Transcript European Biotechnology Symposium

The new EU pharma legislation: who
came out ahead? Generics or
innovators?
6th European Biotechnology
Symposium, Copenhagen
13-15 November 2005
Linda Horton, JD, LLM
Hogan & Hartson L.L.P.
Brussels and Washington, DC
Description of our session
The new European pharmaceutical legislation enacted
in 2004 included landmark provisions on regulatory
data protection, generic drugs, and "biosimilars."
Many issues are still being worked out in the new
legislation, and there are many questions about the
level of data needed to show comparability.
Meanwhile, legislative changes are affected by legal
challenges in the EU courts such as the Omnitrop
case. Member States are required to implement the
new laws this month.
Overview
Relationship between regulatory exclusivity law and
patent law
Landmarks in Development of EU Medicinal Products
Law relevant to topic
Generics provisions
Bolar provisions
Biosimilar provisions
Relationship of regulatory
exclusivity law to patent law
Both types designed to create incentives
to innovation.
Patent law provides a period of legal
monopoly (20 years) in exchange for
disclosure of the invention.
Essence of a patent is the right to exclude
others
Relationship of regulatory
exclusivity law to patent law
Regulatory exclusivity is a separate area of innovator
protections recognizing:
• The extraordinary expense involved in testing new
products
• Not all significant discoveries are patentable
Established in EU and U.S. laws
Established in trade agreements providing separate
innovator protections: patents & exclusivity.
Not to be confused with “data protection” under EU privacy
law
Exclusivity: types
With data exclusivity, there can be neither
disclosure of regulatory data to a competitor
nor regulatory reliance upon the data.
• However, unless a patent blocks the way, a competitor can
reach the market by generating his own data on his
version of the drug (“testing his way to market”).
With marketing exclusivity, agency cannot
allow a competing product to enter the market
during a time period in which an innovator has
a right of exclusivity
• Competitor cannot generate own data to get around the
exclusivity
Landmarks in Development
of EU Medicinal Products Law
1965
First European Community medicines law, Directive 65/65
Established framework requirements for authorization of
medicinal products
As amended in 1987:
“The applicant shall not be required to provide the results of
pharmacological and toxicological tests or the results of
clinical trials if he can demonstrate…either that the
medicinal product is ‘substantially similar’ to a product
authorized in the country concerned...or by detailed
references to published scientific literature… For Reference
Landmarks in Development
of EU Medicinal Products Law
1987
…or that the medicinal product is essentially similar to a
product which has been authorized within the
Community, in accordance with Community provisions
in force, for not less than six years and is marketed in
the Member State for which the application is made;
this period shall be extended to 10 years in the case of
high-technology medicinal products …furthermore, a
Member State may also extend this period to 10 years
by a single decision covering all the products
marketed on its territory where it considers this
For
necessary in the interests of public health.”
Reference
Landmarks in Development
of EU Medicinal Products Law
1992
Under 65/65 as amended, Member States were at
liberty not to apply the six-year period past
the date of expiry of a patent.
1768/92: Supplementary protection certificates (re
patent term restoration up to 5 years,
extending ordinary patent term of 20
years)
For
Reference
Landmarks in Development
of EU Medicinal Products Law
1993
World Trade Organization Agreement on TradeRelated Intellectual Property Rights
Article 39.3 protection for undisclosed data,
including trade secrets
For
Reference
Landmarks in Development
of EU Medicinal Products Law
1993
Regulation establishing the European Agency for the
Evaluation of Medicinal Products (EMEA)
10 years of exclusivity for centrally authorised
products.
For
Reference
Landmarks in Development
of EU Medicinal Products Law
2000
Orphan Medicinal Products Regulation141/2000
• The first product to obtain an approval in the EU
blocks for 10 years any existing marketing
authorization for the “same therapeutic indication” in
respect of a “similar medicinal product.”
• Unchanged by 2004 legislation
Commission Regulation (EC) No. 847/2000.
• "similar medicinal product" and "clinical superiority"
For
Reference
Landmarks in Development
of EU Medicinal Products Law
2000
In 2000, the WTO issued a panel report
deciding on a challenge by the European
Union (EU) vs. Canada to Canadian
“Bolar” law.
The WTO Panel concluded that Canada's law
is a "limited exception" within the meaning
of TRIPS Article 30 “[a]s long as the
exception is confined to conduct needed to
comply with the requirements of the
regulatory approval process.”
For
Reference
Landmarks in Development
of EU Medicinal Products Law
2001
Community Code on Medicinal Products
• 2001/83: Human Use Directive
• codification of 65/65, 78/318, 75/319, 89/342, 89/341,
89/381, 92/25, 92/26, 92/27, 92/28, and 92/73
July 2001: Start of Review Process leading to
legislation published April 30, 2004
Commission proposal: harmonise to 10 + 1
For
Reference
Landmarks in Development
of EU Medicinal Products Law
2003
2003/63: New Annex 1 to Directive 2001/83 (ICH
Common Technical Document; different
requirements for biologics)
December 2003: EMEA CPMP Guidance documents
on comparability
For
Reference
The challenge to legislators
Striking the balance between innovator rights,
and generic opportunities, was one of the
most contentious issues in the development
of the recently enacted EU medicines
legislation.
Exclusivity Provisions
In the new Pharmaceuticals
Legislation
Data Exclusivity before amendments
• centrally approved products and concertation
products: 10 years
• nationally approved products:
• 10 years: Belgium, Germany, France,
Italy, Netherlands, Sweden, the UK, and
Luxembourg
• 6 years: Austria, Denmark, Finland,
Ireland, Portugal, Spain, Greece (also
Norway, Iceland)
Data Exclusivity Changes
Future System “8+2+1”
• 8 years data exclusivity: no generic applications fileable
• 2 years marketing protection: no generic applications
approvable
• + 1 year: new indication(s) if it constitutes a significant
clinical benefit
• For all products, regardless of nationally, via central or
decentralized approval procedure
• Not retroactive; does not affect exclusivity periods for
products authorized before effective date
Other Exclusivity Provisions
1 year data exclusivity for a new indication for
a well-established substance
1 year data exclusivity for change of the
classification
Orphan drug exclusivity unchanged
New pediatric exclusivity under consideration
U.S. Exclusivity Periods
In the U.S. there is a:
5 year data exclusivity period for a new chemical
entity,
3 year data exclusivity period for a new indication,
6 month data exclusivity period for pediatric
indications as well as a
7 year marketing exclusivity period for a drug that
FDA has designated as an orphan drug.
U.S. Patent Term Restoration
In addition to exclusivity periods, under the
1984 Hatch-Waxman Act, pharmaceutical
patent owners are granted patent term
restoration to restore part of the loss of
potential patent life due to the need to
develop, test, and seek regulatory approval
of the product (35 USC 156).
A company can get both patent term
restoration and exclusivity.
Bolar provision
In the new EU pharmaceuticals
legislation
Art. 10 (5) – Bolar Provision
“ Conducting the necessary studies and trials with a
view to the application of paragraphs 1, 2, 3 and 4 to a
generic medicinal product and the consequential
practical requirements shall not be regarded as
contrary to patent rights or to supplementary protection
certificates for those medicinal products.”
Providing samples is included in permissible activities
Otherwise, patent law is unchanged.
Why is this called “Bolar”
provision?
In Roche Products, Inc. v. Bolar
Pharmaceutical Co. 733 F. 2nd 858,
certiorari denied 469 U.S. 856 (1984),
the court of appeals held that U.S.
patent law was violated when a
generic company (Bolar) tested its
product against that of the pioneer
(Roche) during the patent life of the
latter’s pioneer product.
Hatch Waxman reversed court
decision
Subsequently, as part of the 1984 Hatch-Waxman law, the
holding of the Bolar case was reversed in a provision
dubbed the “Bolar” provision, 35 USC 271 (e)(1), which
reads in part:
It shall not be an act of infringement to make, use, offer to
sell, or sell within the United States or import into the
United States a patented invention . . . solely for uses
reasonably related to the development and submission
of information under a Federal law which regulates the
manufacture, use, or sale of drugs or veterinary
biological products.
The WTO Case, EU v. Canada, has a
bearing on today’s EU Bolar provision
2000
In 2000, the WTO issued a panel report deciding
on a challenge by the European Union (EU)
vs. Canada to Canadian “extended Bolar” law
which went beyond regulatory testing and
allowed stockpiling.
The WTO Panel concluded that Canada's law is
a "limited exception" within the meaning of
TRIPS Article 30 “[a]s long as the exception is
confined to conduct needed to comply with the
requirements of the regulatory approval
For
process.”
Reference
What the WTO said...
• Even though regulatory approval processes
may require substantial amounts of test
production to demonstrate reliable
manufacturing, the patent owner's rights
themselves are not impaired any further by
the size of such production runs, as long as
they are solely for regulatory purposes
and no commercial use is made of
resulting final products.
Stockpiling not “small and
narrowly bounded.”
The WTO Panel concluded that the
stockpiling exception in Canada’s law
“constitutes a substantial curtailment of
the exclusionary rights required to be
granted to patent owners under Article 28.1
of the TRIPS Agreement….and cannot be
considered a "limited exception" within the
meaning of Article 30 of the Agreement.”
No stockpiling & no sale of
drugs
During the patent life of the pioneer drug, the
generic competitor is allowed to make the
drug only for regulatory review purposes:
Stockpiling is not allowed.
Selling drugs made during patent term is not
allowed.
Bolar provisions an exception
to normal patent law
A Bolar provision allows a generic product producer,
during the patent life of the pioneer’s drug, to conduct
certain testing of the generic product against the
pioneer’s drug as needed to secure regulatory
approval—but not to produce commercial quantities or
fill the pipeline.
Following the WTO case, the EU decided to switch
sides on Bolar.
The innovative industry hoped this was tied to “10+1” on
exclusivity
The 10 new prospective EU members expressed views!
“Generics” provisions
In new EU pharmaceuticals
legislation
Amendments to the Community
Code Directive: “generic medicinal
product”
Art. 10 (2) (b)
“generic medicinal product” shall mean a
medicinal product which has the same qualitative
and quantitative composition in active substances
and the same pharmaceutical form as the
reference medicinal product, and whose
bioequivalence with the reference medicinal
product has been demonstrated by appropriate
bioavailability studies. …
For
Reference
.
Amendments to the Community
Code Directive: “generic medicinal
product”
…The different salts, esters, ethers, isomers, mixtures
of isomers, complexes or derivatives of an active
substance shall be considered to be the same active
substance, unless they differ significantly in properties
with regard to safety and/or efficacy. In such cases,
additional information providing proof of the safety
and/or efficacy of the various salts, esters or
derivatives of an authorised active substance must be
supplied by the applicant. The various immediaterelease oral pharmaceutical forms shall be
considered to be one and the same pharmaceutical
form. Bioavailability studies need not be required of
the applicant if he can demonstrate that the generic
medicinal product meets the relevant criteria as
defined in the appropriate detailed guidelines.
Differences from Generics Case
C-368/96 (European Court of Justice)
“Generic medicinal product”
• can include all different salts, esters, ethers,
isomers, etc. provided there is not a different
safety or efficacy profile
• states that all immediate release oral forms
are the same
• Refers to “global marketing authorization”
(Art. 6 (1)).
Abridged applications
(for generic medicinal products)
Reference product need not be approved in the
Member State of application
Member State agencies are expected to cooperate
and share dossiers if necessary
Bioavailability requirements are less strict
“global marketing authorisation” concept to prevent
innovators from “evergreening” their products
with changes
Effect: little reward to innovators for product
improvements
Biosimilar provisions
In new EU pharmaceuticals
legislation
Why different from chemical
drugs as to follow-on products
For chemical drugs that can be exactly copied,
the product is not so process-dependent, and
copies can be produced through reverse
engineering, good chemistry, tight
specifications, and Good Manufacturing
Practices for day-to-day consistency in actual
production.
For biological drugs, there are always
differences among different manufacturers’
products, and “the process is the product,
and the product is the process.”
Biosimilars under EU Medicines Law
“Biosimilars” are products that cannot meet the criteria
for “generics,” generally because they are largemolecule proteins and one cannot be sure they are
sufficiently close to the originator’s product.
First EU regulatory pathway for biosimilars: June 2003
Commission Directive (2003/63/EC)
• amending the Community code on medicinal products
establishing a new Annex on the required contents of
an Application for Marketing Authorization.
• Article 4 of the revised Annex I, Part II, set forth the
specific marketing authorization dossier requirements
for “similar biological medicinal products.”
Biosimilars under EU
Medicines Law
2 guidance documents were published in December
2003 by the key EMA committee responsible for
product assessments, now called the Committee on
Human Medicinal Products (CHMP).
The new 2004 medicines legislation, amending the
Community code on medicinal products for human
use (Directive 2004/27/EC), continues and codifies
this prior law.
Biosimilars: Article 10.4 of the
directive
“Where a biological medicinal product which is similar
to a reference biological product does not meet the
conditions in the definition of generic medicinal
products, owing to, in particular, differences relating
to raw materials or differences in manufacturing
processes of the biological medicinal product and
the reference biological medicinal product, the
results of appropriate pre-clinical tests or clinical
trials relating to these conditions must be provided.
…
Biosimilars: Article 10.4 of the
directive
…The type and quantity of supplementary data
to be provided must comply with the relevant
criteria stated in Annex I and the related
detailed guidelines. The results of other tests
and trials from the reference medicinal
product’s dossier shall not be provided.”
Biosimilars under EU
Medicines Law : continued
Also various guidelines under the
International Conference on
Harmonization (ICH) are
recognized by the EMEA
March 2005 guidance from the
EMEA on quality issues in biotechderived biosimilars
Biosimilars
The European Commission has announced that the
European Medicines Agency (EMEA) will be the only
approval authority for biosimilars.
Many, many details remain to be worked out:
• Guidance documents, beyond the 2 December 2003
guidance documents, such as product-class
guidelines.
• Litigation (Omnitrop case in European Court of First
Instance; and now a similar case in the U.S.!).
• In individual approvals? In both the EU and the U.S,
there is more transparency for stakeholders where a
public process and guidance documents are used
(compared with approval process).
What are the EMEA
Guidelines?
On May 16, 2005, the European Medicines Agency (EMEA)
issued a final guideline describing general principles for
clinical and non-clinical issues involved in the approval of
similar biological medicinal products (biosimilars).
The guideline is accompanied by 4 annexes providing more
targeted guidance on approval requirements for these
recombinant proteins:
• Erythropoietin (EPO),
• Granulocyte-colony stimulating factor (GCSF),
• Insulin, and
• Somatropin, i.e., human growth hormone (HGH).
What Do the Guidelines Say? (1)
Require full quality dossier, extensive non-clinical and
clinical studies, immunogenicity studies, ‘extensive’
comparability, comparative pharmacokinetics.
For clinical safety and pharmacovigilance
requirements, the guideline distinguishes:
• pre-approval phase: safety data from
preauthorization studies, from
• the post-approval phase: close monitoring of the
product.
What Do the Guidelines Say? (2)
The applicant should include in the application:
• a "risk specification" (describing possible safety
issues due to the manufacturing process being
different from that of the innovator),
• a pharmacovigilance plan in accord with EU
legislation/guidelines.
The EMEA warns that compliance will be strictly monitored
• Penalties regulation in preparation in case of noncompliance
=>Hefty requirements, certainly in relation to those for
traditional generics
…other points to note
Each application will be handled on a case-bycase basis.
Each biosimilar applicant must justify the approach
taken and is encouraged to seek early
discussions with the EMEA.
The same reference product should be used for all
aspects of the application (quality, safety, and
efficacy).
The EMEA recommends use, in the required
clinical trials, of the test product produced with
the final manufacturing process.
What do the
Guidelines Mean?
Europe is serious about getting these biosimilars approved
and wants to do so in the short-term.
There is political pressure (access to cheaper drugs) as
well as scientific pressure
Several applications are pending (BioPartners, Sandoz)
The guidelines likely represent an amalgamation or
compromise of the content of those applications.
(Some) Un-answered
Questions
Data confidentiality : Can the regulators refer to
innovator data files, and do they intend to?
Safety: is the barrier sufficiently high—particularly
if regulators are allowing safety to be shown
post-marketing?
Comparability: confusion between intra-company
and inter-company
Will product substitution be allowed?
Is patient consent needed where pre-market trials
were small?
And a Few
Inconsistencies….
For example, the EPO annex calls for:
• Safety data from at least 300 patients is adequate in
efficacy trials
• Postmarket reporting will add to this database.
• The applicant should provide at least 12-months
immunogenicity data in biosimilar-treated patients.
• Retention of samples for both ‘titration’ and ‘maintenance’
studies is recommended.
• For the detection of anti-epoetin antibodies, a validated,
highly sensitive assay should be used.
Yet EMEA is proposing to excuse erythropoietin
biosimilars from many safety studies that had
been carried out by the innovator companies
More worrying, the EMEA is requiring testing on
just one indication to get all authorized
indications!
What is going to
happen next?
The odds are that these guidelines, or something
near, will be approved.
Comment period open until October 31, 2005.
The EMEA is co-sponsoring a workshop in Paris
on biosimilars, organized by the Drug
Information Association (DIA) and scheduled
for December 8 and 9, 2005.
Should Innovators Challenge
Biosimilar Authorizations?
Case-law precedents on “generics” generally pro-generic
Will judges understand how biosimilars differ from
generics (biosimilars are neither “essentially similar” or
the “same”)?
Will the clause on intellectual property help?
How will judges view regulatory reference to innovator
data?
How will they view shortcuts based on “what is known”
How will it play out when everyone is operating in the
dark?
• Biosimilar applicants have not seen the
innovator’s reference product dossier
• Innovators have not seen the biosimilars’
dossiers
• Regulators do not produce pharmaceuticals,
and the dossiers they have in hand present
only a subset of the know-how on biotech
biological production
• Reference products were approved long ago;
regulatory standards have changed and many
changes made in production of the reference
product
Action May Shift PostApproval
Even if products do get approved, questions of price
(not likely much lower) reimbursement (which
countries will reimburse?), switching (will it be
allowed?).
Will physicians/ patients perceive biosimilars as less
safe?
Innovators can be expected to leverage their
reputation/ brand/safety data to discourage
switching.
=> Perceptions of safety may play out against price
New Pathway Redundant?
Are stringent data requirements for biosimilars, plus
risks & uncertainties around post-approval
marketing forcing biosimilar firms into developing
improved biologics, distinguishable from the original
in dosage, convenience, freedom from human
serum albumin etc.?
Which raises the question: how useful will the new
regulatory pathway be after all?
US-EU Issue :: Proprietary
Data Protected Or Not?
May a regulatory reviewer rely on a reference
product’s data in reviewing biosimilar
application?
What about innovator’s trade secret methods or
processes?
See Genentech Petition to FDA
Use of Innovators’ data in Regulatory
Reviews of Biosimilars?
Is Regulatory Reliance on Reference Product Data
Allowed in EU?
Article 10.4 of the EU community code on medicinal
products, as amended: … “The results of other tests
and trials from the reference medicinal product’s
dossier shall not be provided”
Right of Reference
CONTRAST Article 10c
• Following the granting of a marketing authorisation, the MAA
may allow use to be made of the documentation contained in
the file, with a view to examining subsequent applications
relating to other medicinal products possessing the same
qualitative and quantitative composition in terms of active
substances and the same pharmaceutical form
WITH Article 10.4
“The results of other tests and trials from the reference medicinal
product’s dossier shall not be provided”
Concerns with March 2005
EMEA Guidance on Quality
The EMEA continues to use “comparability” to describe
both intra-company comparability—where the use is
proper—and also inter-company comparison—where
“similarity” would be better
In contrast, the ICH guideline (accepted in the US, Europe
and Japan) on comparability deals specifically with
comparability in the context of a single manufacturer
The EU Process Has
Been Closed
CPMP and EMEA Working Groups meet behind
closed doors
Who wrote which document?
Guideline development: opportunity for comment,
but
Where are the responses to previous comments?
Should people re-comment?
No other EMEA public process to date except
through conferences sponsored by other
organisations
1:1 discussions between biosimilar applicants and
CHMP and/or rapporteur
For further information please
contact . . .
Linda R. Horton
Partner
View Building
rue de l'Industrie 26
B-1040 Brussels
Belgium
Tel: +32.2.505.0931
(Brussels)
Tel:+1.202.637.5795
(Washington, DC)
Mobile: + 1.202.250.9880
Email: [email protected]
. . . or visit www.hhlaw.com
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Linda R. Horton, Partner
Hogan & Hartson L.L.P.
[email protected]
rue de l’industrie 26, B-1040 Brussels BE
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