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CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 1
Successfully Navigating the Regulatory Landscape
with Multi-specific Therapeutics
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY
….helping you navigate the drug development process
Presented to the 6th World Bispecific Antibody Summit
Sept 22, 2014
Kaia Agarwal, President, Regulatory Compass, LLC.
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 2
Agenda
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY
• Regulatory Framework for Multi-specific mAbs
– Focus on Preclinical guidelines and considerations
• Discuss options for formal interactions with FDA and EU/EMA
• Practice with a Case Example
2
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 3CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY
• Regulatory Framework for Multispecific Therapeutics
– Focus on Preclinical guidelines and considerations
• Discuss options for formal interactions with agencies including
FDA and EU
– As early as possible (with some preclinical/maybe prior to GLP)
• Practice what you hear about with a Case Example
3
Guide You To :
Consider and develop plans to address regulations
based on the unique properties of your antibody
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 4
First a little background
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 5
Antibody Development (1/2)
• High interest in monoclonal antibody development– High specificity for their targets
– New opportunities for treatments• Unprecedented potential for cancer treatment
– Improved technology for production
– Well characterized domains & ability to manipulate for increased affinity, PK or safety
– Approx. 47 mAbs have been approved by the US FDA and EMA for various indications up to May 2015*
* As posted on Webpage for “the Antibody Society”, Aug 18, 2015
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 6
Antibody Development (2/2)
• Monoclonal Antibody development is complex for regulators
as well as for sponsors
– Long half life (10-21 days on average)
– Inherent risk to adverse immune-mediated drug reactions
– Often targets have broad tissue distribution (AEs)
– Require specifically designed preclinical studies
– Bispecific antibodies and conjugated antibodies add to complexity
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 7
Benefits of Multispecific Antibodies (1/2)
• Advantages when multiple mediators contribute to a disease
• Single antibodies may have limitations on effect regardless of
dose
• Increase specific response to treatment
– Cancer treatments with multi-specific antibodies may improve target
effect
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 8
Benefits of Multispecific Antibodies (2/2)
• Potentially Enable:
– simultaneous inhibition of several cell surface
receptors
– simultaneous blocking of several ligands
– crosslinking of two receptors
– recruitment of T cells to proximity of tumor cells.
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Schematic of dual- targeting agents
Antibodies 2012, 1, 2-18;
Cross linked mAbs (Ag fork)
chemically coupled
F(ab’)-fragments
2 F(ab’)2 coupled to IgG (HexAb)
tandem bispecific
SC Fragment
variable (bsscFv)
(EI-04): two scFvs
genetically fused to IgG
V region of HC
and LC
of 2 Abs cloned
in frame to an IgG
(CVX-241)
heteromeric
peptide
coupled to IgG
scFvs fused
to Fc-domain
(both termini)2 Ag sites on an
IgG (DVD-IgG)
tandem trispecific sctb
Coupled F(ab’)3-
fragment
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 10
Bispecific T cell engager (BiTE) antibody
• Designed to engage two different targets simultaneously,
– One single chain antibody targets a receptor on the malignant cell
– The other specific for CD3 (to the TCR complex of a T cell)
• Juxtaposing the T cells within reach of the targeted cancer cell
– triggering the cell to die (apoptosis) via cytokines.
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Blincyto (blinatumomab)
• First CD19-directed CD3 T-cell engager (BiTE) antibody
approved by FDA
– Indicated for Philadelphia-negative (Ph-) relapsed/refractory B-
precursor acute lymphoblastic leukemia (ALL) patients.
– Approved Dec 2014, first single-agent bispecific immunotherapy to be
approved by the FDA
• FDA granted Breakthrough Therapy Designation (July 2014)
• Approved five months ahead of schedule
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Regulatory Framework
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 13
Regulatory Framework
• Focusing on Early Development:
– Understand the key regulations/guidelines
– Discuss alternate strategies to address specific issues
• One species, carcinogenicity, reproductive tox
– Especially how the science will drive the data required
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 14
Regulatory Considerations
• Antibody approaches involve complex science and
manufacturing
• Agencies have an interest in developing new
treatment options
– Specific scientific expertise and insight across programs
– Willingness to meet with sponsors as needed
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 15
Regulatory Preclinical Considerations
• Early planning for preclinical work through to FIH
(CTA/IND filing) is critical
– Discuss the science behind any potential issues/hurdles
– Develop plans to address and present data to Agencies
� Avoid regulatory issues later in development
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 16
Regulatory Preclinical “First Principles”
Drugs
• MOA and PK/PD
• Toxicology
• Single dose escalation (NOAEL); Repeat dose and Long term (up to 2 yr.)
• Reproductive, Embryofetal Development, and Carcinogenicity
mAbs
• Species selection - in vitro/ex vivo assessments of binding
• Lack of animal model; consider a surrogate antibody for animal work
• PK/PD with tissue cross reactivity
Multi-Specific
• For combination drugs with two or more MOAs:
• Expect safety and efficacy data for each component individually AND impact of combination
• For multispecific mAbs individual binding sites need to be studied and combination justified
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 17
And it always starts with mice……
Licensed from S. Harris via Cartoonstock.com for presentation
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 18
Preclinical Safety Evaluation
• Prior to Clinical Testing:
– Optimal characterization of preclinical PK-PD relationships
in relevant species
• How much drug is needed
– Feasible dose and route, frequency
• If it works and how will we know?
– Potential Safety liability
• For FIH and future trials
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 19
Key Relevant Preclinical Guidelines for mAbs (1/3)
Guideline Title Agency Year
Adopted
Preclinical Safety and Immunogenicity Testing:
ICH guideline M3 (R2): Nonclinical Safety Studies for the conduct of clinical
trials with pharmaceuticals (Step 4)
EMA/FDA/Japan 2010
ICH Guideline S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived
Pharmaceuticals
EMA/FDA/Japan 2012
Points to Consider in the Manufacture and Testing of Monoclonal Antibody
Products for Human Use
FDA 1997
ICH Guideline S8: Immunotoxicity Studies For Human Pharmaceuticals EMA/FDA/Japan 2006
ICH Guideline S9: Nonclinical Evaluation for Anticancer Pharmaceuticals EMA/FDA/Japan 2010
Guideline on Immunogenicity Assessment of Biotechnology-Derived
Therapeutic proteins
EMA 2007
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 20
Guideline Title Agency Year
Adopted
First in Man Human dosing and Minimum Anticipated Biological Effect Level
(MABEL):
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for
Therapeutics in Adult Healthy Volunteers
FDA/CDER 2005
Guideline on Strategies to identify and Mitigate risks for First in Human
Clinical Trials with Investigational Medicine products
EMA/CHMP 2007
Developmental and Reproductive Toxicity Studies:
Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to
Male Fertility
FDA/EMA/Japan 2000
Carcinogenicity Studies:
ICH Guideline S1A: Guideline on the Need for Carcinogenicity Studies of
Pharmaceuticals
FDA/EMA/Japan 1995
Key Relevant Preclinical Guidelines for mAbs (2/3)
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Guideline Title Agency Year
Adopted
Immunotoxicity Testing:
Immunotoxicology Evaluation of Investigational New drugs FDA 2002
Draft Guidance for Immunotoxicity Testing Japan 2001
Key Relevant Preclinical Guidelines for mAbs (3/3)
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Minimum Prior to a FIH Study
• Single dose studies (dose ranging) [ICH S6]
• Repeat dose studies [ICH S6]
– related to the duration of the FIH trial and onwards
• at least n+1 of FIH trial ; 3 to 6 months expected for longer trials/use
– Include safety pharmacology aspects
• Absorption and distribution studies [ICH S6]
• Immunogenicity studies [ICH 7A]
• Local Tolerance Studies [ICH S6]
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 23
Lets Take a break!
BREAK
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Preclinical Expectations
for Multispecific mAbs
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 25
General Expectations
• Assessment of Exposure
– Pharmacokinetics/Toxicokinetics
• Evaluate exposure, absorption, disposition and clearance
– Clinical Assay development for mAb (best same for animals and
humans)
• Safety Pharmacology
– Assess undesirable functional effects on physiological systems
– Incorporate into the toxicity and later in clinical studies
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 26
• Two species (1 rodent and 1 non rodent)
– Ensures assessment of potential variability, esp. if relevant
species is not identified
– Single Dose Toxicity
– Repeat Dose Toxicity
• Duration appropriate to use of the product
– Studies of 6 months has generally been appropriate; shorter
durations can be scientifically justified
General Toxicology Studies
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 27
• Binding vs Functional Activity (downstream effects)
• Species specificity vs. Surrogate antibodies
– Lack of relevant animal models; Need for surrogates to
homologous animal proteins
– Single species rationale needed
• ICHS6 allows for a case by case assessment for
biopharmaceuticals
Challenges of mAbs
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 28
Immunogenicity
• “Immunogenicity” = anti-antibody responses
– Most Mabs are now humanized to avoid this issue
• But could be changes in structure during production, frequency of dosing or due to the patient disease
– Result in:
• potentially serious side effects,
• alterations in PK parameters (mostly increased clearance)
• loss of efficacy
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 29
• Pharmacologically relevant animal model – mAb binds to the target in that species
– mAb elicits same pharmacological effect as that expected in humans
• For Humanized Mabs this is usually nonhuman primates
– May need different models for the different targets of the Bispecific antibody
Species Selection (1/2)
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Species Selection (2/2)
• in vitro and ex vivo assays to justify and validate the species selection
– Binding study for cross reactivity (tissue) with potency and affinity
– Does species exhibit the disease, receptors etc..
• Receptor occupancy via in vitro testing for dose selection
• Consider long term exposure studies (Carc, Repro)
• Single Species Justification (but don’t decide out of hand)
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 31
Alternate Preclinical Strategies (1/2)
• Consider Alternate Models– Antigen presents differently/not available in usual rodent models
– No relevant animal model, aside from non human primate
• Consider a surrogate antibody i.e. Mouse mAb
– Does not represent the behavior of the clinical candidate mAb
– May be needed for full toxicology profile
• Especially if one of more of the domains of a bispecific have not been
licensed
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 32
Alternate Preclinical Strategies (2/2)
• Can consider transgenic animal models
– When there is no animal model of disease
– Allows use of the clinical candidate in animals
– Inherent Issues:• potential alterations in biology/stability of the molecule
• added resources and time
• limited value to predict what will be observed in humans
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 33
• Adverse immune-mediated drug reactions in humans
• infusion reactions, cytokine storms, immunosuppression and
autoimmunity
• Determine activity in animal species for cell depletion,
suppression, activation, cytokine production, effects on global
immune regulators
• Unexpected antibody dependent cell-mediated cytotoxicity
(ADCC) or complement dependent cytotoxicity (CDC)
Immunotoxicity (1/2)
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Immunotoxicity (2/2)
• Historical Example:
– mAb TGN142 (TeGenero) anti-CD28 humanized mAb
• Severe life threatening systemic inflammatory response in a FIH in 2006
• Wake-up call to industry, clinical trial community, and WW regulatory
agencies
• Reports issued on the causes of the adverse events
– animal testing did not detect the problems; MABEL was not helpful
– Avoid future issues in first-in-human (FIH) studies agencies require
standard in vitro assays run in a biologically relevant manner (per
taskforce recommendations 2007)
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 35
Dose Selection (1/2)
• Preclinical data determines dose selection for FIH study
– No observed adverse effect level (NOAEL) vs.
minimum anticipated biological effect level (MABEL)
• Relates to the pharmacologically active dose
– Should evaluate with both approaches; use the one the data and risk concerns dictate
– Build this into the nonclinical development
• Ensure the maximally feasible dose (MFD) is tested
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 36
Dose Selection (2/2)
• Per FDA guidances:
– Determine NOAEL and MABEL
– Convert to a Human Equivalent Dose (HED) from most
appropriate species
– Apply a safety factor – at least 10 fold to give the
Maximum recommended Starting Dose (MRSD)
– Adjust if needed for the pharmacologically active dose via
MABEL
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 37
Long Term Studies Expected for Phase 2/3
Depending on Indication:
• General repeat dose tox study (usually in dogs 9 mos)
• Development/Reproductive Toxicity (DART)
– 3 segments:
• Seg I - Fertility and early embryonic (effects before mating)
• Seg II - Prenatal and postnatal development (teratogenicity)
• Seg III - Embryofetal development (parturition to weaning)
• Carcinogenicity
– Depends on MOA and justification
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 38
Combination Drug Philosophy
• Guidance applied to the combination or concomitant use of a
drug/biologic/device (defined under 21 CFR 3.2(e))
• Rationale required for each active component
– Agencies understand that the bi-specific domains are not
separate entities
– They expect understanding contributions of each binding
domain• efficacy and safety from both domains
• can be in vitro and/or published data
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 39
Conclusion - Preclinical Approach is a “build”
• Can use standard testing as a means to get general “off target”
toxicology
• Additionally need to run alternates studies to obtain more
specific on target information
OFF TARGET ON TARGET
OVERALL PRECLINICAL PROFILE
gap
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 40
Studies in Mice …
Not the Whole Story!
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 41
FDA Review of Blincyto®
• Binds to CD19+ B cells and cytotoxic T cells expressing CD3 T-
cell for ALL (acute lymphoblastic leukemia)
• Comprehensive Preclinical
- High Unmet Medical Need
• MOA Safety in Animal findings � Human Trial
- Black Box Warning
- Risk Evaluation and Mitigation Strategy (REMS)
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 42
Blinatumomab Core Preclinical
� 2 Repeat dose studies
� IV dosing every day / 4
weeks
� SC dosing BID for 13 weeks
� 2 CNS safety pharmacology
studies
� Preliminary Embryo-fetal study
� No Repro/Dev (known MOA)
� Repeat IV dose
once weekly for 5
weeks
� Cellular Binding
� Cellular activtation
� cytotoxicity
� MOA
� Tissue X reactivity
In Vitro / Ex Vivo Mouse Surrogate Monkey
Expected Efficacy Dose SelectionSurrogate Safety
Specific Safety
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 43
Lets Take a break!
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 44
Regulatory Interactions
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 45
Regulatory Agency Interaction
• Start interaction with Agencies earlier than
IND/CTA
– Meet key agencies – FDA, EU Nationals , EMA SAWP
– Address the molecule specific science with the agencies
and prepare for their requests such as:
• Preclinical development - Both on-target and off-target tox
programs
• Transgenic Mice and Surrogate antibody generation
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 46
Benefits of Early Interactions
• Ensures that you have early agreement for development
– Assures you are on the same page
– Creates an atmosphere of shared development
• Establishes an iterative process to discuss new data
– both internally and externally
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 47
Key Regulatory Filings to Consider
• Orphan Drug Designation (US, EU)
• Fast Track (US)
• Trials with surrogate endpoint - oncology (US and EU)
– “accelerated approval” in US
• Breakthrough Designation (US)
• Priority Review
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 48
FDA Accelerated Development
Nature of Program Fast Track Breakthrough
Qualifying criteria - A drug is intended to treat a serious
condition AND non clinical or clinical
data demonstrate the potential to
address an unmet medical need, OR
- A drug designated as a qualified
infectious disease product
- A drug that teats a serious
condition AND preliminary clinical
evidence indicates that the drug
may demonstrate substantial
improvement on a clinically
significant endpoint(s) over
available therapies
When to submit request - With IND or after
- Ideally no later than pre-BLA
meeting
- With IND or after
- Ideally no later than end of phase 2
Timelines for FDA response Within 60 calendar days of receipt of
request
Within 60 calendar days of receipt of
request
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 49
Meetings with Regulators
• Most regions encourage meetings
– FDA allows meeting with each FDA Division
– EMA has meetings with a Scientific Advice Working Party
– EU Nationals allow non binding scientific advice meetings
– Many agencies encourage meetings (S. Korea, Japan)
• All have set processes
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Briefing Package
• For Any Agency:
– Briefing Document for scientific/medical discussion
– Start with a list of objectives: in what key areas do you need feedback?
– Each Question should be drafted with your position in mind (for FDA there is a small preamble included)
– Background Information needs to be written with the answer in mind to each questions
• It is not a “data dump”
• Each section should have a purpose to make your points clear
• (ie. IB is not suitable substitute)
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 51
What Is Important To A Regulator
• Discuss the general guidance for preclinical work and the
issues with the mAb in development
– Develop rational approaches to each topic
– proposed work around that might work to meet regulatory concerns
• Approach agencies prior to conducting your preclinical
program
– gain scientific input on issues and proposals
• Agencies have insight across platforms and products
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 52
Case Study – Try Being the Regulatory Lead!
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 53
Exercise
• Review the brief summary on the fictitious bispecific product
provided
• Work individually to consider how what we have discussed
today can affect the preclinical program (15’)
• Then work as a table to discuss your collective thoughts and
outline them on the flip chart (20’)
• We will share general thoughts and one key item from each
table (20’)
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 54
Questions to Consider
• What areas would you consider might be of concern for this
type of compound?
• Does this compound meet all expectations
– If not, in what ways will it be a challenge?
– How might those challenges be explained with data?
• What will you suggest/highlight to the team?
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 55
Share Thoughts
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 56
Summary
• Monoclonal Antibodies present unique issues
• There is a mutual desire to be cautious for FIH and beyond
• Focus on Early Development:
– We discussed a general framework of the key guidelines
• Alternate strategies offered by regulators to address specific issues with the type of antibody or disease state
– Especially how the science will drive the data required
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 57
Summary
– Use this framework to provide a perspective for the role of regulatory affairs in your work
• To work with you to resolve issues and opportunities to discuss them with regulators
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 58
Role of Regulatory Affairs
• Whether in your company or as externals:
– Use this framework to provide a perspective for the role of regulatory affairs in your work
– To work with you to resolve issues and opportunities to discuss them with regulators
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 59
Thank you for your attention!
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 60
Back Ups
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Meeting with Regulators – US FDA (cont’d)
• Formal Meetings with Sponsors and Applicants for PDUFA (Prescription Drug User Fee Act) Products (2015)
– Outlines types of meetings available, Type A, B or C
– Timelines for arranging the meeting and submission of a supporting briefing document differ
– To use this guidance one needs to have an IND opened in the US
– Steps include formal meeting request letter, briefing document, meeting and submission of post meeting minutes
– Pre-IND meetings are always T/C; others can be in-person or in writing only
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 62
Types of FDA Meetings
Type A B C
Confirmation of
scheduling
14 days 21 days 21 days
Held no later than 30 days 60 days 75 days
Briefing package due With meeting request 1 month 1 month
Description, Comments Dispute resolution,
Clinical holds,
Special Protocol
Assessment
Post action meeting (+3
months after)
preIND, EOP1, EOP2,
preNDA/BLA,
REMs* or PMRs**
Any other than A or B
Written Response
(WRO) only is an option
now
EOP = end of phase; * Risk Evaluation and Mitigation Strategy
**Post Marketing Requirements
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 63
Meeting with Regulators – EU
• Sponsors may request Scientific Advice from the
European Medicines Agency (EMA)
– All member states are represented at a Scientific Advice
Working Party (SAWP)
– Possible at any time during development or post-
authorisation
– Development or Protocol Advice
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 64
• SAWP publishes a year calendar for all steps for SA
– Option to have a pre-submission meeting to review meeting content before the meeting (add 30 days)
• If no questions from SAWP Panel close of procedure at + 40 days
• If questions arise during review SAWP adds a step taken
– Request or clarifications in writing and/or verbally at SAWP meeting Day +60
– Finalisation of procedure and adoption by CHMP Day +75
• Overall takes approx. 4 months from start to finish
Meeting with Regulators – EU (cont’d)
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Timing for SA Meetings Step TimelineSponsor submits Letter of Intent (no presubmission meeting) ~ D - 30Submit draft SA request (or PA request) ~ D -15Validation questions arrive ~ D -10Submission ~ D - 5Final document submitted by sponsor ~ D - 5SAWP review by coordinators of the SA ~ D +20SAWP 2 Discussion of the reports ~ D +30Review Ends OR Questions of clarification sent to the sponsor ~ D + 40 If Questions then SAWP 3 Discussion meeting with sponsor and preliminary conclusion by coordinators; issues a joint report to the Agency Secretariat ~ D +63CHMP adopts the final advice letter ~ D + 70
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 66
Sample Schedule for SAWP
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Removab (catumaxomab)
• First approved triomab for cancer treatment by the EU in April 2009
• The antibody possesses 2 different antigen binding sites
– one targets the human epithelial cell adhesion molecule (EpCAM)
– The other the human CD3 expressed on T-lymphocytes
• The Fc region binds to the Fcγ-receptor-type I (CD64), -type IIa and type III
(CD16), which are expressed on positive accessory cells
• Indication: “intraperitoneal treatment of malignant ascites in patients with
EpCAM positive carcinomas where standard therapy is not available or no
longer feasible”
CONFIDENTIAL – FOR BUSINESS PURPOSES ONLY 68
Review of Blinocyte FDA Review (cont’d)
– Several in vitro cytotox studies
– No single dose tox study
– Repeat dose study in mice with surrogate mAb• 2 CNS safety pharmacology studies
• IV dosing every day / 4 weeks
• SC dosing BID for 13 weeks – MTD identified
• Embryo-fetal study in mice but no repro and dev tox due to known MOA – Preg cat C – only if Benefits outweigh the risks
– Repeat dose in chimps with blinatumomab• 5 weeks once weekly IV
• Increase in cytokines and infection -- similar to clinical patients
– Studied cross reactivity to normal tissues – negative