PRODUCTION OF BIOGENERICS
Key Issues
BIOTEC INDIA INTERNATIONAL 2003
AGENDA:
1) The Vision
2) Market Drivers
3) Obstacles
4) Indian Scenario
5)Strategy
6)Future of biogenerics
BIOGENERICS ARE:
1. Biopharmaceutical preparations involving a biologically active
substance stemming from modern biotech tools.
2. Similar to an original biopharmaceutical whose substance
patent expired
3. Could be approved through a simplified abbreviated registration
process
4. Are sold under the generic substance name as opposed to brand name
(eg. EPO as opposed to Epogen)
The term off-patent biotechnological products
(OPBPs) as an alternative to biogenerics when
describing such products.
MARKET DRIVERS
Let’s review the reasons behind the interest they have
sparked……..
MONEY
• The US market now for biopharmaceuticals is approximately
$20 billion.
• If biogenerics achieve the same, 10-15% medium to long-term
penetration rate of rest of the market,it means there is a
potential biogeneric market of $2 billion in US alone.
• The
two
main
segments
of
biogenerics
are
recombinant protein technology and monoclonal antibodies. The
global sales of recombinant therapeutics are expected to be in
the region of $4,610 billion by 2005.
Manufacturers of biogenerics …….
 Do not have to recover the hefty outlay of
research and development
 Can charge significantly less for their biogeneric
version than the brand-name product and still
make a handsome profit.
 Biogenerics offer large profit margins, with
relatively low impact of cost of bulk
biopharmaceutical on overall price.
Less expensive clearances
In most countries, when the initial patent for a
small-molecule drug expires, other companies
are free to manufacture the compound and
market it (may be) without having to repeat the
expensive development and (complete) clinical
trials process.
Opportunities
 During next five years, top 15 biopharmaceutical will
come off-patent.
 More opportunities for generic formulators.
 Few of biogenerics are already under manufacturing or
development including EPO, hepatitis B vaccines and
CSFs by circumventing the patent issues.
 Some have lost their patent protection( Insulin and
human growth hormones) and therefore open to
generic competition.
Statistics….
Brand
Active
substance
Marketer
Year of
approval
Generics under
development
1999 sales in
millions$
EPOGEN
Epoetin
alfa
Amgen Inc.
1989
Yes
1760.0
Humulin
50% human
insulin isophane
suspension, 50%
human insulin
(rDNA)
Eli Lilly & Co.
1992
Yes
1088.0
Betaseron
Interferon
Beta – 1b
Eli Lilly & Co.
Yes
413.0
Engerix - B
Hepatitis-B
vaccine
Biogen Inc.
Yes
540.0
1993
1989
MARKET EXISTS….
• Manufacturers can be confident that a market exists
for the product.
• Biogenerics satisfy large market size qualification.
Most biotech products expected to come off-patent
comprise several biologics still showing double digit
growth.
• Most health care insurers will now insist that
prescriptions be filled by biogenerics whenever
possible.
OBSTACLES….
1.
2.
3.
4.
Availability of bulk active biopharmaceutical through
non-patent infringing routes.
Patent coverage for biopharmaceuticals represents a
thorny path for biogenerics.
Biogenerics must clear more regulatory hurdles than
traditional small- molecule generics.
Bioequivalence for therapeutic proteins : To produce a
protein identical to a branded drug and to comply with
the regulations , a generic manufacturer must use the
same protein expression system, purification protocol and
delivery technology as in original patent.
OBSTACLES…..
6. Need to demonstrate essential similarity to original product.
7. Even minor modifications in a bioprocess such as changes in
agitation or aeration systems, reactor size, operating
conditions or culture media, not to mention changes in the
cell line or microbial system applied can result in variations
in quality or properties of the biopharmaceutical.
8. A protein can be folded, glycosylated and methylated in
quite different ways if expressed in different systems (for
example, mammalian versus bacterial cultures)and these
differences can radically alter its characteristics.
OBSTACLES …..
9. Lack of clear regulatory framework. Biogeneric
developers need regulatory standards so that
they may avoid undertaking massive
investments to develop the product.
Existing Regulations worldwide:
• Bio-equivalence standard: United States , Canada and the European
Union- requires that the generic drug has a pharmacokinetic profile
similar to brand name drug.
• USA: Manufacturers of generic drugs must file for abbreviated new
drug application(ANDA)-may take 2-5 years to demonstrate
bioequivalence and manufacturing facility certified.
• US FDA: Companies seeking to market biogenerics in US have to file
“process-improvement” application and carry out limited clinical trials
to get approval.
• Health Canada: Preliminary guidelines for approval of generic
biopharmaceuticals and clinical trials to demonstrate safety and
efficacy.
Existing Regulations worldwide:
• In Europe, it is not clear :
• whether a biogeneric should be registered through the
abbreviated procedure applicable for well-defined
traditional generics requiring "that the generic is
essentially similar to a reference product;
• if not, the generic should undergo a full registration
process logged with the European Medicines Agency"
(EMEA Committee for proprietary medicinal products).
Big fish Strikes Back
• Biopharmaceutical innovators are expected to fiercely defend
their franchise, engaging in a wide array of tactics, including
proactive efforts to influence and shape the regulatory
framework and stress to the medical community the value and
safety of the original product, compared to biogenerics.
• The unique aspects of biotechnology patent law and its
complexities certainly represent a fertile ground for
biopharmaceutical innovators to hinder the development of
biogenerics, providing a nightmare for potential generic
producers.
• Amgen defending EPO’s position against Genetic Institutes and
now against Transkaryotic Therapies;
• Repositioning the molecule through new
enhanced formulations offering tangible benefits
in terms of patient compliance, sustained release
forms, lower adverse effects.
• Accelerating the introduction of a second
generation product, and possibly phasing out
the original molecule:
Amgen’s strategy with NESP, the novel erythropoiesis stimulating protein
currently under registration.
• An additional hurdle for the development of
biogenerics whilst providing an additional period
of exclusivity for the originators, is the provision
that the generic company would not be able to start
any substantial development work on the
biopharmaceutical before the effective patent
expiry date.
INDIAN SCENARIO
No price war….
Indian companies are attracted not only by the
size of biologicals going off-patent but also
because there is no price war as in
formulations market.
Companies could price biological product at
five percent less than multinationals and still
grab substantial market.
• The cost of process for R & D is also relatively low
( cost-effective)
• Many companies have manufacturing facilities that
satisfy the economies of scale and adhere to WHO
norms.
• Spate of tie-ups, partnerships and acquisitions for
marketing internationally by Indian companies
• Lack of marketing muscles for biologicals.
STRATEGY
CLEARING HURDLES
• The dogma that the "process makes the product"
has been increasingly challenged. It appears that—
if not strictly identical—at least comparable
biologics can be obtained through different
processes.
• This is the case for most well-characterized
proteins.
HGH is being produced in Europe in a variety of
expression systems , with identical results, a 191-amino
acid sequence copying the human pituitary growth
hormone. All of these products appear to show the same
profiles in terms of amino acid sequence, potency and
safety and efficacy, undermining the belief that "the
process makes the product."
Producer
Expression system
Pharmacia
Ferring
Standard
E.coli
Lilly
Novo
Special strains
of E.coli
Serono
Transformed mouse
Cell line
Product
191 amino acid
sequence
“identical” to the
human
pituitary growth
hormone
Pharming for profits
• Some companies subcontract their protein production
capabilities.
Ex. Genzyme Transgenics has developed mammalian mammary
gland expression systems, primarily in goats, for over 60
therapeutic proteins.
• Some companies may compromise by selling proteins as
generics.
• Some may compromise by collaborating with current
manufacturers to improve production processes, depending
on which route is more feasible for a given drug.
• Small start up companies have partnered with brand-name
biogeneric manufacturers which may offer good short term
insurance against regulatory hurdles and litigation.
• Existing players in the small molecule generics market are also
moving into biogenerics.
Ex. In 1999, generics giants Ivax (Miami,FL) and Teva
(Jeruselam,Israel) bought biognerics capabilities in-house through
partnerships with Indiana Protein Technologies (Indianapolis, IN)
and Biotechnology General ( Iselin,NJ) respectively.
Ex. Biotecnol (Lisbon, Portugal) has cloned and expressed a
large number of proteins coming off-patent between 2001-2007,
and plans to commercialize both the proteins and the company’s
improved bacterial systems.
• The demand for contract expression facilities have
increased.
Ex. Two companies, TranXenoGen (London,UK) and Viragen
(Edinburgh,UK and Plantation.FL,in collaboration with the
Roslin Institute in Edinburgh) intend to express therapeutic
proteins in the albumin of the eggs of transgenic chickens.
Branded for life?
• Several human growth hormones have now been manufactured
which has led to extensive litigation.
ex. Pharmacia (Peapack,NJ) stopped producing plasminogen
activator streptokinase because of competition from biogenerics.
• Some companies have managed to protect their market share
from biogenerics,sometimes unintentionally.
Ex.The original patent for Schering’s recombinant interferonα(Intron) have expired in 2002,but because of a dispute over the
initial discovery of the protein, a competing patent claim was filed
by Roche (Basel,Switzerland) and Genentech (S. San Francisco,
CA).
Future development depends on interrelated variables
BIOGENERICS
• First, the biogeneric market requires the
development of a favorable regulatory and patent
framework.
• The availability of bulk material and bulk
biogenerics suppliers is also a must for the
development of a biogeneric market. Several reliable contract
biopharmaceutical producers are starting to emerge (Boehringer-Ingelheim, CambrexBSCP, Diosynth-Covance, DSM-Biologics, Lonza).
Advances in analytical technologies
New technologies in this field may allow a more
accurate characterization of macromolecules,
opening new frontiers in terms of demonstration of
equivalence or even essential similarity
Policies and approaches
• Many are still waiting on the sidelines, hoping the biogenerics
situation will become clear. Undoubtedly, once the first
biogeneric hits the market, many companies will step up their
efforts in this field.
• The receptivity of the customer base, including patients and
health care providers, to generic formulations also represents a
potential barrier. Most of the biopharmaceuticals on the market
target serious diseases in which the risk of switching patients to
new formulations could be viewed by health providers as
unwarranted and dangerous, given fears about biogeneric
quality.
Hope for the best……..
• Major hurdles are still hindering the development of
biogenerics, but the overall field is rapidly evolving.
• Breakthroughs in the regulatory environment must not be ruled
out.
• Perspective participants, eager to capitalize on this potential
opportunity, must carefully monitor the field, keeping in mind
that timing is of the essence.
THANK YOU
PANACEA BIOTEC LTD.
In support of Life