide Children’s
Hospital
Disclosure and Disclaimer
Unless specified as FDA Guidance or Regulations, this
speech reflects the views of the author and should
not be construed to represent FDA’s views or
policies. I have no financial relationships to disclose.
2
3
3
No Magic Bullets for Preventing or Curing Complex
Infectious Diseases: Failure to Successfully Address
Latent States
•
•
•
•
HIV
EBV
CMV
Ebola
4
4
No Magic Bullets for Complex Diseases
• Most solid tissue advanced cancers
• Autoimmune Diseases
• Muscular Dystrophies
5
5
Immune Responses that Mediate or
Modulate Human Disease
Neurodegenerative Disease
Eg Alzheimer’s
B cells
Neutrophils
ASHD
ILCs
Muscular dystrophies
Eg DMD
Macrophages
Autoimmune Disease
(Eg Type 1 diabetes)
HSC
T cells
NK cells
Cancer
Checkpoint inhibition; IDO;
neovascularization
Eosinophils
Manipulation of T-Cell Populations
and Functions for Disease Indications
Teff
Checkpoint
Inhibitor
Antagonists
Treg
Cancer
Chronic Infection
Teff
Treg
Checkpoint
Inhibitor
Agonists
Teff
Treg
Autoimmunity
Graft Rejection
7
Advanced Cancer is a Complex Disease and
Not Generally Amenable to Single Targeting
“Magic Bullet” Strategy
• Check point blockade only one therapeutic modality
to address cancer
• Emergence of tumor resistance: loss of expression of
target antigens; alternative survival signaling
pathways
• Microenvironment derived suppressive factors (eg
IDO) and cells (Tregs, MDSC)
• Tumor angiogenesis
• Tissue modifying enzymes that facilitate proliferation
and metastases
8
8
Heterogeneity in Cellullar Content and Expression of PDL1 on
Tumors: Tailoring of Cancer Immunotherapy (Smyth M et al 2015)
Median PFS in melanoma patients treated with Nivolumab and ipilmumab: 14 months among patients with PDL1
expressing tumors
9
Tumor-Expressed IDO Recruits and Activates
MDSCs in a Treg-Dependent Manner (Holmgaard R et al 2015)
Systemic
expansion of
CD11b+Gr1int
myeloid cells
Myeloid cells
MDSCs
Migration
to tumors
Tumor cells
Tregs
CTLs
?
Conversion
to MDSCs in
tumors
PD-L1
INOS
Arg1
Activation
of Tregs
IDO
TGFb
CTLs
TNFa
1. Enhanced tumor growth
2. Resistance to immune checkpoint blockade
10
10
Addressing Remodeling of the Tumor Microenvironment to
Facilitate Tumor Angiogenesis and Metastasis: Blockade of
Matrix Degradation Factors
(Spinelli F et al 2015)
11
From Immunologic Tolerance to Robust Tumor
Immunity
IDO
IDO
inducers?
inhibitors
MMP inhib
CD47 block
Tolerizing
Vaccines
Vaccines
Tregulatory
CART
CARTs?
TILs/CPbloc
Therapeutics
to boost/stabilize
Tregs
Diminish
Reprogram
Inflammation
inflammation
and
Induce
& block
Tolerance
escape
Block
Convert
immune
Teff to
tolerance
Tregs
Checkpoint
Activating
Antibodies for
antibodies
Coinhibitory
Molecules
ESTABLISH
CANCER
TOLERANCE
CURES
Stimulate
Stimulate
Adaptive
Tregulatory
immunity
cells
Eliminate
Destroy
Autoreactive
tumor cells
Cells
Combination
Chemotherapy/
Therapeutics?
Radiotherapy
Virotherapy
12
Challenges
• Improved outcomes in melanoma: cures still relatively rare:
greater longevity of PFS
• Improved efficacy in non-melanoma “sterile” tumors with
lower immunogenicity: how to enhance neoantigen expression,
expression of check point targets: radiotherapy, other
modalities?
• Minimize toxicities: avoidance of global autoimmunity; more
specific targeting of tumor vs healthy tissue
• Combination therapies rather than sequential treatments
– Preclinical verification: efficacy and elucidation of
toxicities
– Dosage considerations
13
13
Manipulation of T-Cell Populations
and Functions for Disease Indications
Teff
Checkpoint
Inhibitor
Antagonists
Treg
Cancer
Chronic Infection
Teff
Treg
Checkpoint
Inhibitor
Agonists
Teff
Treg
Autoimmunity
Graft Rejection
14
Contraction
injury
Initiation and Perpetuation of Innate and Adaptive
Immunity in Dystrophic Muscle
Dystrophin deficient muscle
Leaky membrane DAMPs
muscle Ag
ATP
Innate immune
activation
T cells
Macrophage
Innate
immune
cells
Cytokines &
Chemokines
Th2
B cell
CD4
Adaptive immune
activation
IL-2,IL-4,IL-6
CD4
Th1
Plasma
cells
M2
IL-10, TGF-b
IFN-g
Tregs
APC
M1
TNF-a, IL-6,IL-1
CD8
Muscle remodeling,15degeneration, regeneration, inflammation and fibrosis
15
Dystrophin Replacement Therapy
Should be Highly Effective in DMD
but….
• Preexisting, age correlated, dystrophin immunity in a substantial
percentage of patients: revertant fiber expression of dystrophin at
low levels and in an inflammatory environment that promotes
HLA expression on muscle primes dystrophin responses rather
than tolerizes;
• Dystrophin appears as a neoantigen to DMD patients as the
majority have frame shift mutations leading to nonsense
mediated decay of dystrophin mRNAs and lack of protein
expression;
• Dystrophin expression therapy elicits primary or boosts memory
dystrophin specific immune responses
16
16
Preexisting Immunity to Dystrophin: Relationship to
Revertant Fiber Expression of Dystrophin
17
Oligoclonal T Cell Populations at the Site of Muscle Degeneration in
Duchenne Muscular Dystrophy: Specificity for Dystrophin?
DMD Patients Vb1 Vb2 Vb3 Vb4 Vb5.1 Vb5.2 Vb6 Vb7 Vb8 Vb9 Vb10 Vb11 Vb12 Vb13 Vb14 Vb15 Vb16 Vb17 Vb18 Vb19 Vb20
84
85
86
5
pre-implant
1 mo post
6 mo post
6
pre-implant
1 mo post
6 mo post
8
pre-implant
1 mo post
6 mo post
– +
– +
+ +
–
–
+
–
–
–
–
–
–
–
+
+
–
–
+
–
+
+
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
+
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
+
+
+
+
+
+
–
–
–
–
–
+
+
+
+
–
–
–
+
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
+
–
–
–
–
–
–
–
–
+
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
+
+
+
–
–
–
–
–
–
–
–
–
+
+
–
+
–
–
+
+
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
– +
+ +
+ +
–
+
+
–
–
–
–
–
–
–
–
+
–
–
–
+
+
–
+
+
–
–
–
–
–
–
–
–
–
–
–
–
–
+
–
–
–
+
+
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
aQuantitation of TCR transcripts was accomplished through amplification of a Ca-Ca region as an internal control for variation among samples (28), con-comitantly with a
TCR b-chain transcript, to assess the relative amount of each of 20 known TCR Vb families. Quantity of TCR Vb transcripts was expressed as a percentage of the quanity of
the co-amplified Ca-Ca transcripts. In this table, the symbol + indicates values greater than 5%, and – indicates values <5%.
Gussoni E et al J. Immunol 1994
18
Selection for the RVSG Motif in T cells
Infiltrating Muscle in DMD
Patient #5
Patient #8
Pre-implant
TGC AGT GCC CAG CGT GTG TCT GGA AAC
Pre-implant
TGC AGT GCT AGT AGG GTG TCC GGT GAA
C
S
C
S
C
S
A
Q
R
V
S
G
N
Jb 1.3 (Y)
Myoblast-injected leg 1 mo after transplant
TGC AGT GCC CAG CGT GTG TCT GGA AAC
A
Q
R
V
S
G
N
Q
R
V
S
G
N
Jb 1.3
S
A
G
R
V
S
G
N
Jb 1.3 (Y)
Jb 1.3
TGC AGT GCT AGG AGG GTG TCT GGA AAC
C
S
A
R
R
V
S
G
N
Jb 1.3
C
S
A
S
R
V
S
G
N
Jb 1.3
Myoblast-injected leg 6 mo after transplant
TGC AGT GCT AGC CGA GTA TCT GGA AAC
C
S
C
S
A
S
R
V
S
G
E
Jb 1.4
A
Q
R
V
S
G
T
Jb 1.4
Myoblast-injected leg 6 mo after transplant
TGC AGT GCT CAG AGG GTG TCG GGA ACA
TGC AGT GCA GGG AGG GTC TCT GGA AAC
C
S
Placebo-injected leg 1 mo after transplant
TGC AGT GCT CAG AGG GTG TCG GGA ACA
Placebo-injected leg 1 mo after transplant
TGC AGT GCC CAG CGT GTG TCT GGA AAC
A
C
Patient #6
A
Q
R
V
S
G
T
Jb 1.4
Patient #4
Placebo-injected leg 1 mo after transplant
TGC AGT GCC TTG AGG GTG TCG GGC ATT
C
S
A
L
R
V
S
G
N
Jb 2.1 (Y)
Patient #86
TGC AGT GCT AGT AGG GTT TCT GGA AAC
C
S
A
S
R
V
S
G
N
Jb 1.3 (¶)
Pre-implant
TGC AGT GCT TCT CGG GTC TCT GGA AAC
C
S
A
C
S
A
C
S
A
S
R
V
S
G
N
Jb 1.3 (Y)
Placebo-injected leg 1 mo after transplant
TGC AGT GCT TCT CGG GTC TCT GGA AAC
S
R
V
S
G
N
Jb 1.3
Myoblast-injected leg 6 mo after transplant
TGC AGT GCT AAC AGG GTC TCT GGA ACA
N
R
V
S
G
N
Jb 1.3
aNucleotide and amino acid sequences of the Vb2 T cells expressing the RVSG CDR3 motif. In some samples, clones with an identical nucleotide sequence were found
more than one time. The symbol (Y) designates clones found two times, and (¶) designates clones found five times in the same sample
19
Expression of Dystrophin Revertant Fibers in a Patient
with a deletion in Dystrophin exons 46-51
(Arechavala-Gomeza V et al Neuromuscular Disorders 2010)
Time of Diagnosis
+ 6 years
A
B
C
Dys1
Dys2
Dys3
D
E
F
Ex56-60
a-sarcoglycan
B-dystroglycan
G
H
I
Dys1
Dys2
Dys3
J
K
L
a-sarcoglycan
B-dystroglycan
UTR
20
Conclusions:
• T cells invading the muscle of DMD patients transcribe similar receptors.
• A selective T cell response directed to a specific antigen or antigens is
occurring in DMD muscle.
• The nature of the antigen or antigens that trigger these T cells is unknown:
epitope spread within dystrophin and to other muscle specific proteins?
• Likely specific for an ongoing process in DMD muscle, as no similarities
were found in infiltrating T cells from control samples including fresh
samples from muscle degenerating as a result of other diseases or conditions
Gussoni E et al 1994
21
21
Dystrophin Immunity Present Prior to and Boosted
by Gene Therapy with mini-Dystrophin Cassette
A
B
dystrophin
exon
350
MDP1
IFN-g SFC/106 PBMC
300
250
MDP3
200
p74
150
50
MDP2
55/56
CP
100
Revert
Fibers
MDP1 MDP2 MDP3
p74
CP
Pretreatment
Day 30
59
50
0
Pre-treatment
Day 30 Post
Gene Transfer
70
Mendell JR et al NEJM 2010
22
Evidence of Preexisting Immunity
to Dystrophin: Revertant Fiber Expression Priming
Patient
ID
Treatment
Regimen
Mutationa
12
21
74
39
19
35
11
14
59
Naïve
Prednisone
Naïve
Naïve
Naïve
Prednisone
Naïve
Naïve
Prednisone
Splice exon 12
Del ex 45
Del ex 46-50
Del ex 48-50
Del ex 48-50
Del ex 50
Del ex 49-54
Nonsense ex 59
Nonsense ex 69
Truncating Mutation Location of Immune
(prediction)
Response
+
+
+
+
+
+
+
+
+
Location of Response Relative
T Cell
to Mutation Location
Phenotype
Exons 42-50
Exons 1-9
Exons 42-50
Exons 42-50
Exons 17-26
Exons 50-59
Exons 17-26
Exons 70-79
Exons 59-69
Downstream
Upstream
Upstream
Upstream
Upstream
Downstream
Upstream
Downstream
Uostream
CD4
CD4
CD8
CD4
CD4/CD8
CD4
CD8
CD4
CD4
aDel, deletion; ex, exon. All are truncating mutations that are predicted to result in an interrupted mRNA reading frame.
Flanigan KM et al HUMAN GENE THERAPY 24:797–806 2013
23
23
Age Increases the Probability of Dystrophin
Reactive T cells in DMD Patients
1.0
DMD Steroid Naïve
DMD Deflazacort Prednisone
Estimated Probability
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
10
20
Age (years)
24
30
24
Steroids Diminish Frequency of Immunity to
Dystrophin in DMD
Percentage of Patients with
Positive Immune Responses
100
80
p = 0.0423*
60
40
20
0
11/53
20.8%
9/17
52.9%
DMD
Steroid
Treated
DMD
Steroid
Naïve
25
N = 21
Normal
25
Role of Tregs in DMD: Suppression of
Type 1 Pro-inflammatory Responses
Evidence that Tregs modulate dystrophinopathy through the regulation of the immune
response to injured muscle.
Treg
IL-10
M2 Mac
Fibroblasts
Progenitor
populations
M1 Mac
X
T cells
Danger signals
Dystrophin
deficiency
Contraction-induced
injury
Initial bout of injury
and repair
(acute injury)
Subsequent cycles of
degeneration and regeneration
(chronic injury)
Villalta SA and J. Bluestone STM 2014
Tregs are Elevated in Muscle of Human Subjects
with DMD/BMD
CD3/DAPI
A
FoxP3/DAPI
Overlay
B
C
Control
50 mm
D
E
F
Dystrophic
2.E-05
1.E-05
0.E-05
1.6E-06
1.2.E-06
8.0.E-07
4.0.E-07
0.0.E-00
P <0.01
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
NS
IL-10 Fold Change (AU)
3.E-05
P <0.05
FoxP3+ Cell/mm2
CD3+ Cell/mm2
4.E-05
% FoxP3+ Cells Among CD3+
50 mm
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
P <0.05
Villalta SA et al STM 2014
27
IL-2 Complex Treatments Increase Tregs and Reduce
Muscle Inflammation and Injury in mdx mice
Low-dose IL-2c treatment
preferentially induces Tregs in vivo
Y
anti-IL-2 Ab
recombinant IL-2
Treg
non Tregs
Villalta SA and J Bluestone STM 2014
TLRs
DAMPs
Enzymes
CK
P2X7
ATP
Inflammasome/NF-kB
Rawat et al., Am J Pathol. 2010 Jun;176(6):2891-900. 2010
Uaesoontrachoon et al., J Pathol. 2013 Oct;231(2):199-209
Henriques-Pons et al., Hum Mol Genet. 2014 May 15;23(10):2604-17
Pro-inflammatory
cytokines and
chemokines
Myofiber death
Damage Associated Molecular Patterns:
(DAMPS): Endogenous Ligands of Toll
Like Receptors
Sloane et al., 2010
30
TLR7 is Highly Upregulated in the Muscle Fibers in
Infants and in Symptomatic Patients with DMD
DMD
Healthy
A
B
C
D
Isotype-DMD
CMD
Chen YW et al Neurol.2005
31
Myd88, a Common Adaptor of TLR Signaling
Pathways through NF-kB
Cell Membrane
TRAM TRIF
IRAK
TIR
DD
TIR
DD
MyD88
TLR2
TLR4
Nucleus
Endosome
TRAM TRIF
MyD88
NF-kB
activation
TLR 7/8/9
TLR3
IRF3
Inflammation
32
GRMD Muscle Histology Improved by Oral NFk-B
Antagonist CAT-1041
Hammers DW et al JCI Insight 2016
33
Bridge Between Innate and Adaptive Immunity: NF-kB
Activation by TLR Signaling Induces HLA Class I Expression
on Dystrophic Muscle and Antigen Presentation
A
B
C
D
p65 DMD
p65 Cont
Dystro Def Muscle
E
HLA Class I
DMD
F
HLA Class I
Cont
34
Conclusions
• Optimization of dystrophin replacement therapy requires early treatment to
preclude conditions of immunologic sabotage
• Treatment early in disease course (infancy) prior to symptomatology with
appropriate anti-inflammatory agents may prolong muscle viability and
strength and prolong life
• Inhibition of complement activation and generation of C’ attack complex
may diminish C’ mediated destruction of muscle
• The potential of TGF-b to have antithetical disease stage effects should be
further investigated
• Reduction of the inflammatory response may diminish expression of HLA
class I and II, diminishing presentation of dystrophin peptides to the
immune system.
• Reduction of inflammatory response critical in context of boosting and
enhancing Tregulatory cells and suppression of dystrophin specific
immunity
35
35
Strategies to Preclude Dystrophin Immunity Require
Administration of Replacement Therapy in Optimized
Setting
• Newborn screening for early diagnosis
• Diminish the innate immune response
– Anti-inflammatory therapies:
•
•
•
•
•
Steroids
TLR and/or NFkB antagonists;
Complement attack complex inhibitors: ecalizumab
Inflammatory cytokine antagonists: a-TNF, IL-1?
IVIG for immune modulation and protection against infection
• Preclude or Eliminate Dystrophin Specific Immunity
–
–
–
–
Early treatment
Anti-inflammatory therapies
Tregulatory cell promoting therapies: low dose IL-2; rapamycin, IL-10
Treg cellular therapy: per kidney transplant protocols; in phase 2 studies
36
Requirement for Immune Tolerance Induction in Rare Muscle
Wasting Disease: Robust Immune Response Neutralizes Life
Saving Enzyme Replacement Therapy in Pompe Disease
High Titer CRIM+
Low Titer CRIM+
CRIM–
(Kishnani PS et al 2011)
37
Immune Tolerance Induction to Enzyme Replacement
Therapy: Greatly Improved Survival
1.00
3 on ventilator became ventilator free
CN ERT + ITI*
Ventilator Free Survival
(n=7)
*
0.75
0.50
CN ERT Monotherapy
(n=11)
0.25
0.00
0
Banugaria SG et al PlosOne 2013
5
10
15
Months
20
25
30
High Titer and Sustained Antibody Responses:
Unresponsive to Immune Suppressive Agents
(Banugaria SG et al Genet Med 2013)
High Titer Sustained Antibody Responses are Mediated by
Long Lived Plasma Cells:Unaffected by MTX/Rituximab
CD20
Rituximab
Memory
B cell
Methotrexate
Therapeutic
protein
CD20
BCR
Cytokines
B cell
CD20?
Short
lived
Plasma
cell
Peptide
Antibodies
MHCII
APC
TCR
Helper
T cell
Long
lived
Plasma
cell
Bortezomib
Antibodies
Targeting Long Lived Plasma Cells
with Bortezomib Reduces Antibody Titer in Patients with HSAT
(Banugaria SG et al Genet Med 2013)
FDA Tools to Accelerate Clinical Development
of Products Addressing Unmet Medical Needs
43
43
44
Codevelopment Should Ordinarily be Reserved for Situations
that Meet All of the Following Criteria
•
The combination is intended to treat a serious disease or condition.
•
There is a strong biological rationale for use of the combination
– e.g., the agents inhibit distinct targets in the same molecular pathway or steps in
disease pathogenesis; provide inhibition of both a primary and compensatory
pathway; or inhibit the same target at different binding sites to decrease resistance
or allow use of lower doses to minimize toxicity.
•
A full nonclinical characterization of the activity of both the combination and the
individual new investigational drugs, or a short-term clinical study on an established
biomarker, suggests that the combination may provide a significant therapeutic
advance over available therapy and is superior to the individual agents
–
•
A nonclinical model should demonstrate that the combination has substantial activity and provides greater
activity, a more durable response (e.g., delayed resistance), or a better toxicity profile than the individual
agents.
There is a compelling reason why the new investigational drugs cannot be developed
independently
–
e.g., monotherapy for the disease of interest leads to resistance, one or both of the agents would be
expected to have very limited activity when used as monotherapy.
45
Overview of FDA Expedited Development
Pathways
•
•
•
•
Fast Track
Breakthrough
Accelerated Approval
Priority Review
46
Approval Pathways for Drugs and Biologics
Traditional (Regular)
Approval
Based on:
Improvement in a
direct measure of
clinical benefit: eg
Longer life, better
life, or established
surrogate
Accelerated Approval
Initiated 1992 for HIV:
viral load surrogate
Based on:
Improvement in
surrogate endpoint
reasonably likely to
predict clinical benefit
over available therapy
Requires postmarketing studies to
confirm benefit
Used frequently in
Oncology
47
FDA Tools: Expedited Programs for
Serious Conditions – Drugs and Biologics
Program
Qualifying Criteria:
Serious condition and…
Features
Fast Track
-Nonclinical or clinical data demonstrate
potential to meet an unmet medical need
-Or, QIDP
-Actions to expedite development and review
--E.g., meetings; rolling review
Breakthrough
Therapy
-Preliminary clinical evidence indicates drug
may demonstrate substantial improvement
on a clinical significant endpoint over
available therapies
-All Fast Track features
-Intensive guidance on efficient drug
development
-Organizational commitment
Accelerated
Approval
-Provides meaningful advantage over
available therapies
-demonstrates effect on surrogate or clinical
endpoint that can be measured earlier than
irreversible morbidity or mortality
-Approval based on a surrogate or
intermediate clinical endpoint reasonably
likely to predict clinical benefit
Priority Review
-Would provide a significant improvement in
safety or effectiveness
-Or, other qualifying programs
-Shorter review clock goal for marketing
applications
(6 mo vs 10 mo)
QIDP = qualifying infectious disease product;
48
Guidance for Industry
Expedited Programs for Serious
Conditions – Drugs and
Biologics
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 2014
Procedural
OMB Control No. 0910-0765
Expiration Date: 03/31/2017
See additional PRA statement in section X of this guidance.
49
Available at:
http://www.fda.gov/downloa
ds/Drugs/GuidanceComplian
ceRegulatoryInformation/Gui
dances/UCM358301.pdf
FDA Expedited Programs
Breakthrough
Therapy
Fast Track
NonClinical
Early
Clinical
IND
Submission
Dose
Exploration /
Prelim Activity
Priority
Review
Registration
Trial(s)
SPA
NDA/BLA
Submission
Accelerated
Approval
APPROVAL
FDA Review
Efficacy and
Safety Data
If considering accelerated approval, post-marketing clinical trials should be
underway at the time of approval.
50
Breakthrough Therapy Designation
• Signed into law in 2012
• For serious life threatening disease, a drug,
based on preliminary clinical evidence, has
substantial improvement over available therapy
• Approximately 40% of BT requests across drug
center have been in Oncology
– About a third of these have been granted
51
Examples of Breakthrough Therapies in NSCLC
• Osimertinib in T790M mNSCLC
– First in human to accelerated approval ~2.8 years
– <5 month review
• Nivolumab in 2nd line sq mNSCLC
– 3.5 month review;
• Pembrolizumab in 1st line PDL1 high mNSCLC
52
Breakthrough Therapy: Opportunities and
Challenges
– Opportunities:
• “All Hands on Deck” for Transformative Therapies:
– Aligns and Prioritizes Key FDA review teams (Clinical,
Statistics, Manufacturing, Clinical Pharmacology,
Toxicology, Inspections)
• Optimizes communication between FDA and Sponsor
– Challenges:
• What is the right threshold for granting a BT designation?
• What constitutes available therapy?
• How late is too late? Timing of BT designation request
• Resource saturation for both FDA and Sponsor?
• On what basis should we rescind a BT therapy?
• Manufacturing timelines can be a bottleneck
53
Summary
• Expedited programs such as breakthrough and
accelerated approval increasingly utilized to expedite
access of transformative therapies to patients
• Increased proliferation of novel, adaptive master
protocols, seamless designs
• Consideration of new approaches to response metrics,
companion diagnostics, “real world” data
54
Acknowledgements
• Gideon Blumenthal, Office of Hematology and
Oncology Products
• Steven Kozlowski, Director, Office of
Biotechnology Products
• Janet Woodcock, Director, CDER
55
56