08 emerging issues
TRANSCRIPT
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Emerging Issues
Srinivasan N Kellathur, Ph.D
Senior Regulatory Specialist
Pharmaceuticals & Biologics Branch
Therapeutics Products Division
Health Products Regulation Group
Health Sciences Authority
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Emerging Issues
Biosimilars
Human Cell- and Tissue-based Therapeutic (CTT)
Products
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Biosimilars
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Biosimilars
Introduction
Definition Basic principles of biosmilars
Choice of reference product
Submission procedure
Quality documentation requirements Non-clinical documentation requirements
Clinical documentation requirements
Interchangeability & substitutability
Pharmacovigilance requirements
Post-approval batch release requirements
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Introduction
Guideline on Registration & Regulation of Biosimilar Productsin Singapore
Impending submission of biosimilar products
Facilitate access of such products at a more affordable price inSingapore
Proposed guideline would be closely referenced to the EMEAguidelines with consideration of Singapores local regulatoryenvironment
To be published 1Q 2009
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Definition
A similar biological (biosimilar) product is a biological medicinalproduct referring to an existing registered product and submitted
for medicinal product registration by an independent applicant afterthe time of protection of the data has expired for the originalproduct
A biosimilar product would have an abbreviated non-clinical andclinical development programme leveraging on the existinginformation of the original product and focusing on demonstrationof similarity with the original product.
A variety of terms have been used for similar biological products EU: Biosimilar products
US: Follow-on protein products
Canada: Subsequent entry biologicals (SEBs)
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Basic Principles of Biosimilar
Product
A new biological product claiming to be similar to areference medicinal product
Standard generic approach (demonstration ofbioequivalence) is scientifically not appropriate
Biosimilar product approach will have to be based oncomparability (demonstration of similarity)
More likely to be applied to highly purified product, which
can be thoroughly characterised (e.g. proteins)
Product such as vaccines, blood or plasma-derived products,gene or cell therapy products are not acceptable
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Choice of Reference Product
Must be a medicinal product registered in Singapore
A biosimilar product cannot be used as a reference product
Same reference product should be used throughout thecomparability for quality, safety and efficacy
Should be of the corresponding strength and from the Singaporeregistered drug product manufacturing source
Active substance must be similar, in molecular and biological
terms, to the reference product
Pharmaceutical form, strength, and route of administration shouldbe the same as that of the reference product
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Submission Procedure
The biosimilar product should be evaluated and approved byat least one of HSAs reference agencies namely Australia
TGA, Health Canada, EMEA and US FDA
If not, the application is to be submitted with the completedataset as required for a new biological product
Application to be submitted as a new drug application (NDA)via the abridged dossier evaluation route
Timelines and fees applicable for an NDA application via theabridged evaluation route would apply
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Quality Documentation
Requirements
Complete quality dossier (CTD Module 3) as required for allbiological products
Comparability data between the biosimilar product andreference product must be submitted as a separate sectionin the dossier
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Non-Clinical Documentary
Requirements
Non-clinical studies to be submitted
Studies should be comparative in nature and should bedesigned to detect differences in response between thebiosimilar product and the reference product
In vitro studies (assays like receptor-binding studies or cell-based assays), animal PD studies, and at least 1 repeat dosetoxicity study should be performed
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Clinical Documentary
Requirements
PK & PD studies
Comparative clinical studies
In certain cases, comparative PK/PD studies may be sufficient
Conditions of use should fall within the directions for useincluding indication(s), dosing regimen(s) and patientgroup(s) for the Singapore reference product
If the reference product has more than one indication,efficacy and safety has to be justified for each
In certain cases, may be possible to extrapolate therapeuticsimilarity shown in one indication to other indications of the
reference product
Immunogenicity must be studied
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Interchangeability &
Substitutability
A product is interchangeable with another if both productsare approved for the same indication, and can be used for
the said indication
Two products are substitutable with each other if they canboth be used in lieu of the other during the same treatment
period
A finding that a biosimilar product may be approved as safeand effective, is distinct from a determination that the
biosimilar product would be substitutable for the referenceproduct
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For many biosimilar products, in particularly the morecomplex proteins, there is a significant potential for repeated
switches between products to have a negative impact onsafety and/or effectiveness
To establish that two products would be substitutable, the
applicant of a biosimilar product would need additionalclinical data
A statement is to be included in the PI of the biosimilar
product stating that the product is not substitutable withother products containing the same active ingredient
Interchangeability &
Substitutability
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Pharmacovigilance Requirements
In view of the potential for giving rise to differences inefficacy and adverse events such as triggering of patients
immune responses leading to serious consequences,biosimilar products are viewed as potentially higher riskdrugs with different safety concerns
Current systems of detecting safety issues are still applicableto biosimilar products
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Pharmacovigilance Requirements
Following activities proposed in addition to current PVactivities:
Risk management plan at point of submission
ADR reporting of serious & non-serious ADRs (within 15 days)
Submission of global PSURs
Provision of product sales data
Provision of educational materials to physicians
Record keeping of patients to ensure traceability or in case ofproduct recall
PILs for patients
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Post Approval Batch Release
Requirements
Propose that a risk-based post-approval batch releaseprogramme be implemented for all biosimilar products
PLH to submit batch quality documents prior to import andsale of each batch of biosimilar product for evaluation
HSA may also choose to carry out independent batch testingof selected batches
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Human Cell- andTissue-based Therapeutic
(CTT) Products
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Outline
Introduction
Current regulatory controls
Proposed regulatory control
Summary
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Glossary of Terms
Autologous - Cells or tissue removed from and transplantedback into the same person
Allogeneic - Cells or tissue transplanted from one person toanother
Homologous Cells or tissue that perform the same basicfunction that it fulfills in its native state or in the donor
Non-homologous - Cells or tissue that perform other thanthe normal function in a location of the body where suchfunctional purpose does not normally occur
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Tissue Engineering
Cell and Tissue Therapies
Transplantation
Blood Products
Gene Therapy
Cellular Vaccines
Stemcells
Cell & Tissue Therapies
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Pancreatic islets for diabetes
Stem and skeletal muscle progenitor cells for ischemic cardiacrepair
Hematopoietic reconstitution in treatment of malignancies
Stem cells for metabolic disorders, CNS indications
Expanded autologous cartilage for bone repair
Autologous dendritic cells pulsed with antigens
Examples of cells and tissues
for therapeutic usage
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Autologous or allogeneic cells on collagen or synthetic matrix
for wound repair
Cell seeded scaffolds for cardiovascular repair
Encapsulated pancreatic islet cells
Encapsulated erythrocytes containing enzymes
Examples of cells in scaffolds
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Why Develop a New Regulatory
Framework?
Rapidly growing industry cord blood, cellularimmunotherapies, embryonic stem cells, tissue-engineered
products (tissue+device) The complex manufacturing processes and cellular origin of
these CTT products pose additional risk to patients
Use of CTT products in the management of medical
conditions Carticel (autologous cartilage cells implantation for knee repair)
Epigraft (autologous cultured keratinocytes for burn victims)
Provenge (autologous cellular immunotherapy for
prostrate cancer)
Address current regulatory gaps
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CTT Characteristics Complex and highly innovative manufacturing processes
Unclear legal classification
Common public health concerns e.g. risk for transmission ofdiseases
Process can impact safety and quality of product
Challenges in product characterization purity, potency,consistency
Sometimes custom made for individual patients and eachbatch manufactured independently of the next.
Manufacturing process has limited scales of economy, morelabour intensive
IP challenges, high cost, ethical issues, treatmentcomplexity
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Drivers for Regulation
Public health concerns
preventing disease transmission
process controls to prevent contamination and preservefunctionality of tissue
assurance of clinical effectiveness and safety
labeling for proper use
monitoring and communication with industry Fragmented regulatory approach opportunity for unified,risk-based framework that applies to all forms of cell andtissue therapies
Provide overall legal certainty encourage development ofrapidly growing industry
Keep pace with technological advances
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HOTA - Human Organ Transplant Act allows organs to be removed for transplantation on death due to accidents (opt-out scheme)
MTERA Medical (Therapy, Education and Research) Act allows individuals to donate their organs for transplantation, education
or research (opt-in scheme)
PHMCA Private Hospitals and Medical Clinics Act licensing of private hospitals, medical clinics and clinical laboratories
HCOPP Human Cloning & Other Prohibited Practices Act bans reproductive cloning research activities
Organs CellsTissues
liver
heart
kidney
cornea
veins/arteries
ligaments/tendons
cartilagedura mater
sperm/egg/embryo
blood/components
bone marrow
cord blood/stem cells
somatic cells
skin bone chips
substantial manipulation
non-homologous use combine w/ drug or device
MMCTs-
Partiallyregulated
under
PHMCA
minimal
manipulation
same functionHOTA
MTERAPHMCA
Organs CellsTissues
liver
heart
kidney
sperm/egg/embryo
blood/components
bone marrow
cord blood/stem cells
somatic cells
skin bone chips
HighRisk
Lo
wR
isk
substantial manipulation
non-homologous use combine w/ drug or device
HCTs Not regulated
Current Legislative Controls
HCOPP
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Proposed RegulatoryFramework in Singapore
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Development of Regulatory
Framework for CTT Products
Aim
To develop framework for regulating human cells and tissuesintended for therapeutic use whether as part of conventional
medical practice or clinical research
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Objectives of
Regulatory Framework
To safeguard public health by ensuring quality, safety andefficacy requirements for both higher-risk and lower-risk
human cells and tissues intended for therapeutic use
To ensure public has timely access to beneficial cell- andtissue-based therapies that fulfill important medical needs
To provide a clear, transparent, and internationally acceptedregulatory infrastructure and standards to support therapidly growing cell and tissue therapy industry
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Cells and Tissues for
Therapeutic Use
the cells or tissues subjected to substantial manipulation, sothat their relevant biological, physiological or structuralproperties are altered
the cells or tissues intended for non-homologous use
the cells or tissues combined with drug/biologic/device
Proposed Classification of CTT Products
Higher Risk - Human Cellular and Tissue-basedBiological Products (HCTs)
Autologous or allogeneic cells and tissues that meet at least one
of the following criteria:
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Examples include bone, bone marrow, cartilage, oculartissues, skin, vascular grafts (veins and arteries) andreproductive materials (semen, oocytes, embryos).
Cells and Tissues for
Therapeutic Use
Lower Risk - Minimally Manipulated Cells andTissues (MMCTs)
Articles that are minimally processed and undergo simplepreservation and/or storage steps before being transplantedinto a patient.
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Proposed Legislative Controls
Cell- and tissue-based products will be regulated as perother biologic drug products by HSA
HCTs pose a higher risk associated with their use comparedto MMCTs
Propose to regulate both HCTs and MMCTs within a singlelegislative framework while differentiating the levels ofregulatory control between HCTs and MMCTs
A holistic approach which will avoid inconsistency and allowbetter regulatory control
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Proposed Regulatory Approach
Emphasis on assuring clinical efficacy and safety
Regulation of product pre-market review of quality, safety andefficacy
Licensing of manufacturer - Good Manufacturing Practice (GMP)
Post-market pharmacovigilence and surveillance Clinical trial certificate
M i n i m a l l y M a n i p u l a t e d Ce l ls a n d T i ss u e s ( MM CTs )
Emphasis on safety prevent disease transmission
Regulation and accreditation of premises
Compliance with standards (e.g. Good Tissue Practice)
Serious Adverse Events reporting and traceability
H u m a n Ce l l u l a r a n d T is su e - b a s e d B i o l o g i ca l P r o d u c t s
( HCT s )
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Announcement to stakeholders
Intent to develop regulatory framework for cells and tissues
Invitation to participate in the public consultation
Collect information on HCT and MMCT establishments
Conduct industry consultation on definitions, timelines andregulatory framework
Build up expertise
When the framework is implemented
Control of clinical trials Facility audit
Marketing authorization
Adverse events/safety surveillance and reporting
Proposed Regulatory Approach
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Thank You