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