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Second Annual Biotech Supply Chain Academy
Keynote Address
Regulatory Influences in
Biogenerics-the Next
Horizon
Gillian R. Woollett, M.A., D.Phil.
Chief Scientist
Engel & Novitt, LLP
The Law Firm That Knows Its Science
October 19, 2009, San Francisco, CA
The material and viewpoints set forth in this slide deck
and conveyed during this presentation are presented by the author
in her capacity as Chief Scientist of Engel & Novitt, LLP.
They do not represent and do not purport to represent the views of the law firm
or any current or former-client of the firm, and should not be construed as such.
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 1
OUTLINE
The premise of competition when patents expire
Biotech products and the biotech pipeline – a
whole lot more are on the way…
Minimal terminology for the biologics debate
The current US regulatory framework
Biologics - the need for them is global, but can
they be made for a global market?
Biologics business models and lessons from the EU
biosimilars experience
Current legislative efforts to create a new
regulatory pathway
Opportunities and Conclusions
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 2
The Traditional Incentives for Innovation
Incentives created by competition create new medicines & increase access
Patents Expire
Generics offer
high quality drugs for
established treatments
affordable costs
and thereby free up Innovative drugs offer:
healthcare funds for new Net Progress Improved treatment
innovative drugs Radical New Less side effects
Therapies and New therapeutic options
Iterative and thereby replace
older/less effective
Improvements
medications
Obsolescence
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 3
The Context for ALL Biologics
The 200 year history of biologics is the basis for their future:
Started with the very complicated – smallpox vaccine – and the
decisions were empirical, and the studies “unethical”
The biotech industry is much younger (first recombinant insulin
1982), and the original biotech products were “biosimilars” -
essentially biotech was a means of manufacturing previously
approved naturally-sourced products. Now we can do way more
as in Never-before-seen-in-nature products…
FOBs are not just biosimilars, but also bioidenticals, second-
generation products, biobetters, and bio-I-just-don’t-knows
Biobetters can be clinically-better, but also perhaps safer, more
stable, more reliably manufactured and cheaper, or all of the
above
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 4
The Economic Issues for Biologics
Matter NOW
Healthcare costs are high and increasing - all economies are under
pressure, but access is life/death
Individual biopharmaceuticals are more expensive than drugs on a
per-patient basis, so prices have become conspicuous - attracting
political and media attention.
Medicines are a critical part of healthcare worldwide, but there is
considerable price and product disparity, yet the companies and
the patients are the same
Biologics are, or are coming, off-patent
Arguments for free-market pricing of drugs evoke an expectation
of competition in the marketplace at the conclusion of patent
terms
The opportunities from multiple sponsors are increasingly apparent
to all stakeholders; conversely their lack is a liability to biopharma
and patients
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 5
BIOTECHNOLOGY
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 6
Biotech Medicines in Development
700
Represents
Number of Products in Clinical Trials
633
600 pipeline for
future Brand
500
418 products and
400 369 371 then,
324
284 subsequently,
300
for
200 143 biosimilars
81
100
0
1988 1993 1996 2000 2002 2004 2006 2008
ENGEL & NOVITT, LLP The Law Firm That Knows its Science Source: PhRMA Biotech Medicines in Development Surveys 7
The
majority of
Medicines
in clinical
trials for
the US may
now be
biotech
ENGEL & NOVITT, LLP The Law Firm That Knows its Science http://www.phrma.org/images/110308%20biotech%202008.pdf
8
PhRMA Biotech Medicines in Development
2008
Total
Biotech
Medicines in
clinical trials
for the US
633
ENGEL & NOVITT, LLP The Law Firm That Knows its Science http://www.phrma.org/images/110308%20biotech%202008.pdf
9
Current US Regulatory Pathways
STATUTE APPLICATION
NEW DRUG
U.S. FOOD DRUG APPLICATION (NDA)
& COSMETIC ACT AND 505(B)(2) NDA
ABBREVIATED NDA
(ANDA) = GENERIC DRUG
U.S PUBLIC BIOLOGIC LICENSE
HEALTH SERVICE APPLICATION (BLA)
ACT
EXPEDITED
BLA
Derived from a Presentation By Keith Webber, Deputy Director, OPS, FDA. 25Sep07 GWU “Biosimilar 2007”
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 10
Terminology has been distracting…
Biologic – is a prophylactic, in vivo diagnostic, or therapeutic
substance that is made in a living system, and that, generally,
has a large and complex molecular structure
Follow-on Biologic (FOB) – a subsequent version of a biologic,
independently developed and approved, but that shares the same
mechanism of action as a previously approved product (includes
so-called EU Biosimilars, plus some second generation biologics)
Second-generation biologic - subsequent versions of biologics that
are independently developed and approved, share the same
mechanism of action as a previously approved product but are
explicitly different in some manner, e.g. inhaled. Sometimes called
“evergreened”.
Biogeneric, or Generic Biologic Drugs – should only be applied to
ANDAs for biologic drugs approved by FD&C Act. ANDAs are
interchangeable with their reference product
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 11
And please remember, while there may
be a debate on naming…
…THE NAME DOES
NOT CHANGE THE
CONTENTS OF
THE TUBE
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 12
So how do you tell what is in the tube…
…with
DATA
And hence the issue for any biologic sponsor is what data, to
demonstrate what, and to whom, at what price to get what
market…
Answer: data to show safety, purity and potency or a
relationship to a reference product (with known safety, purity
and potency) at the structural, functional, and clinical levels
to the regulators
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 13
Where are we with biosimilars today?
Generally accepted that the science is sufficient for some/most
biosimilars today
Europe, Australia, Canada, Japan have biosimilars and
competition is beginning
No Enacted US legislation but bills in play (albeit drowned in
the larger health care reform debate)
Recognition of need for biologics competition in US as patents
expire, but aggressive defense by some Brands
Huge confusion on the role of reimbursement, and need for
interchangeability to gain savings and access
Health care reform an Administration priority, and biosimilars
seen to have potential to increase access and save money
Global issues
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 14
The Biosimilars Story of Europe – a
Timeline
17Dec03 European Parliament “Future Medicines Legislation” (also
called “Pharma Review Package”)
31Mar04 Directive 2004/27/EC (also known as Directive
2001/83/EC as amended) and Regulation 726/2004. Came into
effect 20Nov05
EMEA published general guidelines on biosimilars, as well as
“class”-specific ones, but accepts and reviews applications
concurrently
Approvals: April 06 First biosimilar approval was Omnitrope
(somatropin); August 07 First glycosylated protein approved as a
biosimilar, Binocrit (Epoetin alfa); March 09 EMEA Guideline on
LMWH – first for a naturally-sourced biosimilar
EMEA meeting on Biosimilar Monoclonal Antibodies Jul09
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 15
Selected Therapeutic Biologics by Product Class
Average
~150Kd
Average
<50Kd
European Biosimilars are based on well-
established regulatory standards
1996 US Guidance on Comparability for Manufacturing Changes for
drugs and biologics developed by FDA and Pharma
Early 2000’s ICH Q5E Comparability standards adopted by EU US
and Japan – HIGHLY SIMILAR
EU Biosimilars based on similarity and guidelines developed, but
MEANWHILE biosimilars were developed and approved.
No central EU regulatory designation of interchangeability, up to
the health authorities in each country
Review and approval not coupled to patents
Innovator exclusivity 8+2+1 for all medicines (drugs and biologics
are the same)
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 17
The Established Definition of Comparability
(EU, US, Japan)
ICH HARMONISED TRIPARTITE GUIDELINE
COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL
PRODUCTS SUBJECT TO CHANGES IN THEIR
MANUFACTURING PROCESS
Q5E
COMPARABLE:
A conclusion that products have highly similar quality
attributes before and after manufacturing process
changes and that no adverse impact on the safety or
efficacy, including immunogenicity, of the drug product
occurred. This conclusion can be based on an analysis of
product quality attributes. In some cases, nonclinical or
clinical data might contribute to the conclusion.
Federal Register, Vol. 70, No. 125, June 30, 2005, pages 37861-37862
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 18
The Comparability Exercise is fundamental to the
Development of an EU Biosimilar Product
Clinical
The comparability/similarity with the reference
with reference product
Confirm comparability
safety & efficacy
product must be demonstrated at all levels of
PK/PD product development:
Preclinical
Analytical comparability - physicochemical
Biological ESTABLISHING SIMILARITY
characterization Functional Comparability in assays, and
Physicochemical shown by animal studies
characterization
CONFIRMING SIMILARITY
Clinical Comparability shown in Phase I and
III studies
development
Product
Complete product
and process
development A biosimilar product is designed to meet the
criteria of the reference product with regards to
quality, safety and efficacy.
This rigorous comparability exercise qualifies
Define
Define and
target
characterize Biosimilars for therapeutic interchange
reference product
Derived from a Presentation By Ingrid Schwarzenberger, Sandoz
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 23Sep08 GWU “Biosimilar 2008” 19
Presented by Thomas Moore at Sanford
ENGEL & NOVITT, LLP The Law Firm That Knows its ScienceBernstein Biosimilars Conference, 3Dec09 20
The Safety and Efficacy of EU Biosimilars
Nicolas Rossignol, then Administrator of the EC’s
pharmaceuticals on questions of safety for EU biosimilars:
"I don't judge case by case, but I have a message:
we have promoted and developed with the European
Medicines Agency a special biosimilars framework.
So we are confident that if a product meets all the
requirements and gets a marketing authorisation
from the commission, it means that the product is
as safe and effective as any other product
authorized by the commission"
SCRIP World Pharmaceutical News 24 April 2008, reporting on EGA
Meeting, London
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 21
The EU Biosimilars approved to date
EU Biosimilar INN Reference Product Auth./Pos. Op. Date
Omnitrope Somatropin Genotropin 12 April 2006
(Sandoz) (Pfizer)
Valtropin Humatrope With
Somatropin 24 April 2006
(Biopartners) (Eli Lilly) approval
Binocrit epoetin alfa Eprex/Erypo 28 August 2007 sponsors
gain
(Sandoz) (Janssen-Cilag)
Epoetin alfa Hexal Eprex/Erypo
(Hexal)
epoetin alfa
(Janssen-Cilag)
28 August 2007 access in
Abseamed Eprex/Erypo all 27
epoetin alfa
countries
28 August 2007
(Medice) (Janssen-Cilag)
Retacrit epoetin zeta Eprex/Erypo 18 December 2007 of the EU,
(Hospira) (Janssen-Cilag)
but
Silapo
(Stada)
epoetin zeta Eprex/Erypo
(Janssen-Cilag)
18 December 2007 reimburse
16 September 2008/
-ment
Biograstim Neupogen
(CT Arzneimittel GmbH)
filgrastim
(Amgen) 24 July & 21 Feb 2008 systems
Filgrastim Ratiopharm Neupogen 16 September 2008 / still vary
filgrastim
(ratiopharm GmbH) (Amgen) 24 July & 21 Feb 2008 by
Ratiograstim filgrastim Neupogen 16 September 2008 / country
(ratiopharm GmbH) (Amgen) 24 July & 21 Feb 2008
Tevagrastim Neupogen 16 September 2008/
filgrastim
(Teva Generics GmbH) (Amgen) 24 July & 21 Feb 2008
Zarzio Filgrastim Neupogen
(Amgen) 13 February 2009/20 November 2008
(Sandoz)
Filgrastim Hexal filgrastim Neupogen
(Amgen) 13 February 2009/20 November 2008
(Hexal)
22
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 22
FDA Precedents for Everything?
Brand Name Generic Name Regulatory Date of FDA Sponsor Reference product
Pathway approval (sponsor, date of
original approval)
Naturally- Repronex menotropins ANDA 10-Jan-97 Lederle/ Pergonal (Serono, 1969)
sourced Ferring
products
Naturally- Repronex menotropins 505(b)(2) 27-Aug-99 Ferring Pergonal (Serono, 1969)
sourced
products
Vitrase hyaluronidase 505(b)(2) 5-May-04 Ista Pharms Wydase (Baxter, 22-
Mar-1950 )
Amphadase hyaluronidase 505(b)(2) 26-Oct-04 Amphastar Wydase (Baxter, 22-
Mar-50 )
Hydase hyaluronidase 505(b)(2) 25-Oct-05 Primapharm Wydase (Baxter, 22-
Mar-50 )
Recombinant Glucagen glucagon 505(b)(2) 22-Jun-98 Novo Nordisk Glucagon (Lilly, 14-Nov-
products hydrochloride 60)
recombinant
Fortical calcitonin salmon 505(b)(2) 12-Aug-05 Upsher Smith Miacalcin (Novartis, 17-
recombinant Aug-95)
Hylenex hyaluronidase 505(b)(2) 2-Dec-05 Halozyme Wydase (Baxter, 22-
recombinant Mar-50 )
human
Omnitrope somatropin 505(b)(2) 30-May-06 Sandoz/ Genotropin (Pharmacia
Novartis and Upjohn, 24-Aug-95)
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 23
But, for all biologics suppliers…
Regulatory requirements have increased as the collective ability to
do “more science” has increased - sameness has become pursuing
everything with every technique every time to show the absence
of a difference…
Reference standards are not routinely available. No API
commercial model for biologics
Comparability has become increasingly difficult, even for
innovators with their own products, e.g. when getting new facilities
on line, resulting in shortages. This drives pressures for more
suppliers. Quality matters.
Alternative sources/products are needed, and also incented by the
expanding markets (range of products, and more patients needing
access), and manufacturing can be more efficient…
Products in one market drive demands in others – global needs
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 24
Innovator comparability complicates the
story
AVONEX (Interferon Beta 1A) approved in 1996 based on
comparability and without clinical studies on final material
MYOZYME (alglucosidase alfa) for the treatment of late onset
Pompe disease. FDA decides material made at different scales are
different products (Oct08)
CEREZYME (Imiglucerase) manufacturing shortages due to viral
contamination such that different products subject to expanded
access studies (Protalix – Glucocerebrosidase) or switching
(Zavesca - miglustat)
FDA authority to use comparability is clear, but their caution
continues to be evident. Hence, it has become a very high
regulatory standard, and innovators inability to achieve it for their
own products suggest that biosimilars sponsors will have challenges
too.
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 25
Biosimilars can enable Regulatory
Progress for all Biologics
The PHS Act (1903) requires a demonstration of safety, purity and
potency. New legislation can enable, not impede, the
accommodation of scientific progress into the regulatory
framework – a win:win for all sponsors.
The goal of regulations for ANY biologic should be only to require
actionable data, i.e. ONLY, but ALL, necessary data on which to
make appropriate decisions. Regulations need to evolve with the
science if innovator products are to be licensed, and the promise of
biotech fulfilled.
Biosimilars are self-evidently possible, and FDA needs to the
authority to evaluate them and when appropriate designate them
as interchangeable. Only FDA will see the data and the licensure
has to be data-driven.
The FDA already has a >12 year old “sameness standard” for
biologics and drugs called comparability
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 26
Progress in science and regulations is a
continuum… …and should be global
Bio-manufacturing- Progress in ALL or
technology ANY give greater
•Process Analytical certainty to the
Technology
•MOA development of:
•Quality by Design
Pre-clinical
Analytics •Better disease • First generation
•Improved models biologics
technology •Comparative
•Orthogonal immungenicity • Follow-on
Clinical
methods & •Critical Path •Better predictive biologics
data safety models
integration •Adaptive clinical
trials design • Including second
•Post-marketing generation
studies
•More predictable
outcomes
•Validation of Note: Biologic can be manufactured
biomarkers as using biotechnology, synthetic
surrogate chemistry or using natural sources;
endpoints
some have been made with all three
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 27
So why are we having these discussions
about biosimilars, and why now?
BIOTECH IS A STORY OF SUCCESS Innovator biologics work
and patents are expiring. Consumers want more of them, both as
innovator products, and as cheaper versions of old products.
Access matters and is an unmet medical need.
ECONOMIC PRESSURES ARE ADDING TO THE NEED FOR A
SOLUTION ASAP Patents ending are visible, as are EU successes
with biosimilars, but cost is the biggest issue by far (both
individual and collective).
WE NEED COMPETITION FOR BIOLOGICS, AS WELL AS
DRUGS A lot can be learnt from the successes and failures of
generic drugs, but we need a process to be appropriate for
biologics. That requires legislation and the details will determine
the savings.
THE ISSUES ARE GLOBAL
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 28
Patient access to Rx depends on market
access for Rx
GLOBAL REGIONAL/NATIONAL
Healthcare systems vary
ACCESS (affects reimbursements
Patients are everywhere and ROI, 1y & 2y markets)
(albeit Dx and healthcare
infrastructure vary)
IP varies, and getting a
Market access is
little better harmonized,
determined by but barely (certain global
regulatory approval, free-trade norms are
Companies develop and
market viability by emerging but limited)
manufacture for the
reimbursement
leading markets, ideally
global standards
COMPETITION REQUIRES
(inconsistent requirements Regulations are regional
MARKET ACCESS & with some
lead to requirements for
FREEDOM TO PRICE harmonization for
different products)
drugs, and innovator
biologics (cost of getting
to market less if can use a
single data set)
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 29
BIOLOGICS/SIMILARS – the need for them is
global, but can they be made for a global market?
Europe US Brazil
Pathway in Legislative 0.19
place debate Largely
THE LEADER
Russia
0.31 Supporting
0.50 0.14
ICH plus others WHO
(1st World) India Guideline
Canada 1.14 Initiative
Japan
Guidance Guidance
China
Final Final
1.13
0.13 0.03
Australia
BRIC plus others
Using EU
(2nd World)
WHO approach
0.02
Biosimilar Guidelines
near final
ROW (Largely 3rd World)
Largely lack health care infrastructure for complex biologics
World Population WHO less relevant, but will recognize those standards
Total 6.7
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 30
Top Approved and Marketed Biologics
ENGEL & NOVITT, LLP The Law Firm That Knows its Science http://www.ftc.gov/bc/workshops/hcbio/docs/fob/rgal.pdf
31
Current US Regulatory Pathways
STATUTE APPLICATION
NEW DRUG
U.S. FOOD DRUG APPLICATION (NDA)
& COSMETIC ACT AND 505(B)(2) NDA
ABBREVIATED NDA
(ANDA) = GENERIC DRUG
U.S PUBLIC BIOLOGIC LICENSE
HEALTH SERVICE APPLICATION (BLA)
ACT
EXPEDITED
BLA
Derived from a Presentation By Keith Webber, Deputy Director, OPS, FDA. 25Sep07 GWU “Biosimilar 2007”
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 32
Licensure of Biologics in the US today:
The only pathway is the “Full BLA”
Raw Product C
Process B
Material A
As long as A and B stay the same, C can be sold without more clinical trials
Raw Product C’
Process B’
Material A’
C’ can be made and licensed today.
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 33
Interchangeability versus Substitutability
SMALL MOLECULE DRUGS BIOLOGICS
Responsibility of regulators (EMEA Responsibility of regulators
or FDA) (EMEA or FDA)
Interchangeability = Therapeutic Interchangeability =
Equivalence (based on Comparability (based on
Pharmaceutical equivalence plus highly similar at structural,
Bioequivalence) functional, and clinical levels)
Responsibility of health authorities Responsibility of health
(Countries or States) authorities (Countries or States)
Substitutability Substitutability
DO PAYORS NEED THE SUBSTITUTABILITY MODEL OF
GENERIC DRUGS TO GET REAL SAVINGS?
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 34
The US is falling behind…
European biosimilars are succeeding – 13 marketing
authorizations, increasing visibility and no evidence of
quality, safety or efficacy problems
The US is the largest biotech market – patents are expiring;
the science is universal; 8 FD&C Act follow-ons to biologic
drugs have been approved as 505(b)(2)s, one ANDA and
two in the wings
Economic pressures have increased as biotech products
have succeeded – free-market pricing for Rx in the US
cannot expect to continue without competition becoming
evident in the biologics market
Health care reform in the works – maybe. Biosimilars bills
are included in both US Senate and US House
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 35
Biologics Patent Expiration Estimates
Highlights important of availability of US pathway from date of
enactment
Now
Summary of Estimated Biosimilars Savings
Source
Entire US Population Entire US population, Medicare Part B Entire U.S. Population
but reported Federal beneficiaries
Population Government savings
Rolling 10-year period 2008-2017, with no “next ten years” beginning “over the next 10 to 20
Timeline savings 2007-2012 with pathway available in years”
2007
Erythropoietin, Interferons Non-specific therapies. All PHS Act regulated Generic versions of the top
Therapies for Multiple Sclerosis, (Erythropoietin biologics within the top 200 12 categories of biologic
Evaluated Growth Hormone for growth
deficiency, Insulin for
excluded almost
entirely due to timeline
HCPCs that are currently
reimbursed by Medicare
treatments with patent
protections that have
diabetes and gradual market Part B expired or are due to expire
movement) in the near future
Product specific analysis to Assumes 10% of Assumes only a single Assumes that a biogeneric
Assumptions calculate movable market biologic spend goes off competitor to each pathway is approved in
share. Substitution rates of patent per year. Market already-approved biologic 2008 and those products
83.4% (directly substitutable) penetration reaches when it goes off patent (and already off patent could be
and 49% (therapeutically 60% over 3-year period. that all patents are valid); approved by 2010.
substitutable). 25% discount Large revenue products that the savings will begin Assumes rapid introduction
on biogeneric products. reach discounts of 30%, at 15% rising to 30% over of biogenerics following
medium revenue 10 years patent expirations of
products achieve 10% original products. Price
discount. discount of 25-35% over a
10 and 20 yr period.
$71 Billion savings Federal Government Medicare Part B can save $67 billion to $108 billion
Conclusion opportunity in ten years can save $3.6 Billion $14 Billion over next 10 over first 10 yrs and $236
following approval of generic over ten years years. billion to $378 billion over
biotech products. 20 yrs
Government Projections for Biosimilars Savings
Source CBO-1 CBO-2 OMB CBO-3
Entire US Population, but Entire US population, but reported Entire US Population, Entire US Population, but
reported Federal Government Federal Government savings with and but reported Federal reported Federal
Population savings without Medicare Coding Reform Government savings Government savings (CBO
Score of Pres. Budget)
10-year period (2009-2018) 10-year period (2010-2019) 10-year period (2010- 10-year period (2010-19)
Timeline 19)
Non-specific therapies. Subset of Non-specific therapies. Subset of None identified. None identified.
Therapies biologics, that make up roughly biologics, that make up roughly three-
Evaluated three-quarters of the current quarters of the current market, that
market, that might face might face competition by Follow-On
competition by Follow-On Biologics over the next 10 years
Biologics over the next 10 years
Assumes S.1695 will be enacted Same assumptions as CBO-1 but with Assumes a period of Assumes a period of
Assumption near start FY 2009 & for the additional assumption that innovator exclusivity innovator exclusivity
interchangeability with 1 yr of Medicare Part B would be modified to “generally consistent “generally consistent with”
market exclusivity to the 1st place the follow-on biologic in the same with” Hatch-Waxman Hatch-Waxman and that
interchangeable FOB, 12 yrs of billing code as the reference product. and that brands would brands would be
exclusivity to the innovator, and be prohibited from prohibited from
accounts for the possibility of “evergreening”. “evergreening”.
“evergreening”. Assumes 35%
market share for FOB and price
discount of 40 % by 4th year of
competition.
Federal Government would save With no coding reform the total savings Federal Government Federal Government can
Conclusion $6.6 Billion over 10 years. Figure to Federal Government on Medicare can save $9.24 Billion save $13 Billion over 10
includes revenue changes. and Medicaid would be $9.2 Billion; over 10 years. It is years. Figure includes
with the modification savings would unclear whether this changes in revenue.
total $12 Billion over 10 years. Figures figure includes revenue
include revenue changes. changes.
The Payor Role in the utilization of
biosimilars is not yet clear
An FDA designation of interchangeability can give options for
automatic substitution with the reference product – the “Generic
Drug Model”
The absence of an interchangeability designation may give greater
or fewer choices for payors, and this will depend on the
reimbursement infrastructure. Options may include:
– Co-pays incentives for patients (tiering)
– Prior authorization for physicians
– Step Therapy and/or switching (happens between payors, but
less likely within)
De Facto therapeutic substitution may give the greatest potential
for savings to payors and patients
The role of Government payors will be very influential
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 39
MedPAC recommendations to Congress
(June2009)
Absent a free-market solution, alternative approaches will be
considered, and they may be difficult for biopharma.
MedPAC examined three strategies to pay for biologics under Parts
B and D that “by considering information about a drug’s clinical
effectiveness, have the potential to improved the value of Medicare
spending on drugs”:
Reference Pricing: Set a drug’s payment rate no higher than
the cost of currently available treatments unless evidence
shows the drug improves beneficiaries outcomes
Payment for results: Link a drug’s payment to beneficiaries
outcome through risk-sharing agreements with manufacturers
Bundling: Create payment bundles for groups of clinically
associated products and services
Thus it would appear to be in biopharma’s interest to find a fair
and sustainable solution.
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 40
So what could legislation for the US
include in order to increase competition…
Delegate authority to FDA to approve biologics that reference a
previously approved PHS Act biologic (data will always be product
specific, and sponsor must show safety, purity and potency). To
maximize competition pathway must be:
– Immediately available
– Apply consistent regulatory standards
– Allow for an interchangeability designations
– Flexible enough to absorb scientific developments
The PHS Act is a paragraph, and works for innovator products, the
ones we know the least about at time of initial approval -
something equally simple will do for biosimilars
Respect IP rights of innovators and biosimilar sponsors, plus a fair
exclusivity incentive for innovator products.
Support global consistency in regulatory requirements, such that a
global market access to biosimilars is possible too
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 41
US Legislation - Overview
• Two Biosimilar Bills are in currently in play in 111th Congress:
• House Energy & Commerce Committee adopted “Licensure
Pathway for Biosimilar Biological Products”
• Senate H.E.L.P. Committee adopted “Biologics Price
Competition and Innovation Act of 2009”
• Both now part of Health Care Reform and to a great extent
dependent on how that develops over the next few months
• Neither have gone to the floor of their respective houses, and
amendments are expected.
• The disparate elements in the two bill will need to be reconciled at
Conference:
• Regulatory Pathways– same
• Exclusivity – similar
• Patent provisions – different
• Even if overall health care reform fails, biosimilars legislation may
become a “lifeboat”
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Senate Biosimilars Bill
• Two-Step regulatory pathway based on “highly similar”
standard (identical to House)
• Biosimilars - analytics, preclinical, clinical (any of which
can be waived by FDA), extrapolation between indications;
• plus switching studies for interchangeability designation
• No blocking guidances or regulations as part of pathway
• REMS required
• Same generic name (INN) possible
• 12 year innovator exclusivity (and 180 notification prior to
marketing biosimilar); 1 year for first interchangeable
biosimilar
• Complex compulsory patent exchange provisions which put
patents at risk early, amends Title 35
• No requirement for regulations to be promulgated
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House Biosimilars Bill
• Two-Step regulatory pathway based on “highly similar” standard
(identical to Senate)
• Biosimilars - analytics, preclinical, clinical (any of which can
be waived by FDA), extrapolation between indications;
• plus switching studies for interchangeability designation
• No blocking guidances or regulations as part of pathway
• REMS required
• Requires unique name, but same generic name (INN) possible
• 12 year innovator exclusivity, plus possibility of 6 month
pediatric extension; 1 year for first interchangeable biosimilar
• Complex compulsory patent exchange provisions which put
patents at risk early, new regulations required, does not amend
Title 35
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FDA Implementation - Expectations
• Will depend on the details in the final legislation
• Hope/expect:
• Pathway implemented immediately (products already in
queue - Woodcock testimony Mar07)
• FDA adequately resourced through user fees
• No requirement for new FDA regulations for pathway to be
available
• Guidances will be developed, as in Europe, concurrently with
the biosimilars being reviewed and approved
• Patent litigation could continue as today for biotech, i.e.
independently of FDA review and approval, but current
proposals have it linked such that FDA completes it review, but
waits for the outcome of litigation before issuing the biosimilar
license. As such patents are at risk early. However, no Orange
Book for biologics.
• Full BLAs, including for second generation products, continue
with patent litigation as today – unencumbered
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Fundamental questions for any biologic
sponsor - what data, what label, what market?
Are the regulatory standards for all biologics to be
consistent, namely safety, purity and potency, and are
separate products evaluatable using comparability (ICH,
basis for EU & WHO)?
Are regulatory authorities to be allowed to designate a FOB
and its reference as interchangeable or will payors decide
individually, absent data and according to their own rules?
Is the US to get a new pathway – what is it and when is it
usable? Is FDA approval to be linked to the patent system?
Is competition in the market going to occur, and be seen to
occur? Or is “sameness” going to be a barrier…
Are the rules enabling access to FOBs going to be consistent
globally?
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Second-generation products, biobetters,
and bio-I-just-don’t-knows
If it costs more to be biosimilar than to do a “full BLA”, why not be
better but use the advantages of:
– An RLD that has already defined the market value
– Lower failure rate as have a model product
– Studies can be focused, and manufacturing efficient
– Tweaks can be market-based too, e.g. devices, stability
– Not constrained by reverse engineering limitations
– Get your own 12 year exclusivity
Avoids innovator exclusivity should it be granted in US legislation
(albeit patents still apply – same as today)
We all learn from prior knowledge, so biobetter can be just not-
shown-to-be-the-same
Biobetters can be developed for a global market
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Opportunities and Conclusions
We can learn from generic drugs, but we do not repeat the
mistakes – no need to reinvent the patent morass
All stakeholders understanding their own interests, and engaging
to generate an expedited pathway to enable/increase competition
and access will be a collective win:win. Poles are not helpful.
Quality will always matter, especially in the Post-Eprex and Post-
Vioxx world, and that affects the whole supply chain
Realistic expectations of biologics, as well as drugs, such that the
new products can reach patients and drive the upward cycle of
innovation, access and health matters. That means new biologic
approvals too
Global consistency in regulatory requirements key – lessons from
Europe and beyond are useful
Reimbursement models must recognize biosimilars in a manner
that fosters legitimate competition, not therapeutic substitution
Result can be creation of a regulatory pathway for FOBs in the US,
that enables competition in the biologics market when patents
expire
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Thank You!
Gillian R. Woollett, M.A., D.Phil.
Chief scientist
Engel & Novitt, LLP
The Law Firm That Knows Its Science
www.engelnovitt.com
202.207.3307
gwoollett@engelnovitt.com
The material and viewpoints set forth in this slide deck
and conveyed during this presentation are presented by the author
in her capacity as Chief Scientist of Engel & Novitt, LLP.
They do not represent and do not purport to represent the views of the law firm
or any current or former-client of the firm, and should not be construed as such.
ENGEL & NOVITT, LLP The Law Firm That Knows its Science 49
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