Strategies and CMC Issues for the Development and

Strategies and CMC Issues for the
Development and Licensure of
Breakthrough Protein Products
Emily Shacter, Ph.D.
Independent Consultant
LLC
2014 CASSS Strategy Forum on
Accelerated Product Development
Jan. 27, 2014
2
Topics
 What does Breakthrough Designation get you?
 Common and predictable CMC issues associated
with development of breakthrough protein products
 What does Breakthrough Designation NOT get you?
 Strategies for managing the potholes
 Regulatory risk
 FDASIA versus PDUFA V
FDA Safety and Innovation Act
of 2012 (FDASIA)
• Section 902 –Breakthrough Therapy Drugs
– Expedite the development and review of a drug for
serious or life-threatening disease or condition and
preliminary clinical evidence indicates that the drug
may demonstrate substantial improvement over
existing therapies
• Section 901– Fast Track Drug Products
– Facilitate development and expedite the review of drugs
for the treatment of a serious or life-threatening disease
or condition that demonstrates the potential to address
unmet medical need
3
4
Acceleration of Development and Review
• Fast Track speeds up the review process
• Priority Review shortens it
• Accelerated Approval makes the process
start earlier
• Breakthrough increases communication with
FDA during development
5
Breakthrough Therapy Designation
Provides for:
• Intensive guidance to promote efficient drug
development during IND, beginning as early as
Phase 1

Frequent communications with FDA

Much less waiting to get answers to critical questions
• Organizational commitment involving senior
managers
6
Timelines for product development
(not exactly to scale)
Pre-IND Mtg
IND Phase I, II, III clinical trials
EOP2
mtg
BT
Drug
Candidate
Research
(in vitro)
Proof of
Concept
(animal
models)
Safety
Tox, dose
(acute,
chronic)
Early
human
safety, PK,
PD trials
Human
dose
finding/
efficacy
Larger safety &
efficacy (S&E)
trials (years)
Molecular analysis of product, assay development & validation
Process development & characterization; Scale up
Commercial manufacturing process; PPQ
Collect stability data
BLA
S&E trials
to expand
clinical
indications
7
Plan ahead!
8
Common & Predictable CMC issues for
Breakthrough Products
• Manufacturing

Scale-up, optimization, characterization,
Validation
• Stage of analytical development
• Stability data & expiration dating
• Elevated role of comparability data
 Earlier
in development
9
Common & Predictable CMC issues for
Breakthrough Products:
Manufacturing experience likely less than
for standard product development
 Less
time to scale up & optimize
manufacturing process
 Less
extensive knowledge of how
process impacts product
 Challenge
for Process Performance
Qualification requirements and timing
Clinical Experience with Proposed
Commercial Product?
Clinical trial experience with lots &
manufacturing process comparable
to commercial process?
– Supports determination of safety
& efficacy of commercial product
 Yes

Probably rare for a breakthrough product
– Need excellent comparability data
with suitable analytical methods
 No

Build bridges between processes, lots, methods
10
Common & Predictable CMC issues for
Breakthrough Products
11
Accelerated analytical method development

Methods used earlier in development typically
not yet optimized or validated


But suitable for intended purpose?
Must be validated for process performance
qualification and specifications

Less time for optimization & validation

Bridge between results from earlier vs later methods
12
Common & Predictable CMC issues for
Breakthrough Products:
Accelerated method development


Identify CQA’s as early in development as
possible

Understanding of structure-function relationships
dependent on quality & relevance of assays

Process control dependent on understanding of
product
Elevated importance of assays to predict
potency, biodistribution, & safety
13
Common & Predictable CMC issues for
Breakthrough Products:
Accelerated method development

Fewer lots for determining Specifications

Results using earlier methods relevant for setting
specifications? Leverage earlier data?
Need to identify stability-indicating
assays earlier


Collect appropriate stability data to:

Understand product decay

Set shelf life
Use stress and forced-degradation studies
14
Common & Predictable CMC issues for
Breakthrough Products:
Accelerated method development

Implementation of non-critical assays can
deferred to post-licensure

e.g., a process-specific assay for host cell
proteins

Demonstrate that attribute otherwise
adequately controlled
15
What Breakthrough Designation
will NOT get you
• A longer shelf-life than justified by the
stability data
• Same principles and requirements for setting
initial shelf life prevail (Q1E and Q5C)

Less extensive stability data will shorten
approved shelf-life

Leverage ability to submit a simple stability
update during BLA review (up to 4 mo into 6 mo
clock) to enhance shelf-life determination
16
Breakthrough CMC Issues:
Stability Data & Expiration Dating
• Need real time data on commercial product
to set shelf life, but
• Support with data from all clinical lots
• Demonstrate comparability between earlier
lots & commercial product
• Ideally use same container closure system

Enhances ability to extrapolate stability data from
supporting lots to proposed commercial lots
• Use stability protocol to extend expiration
dating post-licensure
17
Elevated Role of Comparability
For many reasons, need to leverage data from lots manufactured
earlier in development
• Can’t be done without strong comparability data

No set number of lots required

May not have many lots available
• Accelerate analytical method development as much as possible 
resolution and sensitivity to make comparability determination
• Use extended characterization studies on a routine basis
• Put together a strong data package

Compelling data can’t be ignored, even by the most risk-averse reviewer
18
Breakthrough Therapy Designation:
Not Easy to Get
CDER values - Oct 1, 2012 – Jan 3, 2014
Total Requests Granted
Received
119
35
Denied
Approved
58
3
(1 protein, 2 chemical drugs)
http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significa
ntamendmentstothefdcact/fdasia/ucm341027.htm
19
Regulation of Breakthrough (BT) Therapies:
The FDA Reviewers
Reviewers doing triple backwards
somersaults to facilitate development of
BT products

Holding many extra meetings with Sponsors
to provide timely feedback

Seeking to apply flexibility whenever possible

Decisions for licensure will combine clinical
and CMC reviewer perspectives
20
Regulation of Breakthrough Therapies:
The FDA Reviewers
• Biggest reviewer fear is that a
Sponsor will think that anything goes
– It won’t!
 Quality
still needs to be ensured
• Only make legitimate & scientifically
justified requests for post-marketing
commitments
21
What Breakthrough Designation
will NOT get you
You still need to have:

Demonstrated control over the process and
product

Consistency of commercial manufacture

Sufficient product & process characterization to
control critical quality attributes

Justifiable specifications

Adequate stability data to ensure quality of product
on the market

Sterile product free of adventitious agents
Same Ole’ Requirements for Manufacture and
Control of Breakthrough Protein Products
Alphabet Soup!
GMP
22
23
Regulation of Breakthrough Therapies:
Making Products Available
Lot release could be a work-around when
there is insufficient manufacturing
experience to understand impact of
process on product
24
Development of Breakthrough (BT)
Therapy: Regulatory Risk
• Unlike a me-too drug  Special treatment

Shifts the risk-benefit equation

Increased tolerance for risk

Not unlimited!
• Extent of clinical benefit influences level of flexibility
• Clinical data need to be strong to get BT status in
the 1st place
• Must continue to show exceptional benefit to be
licensed with > average regulatory risk
Bottom line: Apply common sense and good science to
meet an unmet medical need
25
FDASIA versus PDUFA V
• PDUFA V

Sets tighter rules for BLA submissions

Extends the review clock (2 mo)
 Delay of BLA approval and marketing of drug
• FDASIA

Emphasizes importance of expediting availability of
important new medicines to patients in need
FDA balances need for rules vs need for speed
26
Need for Speed vs Need for Rules
versus
FDASIA
PDUFA V
27
Breakthrough Therapy Designation:
Communications
• Transparency!

In both directions
• Don’t be afraid to ask & tell
 Better
to learn FDA’s positions sooner
than later
 Increased
likelihood of successful BLA
28
Summary of breakthrough & other
manufacturing issues compiled by
IPQ
(International Pharmaceutical Quality)
http://www.ipqpubs.com
29
Special thanks to:
My former co-workers in the
Office of Biotechnology Products
[Emanuela Lacana]
&
My Clients
[email protected]
Takoma Park, MD

Download Report