Biosimilars: Regulatory Perspective in IrelandJoan O’Callaghan

IPPOSI Breakfast Seminar: Biologics and Biosimilars in Ireland5th April 2016

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Overview • Biological medicines• Biosimilar medicines• Biosimilar approval process• Pharmacovigilance of biological

medicines• Interchangeability

Biological Medicines

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What is a biological medicine?• Biological medicines contains active

substances made by a biological process or are derived from a biological source.

• Broad term and examples include– Hormones (e.g. insulin)– Enzymes (enzyme replacement therapy)– Monoclonal antibodies (targeted treatment)– Blood derived products (clotting factors)– Animal derived products (e.g. heparin,

vaccines)

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What is a biological medicine?• Biological medicines provide

effective treatments for a wide variety of serious conditions. Examples include– Diabetes mellitus (Lantus®)– Rheumatoid Arthritis (Humira®)– Cancer (Herceptin®)– Multiple Sclerosis (Tysabri®)

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What is a biological medicine?• Most biological medicines are

produced from the cell cultures of living organisms

• Often the cells have been engineered in order to produce a therapeutic molecule or group of molecules, usually proteins

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Biological medicines have a complex manufacturing process

Source: Slide by Nanna Aaby Kruse, Mediacademy, Oct 2011

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Biological Medicines and Chemical Medicines

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Biological Medicines and Chemical Medicines

Biological medicines Chemical MedicinesLarge complex structure

Inherent natural variability

Synthesis in living organisms- difficult to reproduce

No two batches likely to be identical

More likely to cause an immune reaction due to size and structure

Generally given by injection/infusion

Generally prescribed by specialists

Small simple structure

Single well defined chemical structure

Made by combining chemical ingredients

Reproducible manufacturing process

Unlikely to cause immune reaction due to small size

Often taken orally

Prescribed by GPs and/or specialists

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Relative complexity of chemical and biological medicines!

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Biological Medicines• Biological medicines have revolutionised

the treatment of many diseases including cancer, rheumatoid arthritis, psoriasis, inflammatory bowel disease and diabetes

• Biological medicines are high cost and use is often limited

• Patents of many ‘blockbuster’ biological medicines have expired or are nearly expired

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Sales and patent expiry

Biosimilar medicines

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What is a biosimilar medicine?

A biosimilar is a biological medicine that is highly similar to another biological medicine (reference product) that has already been approved for use in patients

A biosimilar is not a generic

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Biosimilars v’s Generics• Generic medicines are

usually small molecule ‘chemical’ medicines

• A generic medicine is an exact copy of a reference medicine

• It is not possible to make an exact copy of a biological medicine

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Biosimilar medicines • Only comes on market after

patent of reference product has expired

• Encourages competition which can lead to price reductions and improve patient access to high cost medicines

“Similar but not identical”

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Biosimilar medicines in EuropeActive substance

Reference product

Biosimilars

Epoetins Eprex Absamed, Epoetin Alfa Hexal, Binocrit, Retacrit, Silapo,

Etanercept Enbrel BenepaliFilgrastim Neupogen Filgrastim Hexal,

Biograstim, Ratiograstim, Grastofil, Tevagrastim, Nivestim, Zarzio, Accofil

Follitropin GONAL-f Ovaleap, BemfolaInfliximab Remicade Remsima, InflectraInsulin glargine

Lantus Absaglar

Somatropin Genotropin Omnitrope

Biosimilar approval process

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Biosimilar approval process Manufacturers must demonstrate to

regulators that biosimilars have similar quality, safety and efficacy to the reference product and there are no clinically meaningful differences between the two

Tailored approach which involves a comparability exercise against the reference product

First step: quality comparability Second step: pre-clinical

comparability Third step: clinical comparability

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Quality comparability• Quality testing is cornerstone of

biosimilarity• Large number of physiochemical

and biological tests• Quality comparability exercise

must show biosimilar is highly similar to reference

• Potential impact of any (minor) quality differences on safety and efficacy must be addressed

Quality

Clinical

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Pre-clinical comparability Pre-clinical studies are required for all new

medicines. Involves testing in cell culture and in animals in order to determine safety profile prior to use in humans

For biosimilars preclinical studies relate to mechanism of action of medicine and could uncover subtle differences between reference and biosimilar

Testing in animals may not always be necessary

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Clinical comparability Clinical trials are designed to see if

clinically meaningful differences exist between reference and biosimilar

Generally includes data on pharamacokinetics, pharmacodynamics, safety and efficacy

Testing for immunogenicity required

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Indication extrapolation

• Clinical data may not be required for the biosimilar in all indications

• Must be scientifically justified

• Similar approach is used to justify post-approval changes for other biological medicines

• Approved on case by case basis

Pharmacovigilance

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Pharmacovigilance Science of monitoring, evaluating and

preventing drug-related adverse events Clinical safety of all biologicals must be

monitored on an on-going basis after approval

New medicines including biosimilars are subject to additional monitoring for a certain time period after authorisation

Patients should report side effects to the HPRA and/or their healthcare professional

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Traceability of biological medicines

Biological medicines exhibit variability: therefore

biological medicines with the same international non-

proprietary name (INN) should not be considered

identical

Prescribe, dispense and

record using brand name

Changes in manufacturing

processes can affect likelihood of medicine

causing an immune reaction

Adverse reaction reports should include brand name and batch

number

Information for patients on the approval process of a medicine

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Information for patientsEuropean Medicines Agency website: ‘Find Medicine’ section• Summary of assessment

available• Further information: Package

leaflet etc.

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HPRA Guideline on biosimilars

• Regulation• Product information• Prescribing• Dispensing• Traceability

Interchangeability

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Interchangeability, substitution and switching

Interchangeability: medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting and in any patient (prescriber is involved)

Substitution : practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber

Switching: decision from treating physician to exchange one medicine for another medicine with the same therapeutic intent in patients who are undergoing treatment.

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Substitution in Ireland• ‘Generic substitution’ allows for

most chemical medicines to be substituted for each other at the pharmacy level

• Biological medicines are excluded from ‘generic substitution’

• Pharmacists cannot ‘substitute’ a reference medicine for a biosimilar or vice versa unless there is prescriber agreement

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HPRA position on interchangeability and switching If it is planned to change the

medicine a patient receives from a reference to a

biosimilar medicine or vice versa, the treating physician

should be involved; this should involve discussion

between the prescriber/patient and prescriber/dispensing

pharmacist• Ongoing engagement between prescribers,

dispensers and those with responsibility for procurement

• Stakeholder engagement to ensure optimal use of resources and ensure the best patient outcomes

• Switching back and forth not recommended as currently availability of data on the impact of this is limited

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International policies• Tendering process determines which brand of

biological medicine is used in hospitals• High uptake of infliximab biosimilar (new patients

and switching)Denmark

• Pharmacist substitution possible if brand is given an ‘a’ flag following evaluation by the reimbursement body

• Prescriber and patients retain right to decline substitution

Australia• Category for ‘interchangeable biological product’ (no

medicine approved in this category to date) • Legislation to allow pharmacist substitution of

‘interchangeable biological products’ passed in 16 states

United States

Regulatory Science Ireland: Biosimilars Research Project

Regulatory Science Ireland

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RSI: Biosimilar Project• Research activities: HPRA and UCC • Supported by: HPRA, UCC and IPHA• Industry Advisors: Merck, AbbVie, Novartis • Objectives

• Peer reviewed scientific publications (practical considerations for healthcare professionals)

• Survey perspectives and understanding of biosimilars

• Comparative studies of international models for providing safe and effective use of biosimilars

• Develop training materials and online resources

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RSI Biosimilar ProjectPublications to date

• Biosimilar Medicines: Opportunities and Challenges in the clinical use and supply of Biosimilars (IPN and HPN)

• Biosimilar Medicines: Recent Developments (HPN)

Prescriber survey• Knowledge, behaviours and attitudes towards

biological medicines specifically biosimilars

Any questions?

joan.ocallaghan@hpra.ie