2014 European Meeting of ISMPP:

A New Era in Global Medical

Publications

BIOSIMILARS – LOOKING BEYOND

BRANDED PHARMACEUTICALS

Isabel Zwart

PAREXEL consulting

BIOSIMILAR REGULATORY STATUS: WORLD VIEW

United States

Biologics Price

Competition and

Innovation Act 2009

(BPCIA). New pathway

(351K) introduced into

PHS Act

Draft guidances

published 2012

Europe

Legal pathway clearly

defined

First biosimilar

approved in 2006

Overarching, general

and product-specific

guidances published

Rest of World

Brazil, Australia, Turkey,

Taiwan, Malaysia,

Argentina, Mexico, Japan,

Canada, South Africa, South

Korea, Egypt, Jordan all

have defined pathways

New countries introducing

guidelines / legislation

regularly

Highly regulated, semi regulated, unregulated

Japan similar to EU

4

Highly similar to the RMP in

physicochemical and biological terms.

Any difference would be justified with

regard to potential impact on safety and

efficacy.

Similarity in terms of quality

characteristics, biological activity, safety

and efficacy based on a comprehensive

comparability exercise.

Highly similar to the RMP

notwithstanding minor differences in

clinically inactive components

No clinically meaningful differences in

terms of the safety, purity, and potency

HOW SIMILAR IS SIMILAR?

SUBSTITUTION AND INTERCHANGEABILITY 5

• Not regulatory concept

• Decision at national level

• General view biosimilars

not interchangeable

• Substitution at pharmacy

is not allowed generally

– Defined as separate

category in BPCI

– Assessed by the FDA

– Very high hurdle

• “same clinical result in any

given patient;” and risk of

alternating or switching no

greater than use of reference

product

HOW SIMILAR IS A BIOSIMILAR?

• EU Guideline on similar biological medicinal products containing

biotechnology-derived proteins as active substance: quality

issues (revision 1 draft):

“The aim of the comparability exercise is to demonstrate that the

biosimilar product under development and the reference

medicinal product chosen by the applicant are similar at the level

of the finished product, i.e. the material that will be used to treat

the patient. It is not expected that all quality attributes will be

identical and minor differences may be acceptable, if

appropriately justified. Particular attention should be given to

quality attributes that might have a potential impact on safety or

efficacy (e.g. impact on immunogenicity or potency) or that have

not been identified in the reference medicinal product).”

- 7 -

SUBTLE CHANGES CAN IMPACT QUALITY, SAFETY &

EFFICACY

• Pharmacokinetics

• Pharamcodynamics

• Efficacy

• Safety

• Immunogenicity

- 8 -

COMPARABILITY IS BASED ON TOTALITY OF THE

DATA

Relevance VS Accuracy

Physicochemical Biological

Animal Model Clinical Setting Pharmacology Setting PK/PD

Batch Comparison

STEPWISE APPROACH TO CLINICAL PLAN

• A stepwise approach is normally recommended

• EU: start with comprehensive physicochemical and

biological characterisation. The extent and nature of

the non-clinical and clinical studies to be performed

depends on level of evidence obtained using the

physicochemical, biological and non-clinical in vitro

data.

• If rigorous structural/functional comparison shows

minimal or no differences, the stronger the scientific

justification for a “selective and targeted approach to

animal and/or clinical testing to support demonstration

of biosimilarity”

- 9 -

CLINICAL EXPECTATIONS

• The biosimilar paradigm follows the main concept that clinical

benefit has already been established by the reference

medicinal product

• Biosimilar product development should serve to confirm that:

– Demonstrated to have similar (comparable) pharmacodynamics

– Demonstrated to have similar (comparable) PK

– Demonstrated to have similar safety (immunogenicity?) and efficacy

• Biosimilars, therefore, do not demonstrate clinical benefit

CLINICAL STUDIES

• An abbreviated clinical pathway is allowed for biosimilars, which

serves to provide a direct comparison between the two products

of:

– pharmacokinetics

– pharmacodynamics

– efficacy

– safety and immunogenicity

– pharmacovigilance

• Clinical comparability margins should be pre-specified and

justified, primarily on clinical grounds

Phase 1 bioequivalence trial

Phase 3 therapeutic

equivalence trial

Phase 4 surveillance

study/Patient registries/Routine

PV

•Extrapolation accepted in (draft) guidelines in EU, USA,

Canada and Japan, if MOA is the same

•Requires adequate justification

• Immunomodulator and anticancer (cytotoxic)

antibody, extrapolation more challenging

• Antibody-dependent cytotoxicity (ADCC) appears to

be more important in some indications than in others

12

EXTRAPOLATION TO OTHER USES?

INDICATION – DOSE – POPULATION

COMMERCIAL ASSESSMENT

• Market Penetration: How wide is product uptake?

– Worldwide biosimilars account for small percentage of the market

– Emerging markets vs Western markets

• What is the pricing?

– Discount of 20 - 40 % of innovators for biosimilars

• Will health care payers/insurance cover use of these

biosimilar products?

– What price reduction is needed to gain reimbursement?

• EU opinion: ideally 30 – 40%

• US opinion: 27 – 35%

– What happens when there are multiple biosimilars?

– Will level of reimbursement/copay be same for biosimilar than

innovators?

13

ROLE OF PUBLICATIONS – TARGET AUDIENCE

• Practitioners (and patients):

• Raising awareness and understanding of the biosimilar paradigm and products

approved (consider that legislation defining a biosimilar pathway for the US is

only recent)

• Provide peer-reviewed publications of studies that demonstrate the therapeutic

equivalence of the product (many clinicians are still reluctant to use biosimilars)

• Evidence of efficacy and safety in indications where regulatory approval was

based on extrapolation

• Insurers/healthcare payors:

• Studies on cost savings associated with use of biosimilars

• Industry and regulators:

• Research that identifies novel mechanisms of action of a drug or further

characterisation of its structure and function that could serve as a tool for

comparability studies to support/disprove biosimilarity

- 14 -

PUBLICATIONS – DISPELLING MYTHS?

• Peer-reviewed publications can serve:

– To dampen the perception that the biosimilar is somehow “inferior” to

the innovator in safety/efficacy

– Identify potential issues with products claimed to be biosimilar or sold

as a substitute without adequate regulatory vetting or data

– Provide forums for discussion:

“For patients, physicians, payers and governments, it really doesn't matter who produces the

biologics that a nation needs, as long as the market operates in a way that equivalent

products compete on price. However, this does not seem to be how the biosimilars market is

being molded to work. The question for policymakers is whether they realize how meager

the economic advantages are likely to be of introducing a biosimilar onto the market

compared with a generic small molecule, especially under the constraints currently being

erected by the brand industry.”

Source: Building a wall against biosimilars, Nature Biotechnology 31, 264 (2013) - 15 -

DEVICE-RELATED STUDY REGISTRATION/

PUBLICATION IN THE ENVIRONMENT OF

INCREASING TRANSPARENCY

• 2007 – ICMJE adopted WHO definition of a clinical trial:

– Pretty much any prospective clinical trial – including Phase I drug, and

early device feasibility studies. Only excludes observational studies

• 2007 – FDAAA

– Specifically excludes Phase I drug trials. Applicable device trials are

prospective, controlled trials evaluating health outcomes (other than

feasibility studies) and paediatrics post-marketing surveillance

• So, now what???

16

• Devices require design verification and validation

– Studies often ‘dry and technical in nature’

• How to balance goal of publication versus the utility of the

information

– Device design is iterative before design freeze, and continues

post-marketing

– When do you publish???

• General approach: Register trials according to FDAAA and

disclose results accordingly. Err on the side of more, not

less, publication

17

Practical Implications

AN UNUSUAL CASE STUDY

• Prospective, controlled study undertaken in Japan comparing a new BD insulin pen needle to a marketed competitive product

– Trial registered appropriately

• Study results clear; favour new needle (p < 0.05)

• PI refuses to proceed with publication

• BD company policy states, “We commit to seek publication of results of completed applicable clinical trials on any marketed product…, regardless of trial outcome.”

18

What do you do?

SUMMARY:

PUBLICATION CHALLENGES

• Routine nature of technical data – difficult to publish?

• Timing and utility of publications with devices, assays,

diagnostics that are studied but never commercialized

• Objective evidence required on accuracy, precision,

reliability, safety, assay accuracy/references between

labs and compared to competitors

• Early alignment of clinical/technical and health

economics objectives to ensure market access

19

LOOKING BEYOND BRANDED

PHARMACEUTICALS:

MEDICAL DEVICES AND

DIAGNOSTICS

Kelly Wesemann, MS

Principal Clinical Research Specialist, Medtonic Inc.,

Alisa Davis, PhD Publication Lead, Medical and Scientific Affairs,

Roche Professional Diagnostics

Larry Hirsch, MD Worldwide Vice President, Medical Affairs

Diabetes Care, Becton Dickinson;

Third President, ISMPP

• Drugs

– Molecular entities (small molecules, chemically synthesized)

– Biologicals – (proteins, nucleic acids, or cells and tissues)

• Devices

– Class I

– Class II

– Class III

21

Therapeutics

DEVICES ≠ DRUGS!

DIFFERENCES IN PIPELINES

Pharma

For many devices, lifespan is ~ 2–3 years http://blogs.berkeley.edu/2013/08/20/reinventing-life-science-startups-medical-devices-

and-digital-health/

22

Medical

Devices

IMPLANTABLE DEVICES:

DATA SOURCES

Preclinical and

bench testing

Clinical efficacy and

safety for new

indication

Justify

cost

23

IMPLANTABLE DEVICES:

STUDY TYPES AND DATA

Clinical Study Types

• Research: Exploratory/Pilot/

Feasibility

• Pre-Approval: Clinical efficacy,

performance, safety, clinical

utility, health economics

• Post-Approval: Clinical

performance, clinical

effectiveness, clinical utility,

usability, health economics

Clinical Study Data

• Therapy efficacy or

effectiveness, healthcare

utilization, safety

24

DIAGNOSTICS:

STUDY TYPES AND DATA

Study Types

• Research: Exploratory/Pilot/

Feasibility/Sample Bank

• Pre-Registration: Analytical

performance, clinical

performance, clinical utility, health

economics, etc

• Post-Registration (System or

Assay on Market): Clinical

performance, clinical utility,

usability, health economics, etc

Study Data

• Precision (within-run and

intermediate), accuracy,

functional sensitivity, limit of

quantitation, reference method

validation, external quality

assessment scheme/programme

performance, method

comparison, sensitivity and

specificity, validation of economic

models, etc

25

DIAGNOSTIC SYSTEMS AND

ASSAYS – CHALLENGES

Publications

• Data are ‘dry’ and journal selection

limited to lower impact factor

• From industry perspective, difficult to

find medical communications agencies

with sufficient writing experience in

diagnostic data and assays

• Registration timelines in the US and

ROW are very different due to CE

marking, resulting in multiple studies to

register platforms and assays

Registration

• In 2012, an amendment to Directive

2001/83/EC, Regulation (EC) No

178/2002 and Regulation (EC) No

1223/2009 has been proposed to the

European Parliament (http://ec.europa.

eu/health/medical-devices/documents/

revision/index_en.htm). This will change

the scope of data required to register

diagnostic devices in Europe

• Vote expected ~2015 to adopt new

directive

• Transition period anticipated from 2015–

2020 for adoption of the amended

Directive 26

DEVICE-RELATED STUDY REGISTRATION/

PUBLICATION IN THE ENVIRONMENT OF

INCREASING TRANSPARENCY

• 2007 – ICMJE adopted WHO definition of a clinical trial:

– Pretty much any prospective clinical trial – including Phase I drug, and

early device feasibility studies. Only excludes observational studies

• 2007 – FDAAA

– Specifically excludes Phase I drug trials. Applicable device trials are

prospective, controlled trials evaluating health outcomes (other than

feasibility studies) and paediatrics post-marketing surveillance

• So, now what???

27

• Devices require design verification and validation

– Studies often ‘dry and technical in nature’

• How to balance goal of publication versus the utility of the

information

– Device design is iterative before design freeze, and continues

post-marketing

– When do you publish???

• General approach: Register trials according to FDAAA and

disclose results accordingly. Err on the side of more, not

less, publication

28

Practical Implications

AN UNUSUAL CASE STUDY

• Prospective, controlled study undertaken in Japan comparing a new BD insulin pen needle to a marketed competitive product

– Trial registered appropriately

• Study results clear; favour new needle (p < 0.05)

• PI refuses to proceed with publication

• BD company policy states, “We commit to seek publication of results of completed applicable clinical trials on any marketed product…, regardless of trial outcome.”

29

What do you do?

SUMMARY:

PUBLICATION CHALLENGES

• Routine nature of technical data – difficult to publish?

• Timing and utility of publications with devices, assays,

diagnostics that are studied but never commercialized

• Objective evidence required on accuracy, precision,

reliability, safety, assay accuracy/references between

labs and compared to competitors

• Early alignment of clinical/technical and health

economics objectives to ensure market access

30

CONSUMER HEALTH AND

WELLBEING

Helen Darracott

Director of Legal & Regulatory Affairs

Proprietary Association of Great Britain

Consumer Health and Wellbeing Products

Non prescription (OTC) medicines

Herbal medicines

Homoeopathic medicines

Medical devices

Food supplements

Foods

Cosmetics

Operate in a fast moving & competitive

retail environment

Direct to consumer advertising

Selected and used by consumer

Little or no professional

intervention/supervision

Foods

May be used by several people (family

resource)

Food Supplements Regulatory Framework

Consumer protection

• Regulations governing

• Food Safety

• Food Hygiene

• Contamination etc

• Food Supplements

Directive 2002/46/EC

• Food Information for

Consumers Regulation

1169/2011

• Nutrition and Health Claims

Regulation 1924/2006

Safety Composition/Labelling

Getting Food Supplements to Market: Food Supplements Directive 2002/46/EC

Governs permitted ingredients

Controls composition of food supplements

Will set maximum and minimum levels

Safety based

Labelling requirements

Notification system available

No mandatory pre-market scrutiny of products by regulator (except for novel foods)

No formal post market surveillance requirements (except for novel foods)

but not mandated in all countries

Positive lists of vitamins and minerals (ingredients & sources)

(permits other substances with nutritional or physiological effect including botanicals)

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Who is the target audience?

• Consumers or health professionals/trade

What do you want to say?

Why do you want to say it?

• Promotion vs information • Is the copy a commercial communication?

When do you want to say it?

Writing About Food Supplements

What Do You Want To Say?

Key principles

Copy must be scientifically correct, accurate, balanced and fair and not misleading

Principles reflected in ISMPP Code of Ethics

No medicinal claims

Food & supplements are not intended to treat, prevent or cure disease

Care is needed to ensure that claims to do so are not made

What Do You Want To Say And Why?

What regulatory requirements apply?

Nutrition and Health Claims Regulation Food Information for Consumers Regulation Advertising controls etc Will the copy

include references to ingredients and/or products?

There are no legal restrictions on the timing of communications to professionals or consumers

Practical considerations will apply in some circumstances eg, stock availability for product promotions

When Do You Want To Communicate Your Message?

Who Is The Target Audience?

Consumers (purchasers/end users) NHCR applies

Health Professionals/Trade Dieticians, Nutritionists, Nutritional

Therapists, Doctors, Pharmacists, Nurses, Academia

Trade buyers NHCR does not apply

What Is The Purpose Of The Copy?

Scientific publications Study reports Abstracts Articles Conference reports

Product labelling Product advertising & advertorials Branded press releases & media reports

Press releases & media reports on study findings

Increasing Regulatory Control

Purely factual information Promotional material

Scope

Applies to food in general

• Applies to commercial communications

• Communications aimed at the final consumer

It does not control

• Claims communicated within trade, to doctors or other health professionals, or to their organisations

• Non-commercial communications such as non-branded information in the press and scientific publications

Nutrition And Health Claims Regulation 1924/2006

Nutrition And Health Claims Regulation 1924/2006

No claims may be made unless ‘approved ‘ at EU level

Restricts nutrition claims to those in Annex Claim for beneficial properties due to the energy, nutrients or other substances a food contains, contains at reduced or increased amounts, or does not contain

Can only make authorised health claims A claim which states, suggests or implies a relationship between any food and health

Claims must be based on, and substantiated by, generally accepted scientific evidence – assessed by European Food Safety Authority (EFSA) and adopted by European Commission

Claims must comply with the conditions of use

Approved claims go through a legislative process and are placed on the Community Register: http://ec.europa.eu/nuhclaims/?event=search&status_ref_id=4

Health Claims Substantiation Process

Member states identified 44,000 claims which became 5,000 separate claims submitted to EFSA by the European Commission for evaluation

Scientific dossier to describe the relationship between the food/constituent and the claimed effect, the outcome measure(s) used to assess the claimed effect in humans and the mechanism(s) by which the food/constituent exerts the claimed effect

Evidence in healthy subjects Cannot extrapolate from studies involving diseased states Literature review etc Protection of proprietary data possible for some claims

General function health claims (well established)

New function health claims, disease risk reduction, children’s development & health

Approval of Health Claims

Valid applications transmitted to EFSA by competent authorities in Member States

EFSA required to deliver its opinions within five months. If supplementary information is needed, EFSA has an additional month for the evaluation

EFSA opinion is considered by standing committee (SCoFCAH) & if agreed draft regulation goes to Working Group. Discussions may take years

EC must notify World Trade Organisation before agreed regulation lays in European Parliament for 3 months. If no objections are raised regulation published in Official Journal and comes into force 21 days later

Claim may be used

Both authorised and rejected claims placed on the Community Register

Types of Health Claims

Article 10 General, non-specific benefits of the nutrient or food for overall good health or health-related well-being

13 Claims other than those referring to disease risk reduction and to children’s development and health

13(1)a Claims describing or referring to the role of a nutrient or other substance in growth, development and in the functions of the body

13(1)b Claims describing or referring to psychological and behavioural functions

13(1)c

Slimming or weight control; or

a reduction in the sense of hunger; or

an increase in the sense of satiety; or

to the reduction of the available energy from the diet

13(5) Claims based on newly developed scientific evidence or protection of proprietary data

14(a) Reduction of disease risk claims

14(b) Claims referring to children’s development and health

Recommendations: Health Professionals

Statements relating to research appear to be acceptable

– but must be supported with a permitted health claim

Specified products from individual health professionals where a health

claim is made:

”Jo Smith, Dietician recommends Product X because it contains

vitamin A which is needed for normal vision”

Specified nutrients from individual health professionals:

“Jo Smith, Dietician, says that vitamin A is needed for normal

vision”

Specified products from individual health professionals with no

health claims made (be careful of product names):

“Jo Smith, Dietician recommends Product X”

Recommendations: Associations of Medical Nutrition and Dietetic Professionals

Recommendations by International associations not allowed

“The International Association of Healthcare Professionals recommends X”

is not acceptable as the association is international

Recommendations by National associations are permitted

“The British Dietetic Association recommends X” is considered acceptable (assuming the relevant permissions are granted) as the BDA is a national association

Government Health Messages

Would need to comply with the Regulation: “The Government recommends eating two portions of fish a week, one of which should be oily, because it’s good for your heart”

Not in scope of the Regulation: “The Government recommends eating two portions of fish a week, one of which should be oily”

Not covered by the Regulation unless they make an explicit nutrition or health claim

Claims Linked To Charities

Recommendations by charities (eg use of charity logo)

Implied claims must not be medicinal

May imply a health claim, and MUST be based on an authorised Nutrition or Article 13 or 14 health claim

‘The British Heart Foundation recommends X’ promote heart health in general population

‘Arthritis Care recommends X’ medicinal claim

Self-Regulation And Reinforcement

Advertising

Labelling

Advertising controlled by Codes of Practice (CAP & BCAP) and industry codes

Pre-vetting by trade associations Advertising complaints adjudicated by

Advertising Standards Authority (ASA)

Label compliance checks by trade associations

Trading Standards

Resources

Health Supplement Information

Service (HSIS)

PAGB Food Supplements Advertising

Guideline

PAGB Guidance on Food Information

for Consumers Regulation

MHRA Guidance Note 8 – A guide to

what is a medicinal product

www.hsis.org

WWW.PAGB.CO.UK