Biogenerics*

a/k/a Follow-on biologics** or biosimilars*** or

biopharmaceuticals****

Albert Wai-Kit Chan, Ph.D

Law Offices of Albert Wai-Kit Chan, PLLC

*Term to refer to interchangeable biosimilars

**Term used by Biotechnology Industries Organization
***Term used to determine the comparability and similarity of a medicinal biological product
alternative to a reference product.
****Term preferred by GPhA to refer to non-interchangeable biosimilars
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
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 History: Regulation of Biologics in
the U.S.
• Biologics have been around since the development of vaccines.
• Biologics were first regulated in 1902 by the Biologics Act when
the diphtheria vaccine was being produced.
• Public Health Service Act (PHSA) was passed in 1912 to regulate
biologics. The Act was revised in 1944 to require licensure and
the criteria for license approval was established.

• The definition of drug was expanded to include biologics under

the FDCA (Food, Drug & Cosmetic Act); which mostly governs
chemical drug development.

• The PHSA primarily governs biologics and requires a biologics

license application (BLA).
• The BLA is the equivalent of a NDA for chemical drugs.

History taken from Michael E. Clark et. al, Pharmaceutical Law: Regulation of Research, Development, and Marketing, 56-60 (2007).

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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History: Development of the
Biotechnology Industry in the U.S.
• The development of the biotechnology industry began in
the 1970s with advancement in technology.

• There was no patent approval process for biotechnology

because the biological components were considered to
have been found in nature.

• In 1980, the Supreme Court approved the principal of

patenting genetically engineered life forms in Diamond v.
Chakrabarty, 447 U.S. 303 (1980).

• This landmark decision paved the way for patenting

biotechnology that resulted in the growth of the industry.

Information from History of Biotechnology – Time available at www.biotechinstitute.org/what_is/timeline.html and

http://bio.org/speeches/pubs/er/statistics.asp.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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History: Biotechnology Industry in
the U.S.
• In 1982, Humulin, an insulin produced by genetically
engineered bacteria, developed by Genentech, became the
first biotech drug to be approved by the FDA (Food & Drug
Administration) for treatment of diabetes.*
• Today, there are approximately 1500 biotechnology
companies in the U.S.**
• The total GDP of these companies are over $60 billion
dollars.**

*Information from History of Biotechnology – Time available at www.biotechinstitute.org/what_is/timeline.html.

**Information from Bio at http://bio.org/speeches/pubs/er/statistics.asp.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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 Today
• According to the California Public Employees Retirement
System, its average cost for chemically based prescription
drugs are $2 per day while biopharmaceutical drugs cost
$55 per day.
• Biotech drugs are being used increasingly to treat diseases
such as diabetes, cardiovascular diseases and cancer.

Taken from GPhA at http://www.gphaonline.org/AM/Template.cfm?Section=Federal_Affairs&TEMPLATE=/CM/HTMLDisplay.cfm&CONTENTID=1948

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Hatch-Waxman Act

• In 1984, Congress passed the Hatch-Waxman Act, (PL 98-

417).

– Created the Abbreviated New Drug Application (ANDA)

that streamlined the approval process if the chemical
agent used is shown to be a bioequivalent of the original
patented drug.

– Created a process for challenging a Patented chemical

drug.

– To date, there is no equivalent legislation for biologics.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Requirements for Biologics
License Application (BLA)

• 42 U.S.C. §262 requires:

– The biological product that is subject of the application is
safe, pure and potent;

– The facility in which the biological product is

manufactured, processed, packed, or held meets
standards designed to assure that the biological product
continues to be safe, pure and potent;

– Applicant consents to the inspection of the facility that is

the subject of the application.

From Michael E. Clark et. al, Pharmaceutical Law: Regulation of Research, Development, and Marketing, 60-62 (2007).

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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 Requirements for Biologics License Application
The BLA must also contain:
1. a full description of manufacturing methods;
2. data establishing stability of the product through the dating
period;
3. sample(s) representative of the product for introduction or
delivery for introduction into interstate commerce;
4. summaries of results of tests performed on the lot(s)
represented by the submitted sample(s);
5. specimens of the labels, enclosures, and containers;
6. any medication guide proposed in the use of the product; and
7. the address of each location involved in the manufacturing of
the biological product.

From Michael E. Clark et. al, Pharmaceutical Law: Regulation of Research, Development, and Marketing, 60-62 (2007).

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Requirements for “well-characterized therapeutic
recombinant DNA-derived and monoclonal
antibody”

well-characterized means:
• Products with definable, measurable, and controllable identity,
purity, impurities, potency/biological activity, and quantity;
• Recombinant DNA biotechnology products with known amino acid
sequence, known secondary structure (including disulfide bonds),
and post-translational modifications (such as glycosylation); or
• Monoclonal antibodies with an identity that could be determined
by rigorous physicochemical and immunological tests without full
knowledge of chemical structure.

From Michael E. Clark et. al, Pharmaceutical Law: Regulation of Research, Development, and Marketing, 60-62 (2007).

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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BLA Approval

Must demonstrate:

– No microbial or viral contamination;

– No endotoxin, exotoxins, pyrogens; and
– No nucleic acids (which were thought capable of
delivering oncogenes and transforming the DNA of a
potential patient.

• Once BLA approved, then Clinical trial phases

begin.

From Michael E. Clark et. al, Pharmaceutical Law: Regulation of Research, Development, and Marketing, 60-62 (2007).

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Biogenerics Debate

• The debate between the innovator companies

and generic companies on whether or not a
biosimilar developed would have the same result
as the innovator drug, have been going on for
more than a decade.

• Is it a question of science or politics?

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Biogenerics Debate
• Bio (Biotechnology Industry Organization), the leading lobby
organization of innovator companies’ position:
– Safety: Biologics are much more complex in structure than small
molecule drugs and therefore it is not possible to have a “generic”
of the branded drug.

– Immunogenicity: Occurs when our bodies treat a protein as if it is

a foreign substance and produces antibodies to attack it. All
biologics have the potential to stimulate antibody production in
patients. Switching back and forth between products could
trigger an immunogenic reaction.

– Initially wanted at least 14 years of exclusivity to protect incentive

for innovation.

Taken from Bio at http://bio.org/healthcare/followonbkg/.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Biogenerics Debate
• Bio’s position, continued.:
– Science not available to adequately review biogenerics without
clinical studies.

– Biopharmaceuticals cannot be properly and completely

characterized.

– “Even if it were possible to establish the ‘sameness’ of a follow-

on biologic without clinical trials, agency reviewers would be
unable to perform the rigorous scientific assessment necessary
to reach legitimate conclusions about ‘sameness’ without first
examining trade secret data concerning the manufacturing
processes of the innovator, which is prohibited by law.”

– Cites the EMEA (European Medicines Agency) which requires

case-by-case review that includes clinical trials.

Taken from Bio at http://bio.org/healthcare/followonbkg/.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Biogenerics Debate

This is Genentech’s illustration of the difference between

biologics and small molecule drugs and why it is not
possible to have a “biosimilar,” it’s too complex.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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 Biogenerics Debate
• Generic Pharmaceutical Association’s (GPhA) positions:
– Terminology/Nomenclature – what the drugs are called is important to
the effects it has on consumers.
• Non-interchangeable entities should be called
“biopharmaceuticals.”
• Interchangeable entities should be called “biogenerics.”

– A streamlined or abbreviated review process should include the

following criteria:
• Extent of Characterization
• Comparability of biopharmaceutical product to reference
product
• Observed variability in the reference product
• Available data linking analytical test parameters and clinical
effects
Taken from GPhA’s White Paper on Generic Biopharmaceuticals (2004) at
http://www.gphaonline.org/AM/Template.cfm?Section=Federal_Affairs&Template=/CM/ContentDisplay.cfm&ContentID=1573.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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 Biogenerics Debate
GPhA’s positions:

– Characterization – modern advances in technology enables current

analytical methods to completely characterize certain proteins, albeit
not all complex proteins. Proposes the following criteria:

• Observed variability in the reference product – measuring lot-

to-lot variability of the reference drug for a baseline
assessment.
• Clinically tested range of variation and product changes – the
range of variation in the reference product used in clinical
studies be used as the boundaries to compare in terms of
compositions, processes and/or formulations.

Taken from GPhA’s White Paper on Generic Biopharmaceuticals (2004) at

http://www.gphaonline.org/AM/Template.cfm?Section=Federal_Affairs&Template=/CM/ContentDisplay.cfm&ContentID=1573.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Biogenerics Debate
• Characterization continued:
– Available data linking analytical test parameters and clinical
effects – use publicly available information of in vivo – in vitro
correlation, if they are available.

– Interchangeability versus approvability – characterization

acceptance criteria should be designed with a few toward
whether a determination of interchangeability or approvability is
sought.

– Biological activity assays – allow the development of similar

biological activity assays or employ some combination of tests
that yield the same information as the reference’s biological
activity assays so long as the results show comparability I
identity, purity, potency, quality and safety.
Taken from GPhA’s White Paper on Generic Biopharmaceuticals (2004) at
http://www.gphaonline.org/AM/Template.cfm?Section=Federal_Affairs&Template=/CM/ContentDisplay.cfm&ContentID=1573.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Biogenerics Debate
GPhA positions continued:

• Manufacturing – should ensure the identity, potency, purity, quality and

safety of the final product rather than whether the process is the same as
the original (reference product) process
– Full CMC (Chemistry, Manufacturing and Controls) should be submitted

• Pre-Clinical Studies – should depend on whether there remains

unanswered questions after review of the analytical characterization
studies.
• Pharmacokinetic/Pharmacodynamic Studies – only if the reference
product necessitates a PK/PD study then the “generic” would be
required.

Taken from GPhA’s White Paper on Generic Biopharmaceuticals (2004) at http://www.gphaonline.org/AM/Template.cfm?

Section=Federal_Affairs&Template=/CM/ContentDisplay.cfm&ContentID=1573.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Biogenerics Debate

GPhA positions continued:

• Clinical Studies – only when necessary and required when other
comparative analytical data is inadequate.
– Criteria for determining if clinical studies are necessary should be
a rational, scientifically sound decision.

– Characterization of reference product should be the baseline for

comparison
– Study should be on a smaller patient population and should not
exceed the size of the study population of the reference product.

Taken from GPhA’s White Paper on Generic Biopharmaceuticals (2004) at http://www.gphaonline.org/AM/Template.cfm?

Section=Federal_Affairs&Template=/CM/ContentDisplay.cfm&ContentID=1573.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Biogenerics Debate
GPhA positions continued:

• Immunogenicity
– not unique to only biopharmaceuticals but also known to occur in chemical
drugs;
– Evaluations should focus on whether or not the antibodies are harmful and
detrimental vs. transient;
– Consider taking a risk management approaching which resources
are focused on assessing product factors with the greatest risk of
immunogenicity, i.e. aggregation;
– Clinical trials do not necessarily detect all incidents of immunogenicity,
particularly in rare incidences, including the reference product. Chiefly,
clinical trials done solely to evaluate differences in immunogenicity
in a limited patient population would be of limited utility.

• Exclusivity period should be the same as Hatch-Waxman Act, five years.

Taken from GPhA’s White Paper on Generic Biopharmaceuticals (2004) at http://www.gphaonline.org/AM/Template.cfm?

Section=Federal_Affairs&Template=/CM/ContentDisplay.cfm&ContentID=1573.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Most Recent Legislation
H.R. 5629 introduced by Rep. Anna
Eshoo on March 13, 2008 with 43 co-
sponsors in the House of
Representatives. (mostly supports
Bio’s positions) [has not been
reintroduced as of 2/2/2009]
Highlights of differences
Approval Requirements
• Similarity to reference product with
respect to each condition of use for
which reference product was approved
for, including clinical studies
• Clinical studies may be waived at
discretion of the Secretary only after a
draft guidance has been published for
the product class to which that product
belongs and public comments have
been taken into consideration.
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
S. 1695 – introduced by Sen. Ted
Kennedy with four co-sponsors,
including Sen. Hatch on June 26,
2007 in the Senate; [mostly supports
GPhA’s positions [has not been
reintroduced as of 2/2/2009]
Highlights of differences
Approval Requirements
• Biological product is biosimilar to a
reference product based upon data
derived from studies; where clinical
studies may be waived by the
Secretary if deemed unnecessary
for an application.
• Whether or not a final guidance is
published is not a hindrance for
review and approval of the
application.
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Most Recent Legislation
H.R. 5629
Interchangeability:
• show that the biological product is
Same as S. 1695, except:
– Requires the Secretary to
issue a draft guidance of
the product class that the
application’s product
belongs to for public
comment and then after
consideration of the public
comments, can publish a
final guidance determining
that the product is
interchangeable with the
reference product.
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
S. 1695
• Requires Secretary to license if the
information submitted is sufficient to
biosimilar or interchangeable with the
reference product.
• Product is interchangeable if:
– Product is biosimilar to reference
product and can be expected to
produce the same clinical result in
any given patient;
– For a product that is administered
more than once, the risk of safety
or efficacy of switching between
the biological and reference
product is not greater than the risk
of using the reference product
without switching.
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Most Recent Legislation

H.R. 5629 S. 1695

• Requirement for
• Requirement for
application consideration:
application consideration
– The Secretary may not
accept an application – No requirements of the
until proceedings have issuance or non-
been initiated for the issuance of a guidance
issuance of guidance. is required for review or
action on the
– The Secretary may not application.
approve an application
until process for
issuance of the
guidance has been
completed.
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
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Most Recent Legislation

H.R. 5629 S. 1695

• Exclusivity of “generic” • Exclusivity of “generic”

– Cannot approve a – Sets different time

second “generic” before period that takes into
24 months. consideration the
possibility of on-going
• Naming litigation; but minimum is
12 months.
– Name must uniquely
indentify the “generic” • Naming
and distinguishes from
the reference product. – Not addressed.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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Most Recent Legislation

H.R. 5629 S. 1695

• Exclusivity of the reference • Exclusivity of the reference
product product
– Same as S. 1695, but if a – No approval of a “generic”
supplement to the until 12 years after the
reference product is reference product was first
approved, then exclusivity licensed regardless of
is extended to 14 years whether a supplement was
from when licensed. subsequently approved.

– Allows application to be – Allows application to be

submitted 4 years after submitted 4 years after the
license issued, OR after reference product has
the date of proceedings been licensed.
commenced for issuance
of guidance, whichever is
later.
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
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Most recent legislation: Infringement
H.R. 1695
Process as proposed:
1. Within 30 days of acceptance of
application the Secretary shall
publish a notice identifying the
reference product and name and
address of designated agent.
2. Within the same 30 days, Applicant
shall provide reference product
sponsor with a copy of the
application including:
– Detailed description of the
“generic” product
– Method of manufacture
– Materials used in
manufacturing
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
S. 1695
Process as proposed:
1. Application submitted for review
2. Applicant informed that the
application has been accepted for
review
3. Applicant shall provide a copy of
the application to reference
product Sponsor within 20 days.
4. Applicant may provide additional
information requested by Sponsor
5. Within 60 days of receipt of
application, Sponsor shall provide
a list of patents Sponsor believes a
claim of infringement could
reasonably be asserted.
6. Sponsor can provide a list of
patents Sponsor would be willing
to license to Applicant.
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Most Recent Legislation: Infringement
H.R. 5629
3. Within 60 days of receipt of the
information from Applicant, Sponsor
shall provide a list of relevant
patents owned by the Sponsor.
4. Within 45 days of receipt of
Sponsor’s patent list, Applicant shall
either:
• State that Applicant will not
commence marketing and has
requested the Secretary not to
grant final approval; OR
• Provide a detailed written
explanation as to why
Applicant believes the making,
use, sale or importation of the
“generic” will not infringe
Sponsor’s patent(s); OR
• State that the patent is invalid
or unenforceable
5. Sponsor has 60 days to file an
infringement suit; if Sponsor
prevails, application can only be
approved after the patent expires.
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
S. 1695
7. Within 60 days of receipt of list by
Sponsor, Applicant may provide a
list of patents that the Sponsor may
assert a patent infringement claim;
8. Applicant shall provide either:
• provide a detailed statement, on
a claim by claim basis, the factual
and legal basis of why such
patent is invalid, unenforceable,
or will not be infringed by the
commercial marketing of the
“generic” product; or
• a statement that the applicant
does not intend to begin
commercial marketing of the
“generic” product before such
patent expires; and
• Shall provide to reference product
sponsor a response regarding each
patent identified Sponsor is willing to
license.
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Most Recent Legislation: Infringement
H.R. 5629
6. If Sponsor does not file suit, then
Applicant can only file a Declaratory
Judgment action three (3) years prior
to the expiration of the 12 year
exclusivity of the issued license.
7. This bill also provides for an
interested third-party to file suit if the
third-party deems that the application
may infringe upon one or more of its
patents.
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
S. 1695
• Not later than 60 days of Applicant’s
statement of why the patent is
invalid, unenforceable or will not be
infringed, Sponsor shall provide a
response, on a claim by claim basis,
the factual and legal basis of the
opinion of the Reference Product
Sponsor that such patent will be
infringed by the commercial
marketing of the biological product.
10. Both parties must then engage in
“good-faith” negotiations on which
patents both can agree shall be the
subject of an action for patent
infringement.
11. Failure to reach an agreement within
15 days of beginning negotiations,
both sides will submit a list of
potential patent infringements.
12. Sponsor has 30 days of agreement
or no agreement of the list of
patents, to file a patent infringement
action.
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Assessment/Realistic Assumptions
• Under the House bill, at
minimum, it would take 195
days or 6½ months before an
infringement suit is filed.
• But if the Sponsor does not
file a suit, a declaratory
judgment could not be filed
until at least 5 years later.
[assuming that an application
is filed 4 years after the
issuance of the Sponsor’s
license and Applicant must
wait until 3 years prior to the
expiration of the 12
exclusivity period.]
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
• Under the Senate bill, at
minimum, it would take 245
days or 8½ months before an
infringement lawsuit would be
filed.
• The Senate emphasizes
negotiation and even if an
infringement suit is filed, both
sides would have already
presented their legal
arguments which potentially
makes it easier for a
summary judgment motion
on either side ending
litigation much sooner.
• The average length of
litigations under Hatch-
Waxman takes 3 ½ years.
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Assessment/Realistic Assumptions
• What was highlighted were the differences in the
two competing bills.
• As you have seen, the differences appears to be
more “political” than “scientific.”
• The purpose of the Hatch-Waxman Act was to
enable generic companies to file an abbreviated
application to be approved by the FDA that is
streamlined and does not require the extensive
clinical trials as that of the “patented” application.
• The application can be filed after the patent has
expired OR by challenging the validity of the
patent 5 years after its NDA was approved.
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
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Assessment/Realistic Assumptions

• Therefore, based upon the purpose and intent of

Hatch-Waxman, it would appear that Congress
would pass a bill that would be closer to the
Senate’s version with some compromise with the
House’s version.

• The Obama administration has signaled its

support for a biogenerics bill and it is believed
that legislation could pass within the next 4 years.

©2009 Law Offices of Albert Wai-Kit Chan, PLLC

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European Union: EMEA guidelines

• In 2004, the European Union passed Directive 2004/24/EC

and 2004/27/EC to provide for approvals of biosimilars for
drugs once the patents expires.

• Since this Directive and its subsequent guidelines, there

are 7 biosimilars that have been approved by the EMEA for
sale after patent expirations.

• Two for human growth hormone somatropin*, three for

epoetin alfa*, a treatment for anemia and most recently one
for sifrol**, a treatment for Parkinson’s disease and
rebetol**, a treatment for hepatitis C.
*Sean Milmo, Report from:Europe, PharmTech.com, October 2, 2008 at
http://pharmtech.findpharma.com/pharmtech/Article/Report-From-Europe/ArticleStandard/Article/detail/558009?
contextCategoryId=35556&searchString=biosimilars .
**EMEA Summaries of Opinions at http://www.emea.europa.eu/pdfs/human/opinion/RibavirinTeva_3449309en.pdf. and
http://www.emea.europa.eu/pdfs/human/opinion/PramipexoleTeva_54961708en.pdf.
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
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Opportunity for Indian pharmaceuticals

• Indian pharmaceutical companies have been one of the

leaders in providing generic drugs in the U.S. market.

• Indian biotech companies are already selling biogenerics in

its home market and therefore have already developed the
technology required.

• The new legislation may cut down litigation costs enabling

Indian companies, including smaller pharmaceuticals to
play a significant role.

• According to GPhA, more and more biotechnology drugs

are relying on the chemical make-up of the biologics, which
is within the expertise of current small molecule generic
drug companies.
©2009 Law Offices of Albert Wai-Kit Chan, PLLC
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