Extrapolation of indications for biosimilars

Regulatory perspective

Dr Michael Coory

Director, Prescription Medicines Clinical Unit 5

Medicines Authorisation Branch

Market Authorisation Division, TGA

ARCS Scientific Congress 2015

7 May 2015

Regulation of medicines is international

• European Medicines Agency (EMA)

• United States Food and Drug Administration (FDA)

• Health Canada

Extrapolation of indications for biosimilars 1

What is a biosimilar?

• Biological medicine that is developed to be ‘similar’ to an existing

biological medicine (the ‘reference medicine’)

• It is not identical to the reference medicine.

– the biological medicine is the process

(“brewed” in living cells; complex processes)

– Biological medicines can never be reproduced as identical molecules

– The concept of identity does not applyExtrapolation of indications for biosimilars 2

What is a biological medicine?

• Medicine produced or extracted from a biological source

Extrapolation of indications for biosimilars 3

Not all biosimilars are the same

• Vaccines

• Blood products

• Enzymes

• Hormones

• Immunomodulators

• mAb

Extrapolation of indications for biosimilars 4

Biosimilarity is a matter of degree

• Different batches of the originator product

– biosimilars of the version of the product used in the pre-marketing trials

– biosimilars of other batches

– ‘drift’

• Some variation must be accepted for all biological medicines

• The claim is similarity in all important aspects

Extrapolation of indications for biosimilars 5

Regulatory balance

Avoid allowing drugs

that are not adequately

tested from coming to

market

Avoid regulatory hurdles

that are unnecessarily

burdensome and do not

protect the public’s health

Extrapolation of indications for biosimilars 6

Costs of developmentIndicative

Small-molecule

generics

$1–2M 1–3 years

Biosimilars $10–40M 6–9 years

New biological

medicine

$B+ 10+ years

Extrapolation of indications for biosimilars 7

CTD Modules

New biological

medicine

3. Quality

4. Nonclinical

5. Clinical

Biosimilar

3. Quality

4. Nonclinical

5. Clinical

• Longer process to

develop the cell line and

manufacturing process

• Takes much longer to

find a cell-line that will

produce a product similar

to the reference product

• Shorter non-clinical and

clinical

• ‘Integrated comparability

exercise’

Extrapolation of indications for biosimilars 8

To maintain a regulatory balance

• Avoid unnecessary clinical trials

• Equivalence/non-inferiority

– Need larger sample size that superiority study

– 100’s of patients

• Timely recruitment can be difficult

Extrapolation of indications for biosimilars 9

EMEA/CHMP/BMWP/42832/2005Guideline on similar biological medicinal product …

• In certain cases … can extrapolate indications

• Justification depends on:

– clinical experience

– available literature data

– mechanism of action

– receptors

• Also need to consider safety in subpopulations

Extrapolation of indications for biosimilars 10

EMEA/CHMP/BMWP/42832/2005/ Rev.1Guideline on similar biological medicinal product …

6. Extrapolation of efficacy and safety from one therapeutic

indication to another

EU

July 2015

Australia

Consultation with industry is due to conclude 22 May 2015Extrapolation of indications for biosimilars 11

EMEA/CHMP/BMWP/42832/2005/ Rev.1

• Needs to be scientifically justified

• Considered in light of the totality of data:

– quality

– non-clinical

– clinical

Extrapolation of indications for biosimilars 12

EMEA/CHMP/BMWP/42832/2005/ Rev.1

It is expected that the safety and efficacy can be extrapolated:

• when biosimilar comparability has been demonstrated

• by thorough physico-chemical and structural analyses

• as well as by in vitro functional tests

• complemented with clinical data (efficacy and safety and/or PK/PD data)

• in one therapeutic indication.

Extrapolation of indications for biosimilars 13

EMEA/CHMP/BMWP/42832/2005/ Rev.1

Additional data are required in certain situations, such as

1. The active substance of the reference product interacts with several receptors

that may have a different impact in the tested and non-tested therapeutic

indications

2. The active substance itself has more than one active site and the sites may

have a different impact in different therapeutic indications

3. The studied therapeutic indication is not relevant for the others in terms of

efficacy or safety, i.e. is not sensitive for differences in all relevant aspects of

efficacy and safety

Extrapolation of indications for biosimilars 14

EMEA/CHMP/BMWP/42832/2005/ Rev.1Immunogenicity is related to multiple factors, including:

• the route of administration

• dosing regimen

• patient-related factors and disease-related factors

(e.g. co-medication, type of disease, immune status).

Thus, immunogenicity could differ among indications. Extrapolation of

immunogenicity from the studied indication/route of administration to other uses of

the reference product should be justified.

Extrapolation of indications for biosimilars 15

Summary

• Regulatory framework is evolving

• Not all biosimilars are the same

• Extrapolation: case-by-case

Extrapolation of indications for biosimilars 16