08 Emerging Issues

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All Rights Reserved 2008 Health Sciences Authority | 2

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

08 Emerging Issues

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