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Cuban
Biotech Plans to Build on Past Successes:
Cuba's Integrated Approach to Research and Production is Rapidly Maturing
Genetic Engineering
News, March 2002.
Simon Reid-Henry
The Cuban biotechnology
industry has seen dramatic growth over the last twenty years,
particularly when taking into account its status as a developing
economy confronting considerable obstacles. Having long claimed
that Cuba holds the world record for developing interferon production
in the least time (from nothing to first-batch production in
just six weeks back in 1981), the Cubans are now keen to demonstrate
to the global marketplace-which for interferon (IFN) products
amounts to some $1.5 billion per year-that their research and
production capacities have recently both deepened and matured.
Back
in 1986, at the inauguration of the Center for Genetic Engineering
and Biotechnology (CIGB), the institution at the heart of the
biotech industry in Cuba, Fidel Castro said that biotechnology
would become "one of the forefront technologies that would determine
the future development of Cuba." An era of state-sponsored
bioscience development was thus introduced that even the economic
stringencies of the "Special Period" of the early 1990s
have not held back.
Recent Advances
The "International
Symposium on Interferon and Cytokines," held in Havana,
bore witness to this persistent growth. The event presented clinical
results mainly from the last two years, including a number of
new products and new forms of administering IFN.
Cuban research
in this area has expanded to include not only the IFN alpha-2b
they have traditionally specialized in, but also other cytokines
and growth factors such as IFN gamma, erythropoietin, granulocyte
colony stimulating factor, interleukins 2 and 15, and results
on the molecular mechanisms of transfer factor.
Although initially
intended to be a small affair, the event brought to the foreground
the growing dialogue between Cuban biotechnology and foreign
companies and researchers.
As
Pedro López-Saura,
M.D., Ph.D., vice director of regulatory affairs and clinical
studies of the CIGB, explains, "We had thought of having
a small reunion of some foreign friends and the groups here from
the CIGB working on interferon to celebrate the [20th] anniversary
of the production of interferon," but in the end, this event
turned out to involve 415 delegates from a number of countries,
with 364 from Cuban research or production centers. The significance
of this event is seen when it is set against the historical context
in which Cuban biotech has developed. In 1986, when the CIGB
was set up, only 5% of the global investment in health research-US$30
billion-was directed to health problems in underdeveloped countries.
This event was therefore a demonstration, 15 years later, of
the realizable potential of an independent biotechnology program
in the developing world and the scale on which this can occur
(see Biotechnology's Impact on the War on Poverty in Kenya, GEN,
October 15, 2001). Today there is not just the CIGB, but a range
of institutions from R&D to production, on a scale to rival
many university-business clusters in the developed world. There
are, for example, over 700 researchers and scientists at the
CIGB alone.
But the major
problem for developing countries, even those with basic science
facilities, remains the cost of research and access to markets.
Cuba has faced problems similar to those of other countries in
this respect.
In the early
1990s, according to Carlos Mella, deputy general manager of Heber
Biotec (Havana), the dedicated marketing arm of the CIGB dealing
with its registered products, the Cuban approach has been to
work through local distributors in the targeted countries to
avoid the high cost that presumes to install a worldwide sales
force. Mella saw this during negotiations with Pasteur Merrieux
(Lyon, France), where, in order to install such level of sales,
the cost to the company was hundreds of millions of dollars and
ten years.
History
Specializing
in IFN production has certainly been the key dynamic in the history
of Cuban biotechnology. By focusing on a delimited portfolio,
the initial group of scientists were able to channel the science
being developed immediately into domestic use, while at the same
time obtaining experience in all the relevant areas, from purification
through to quality control. For example, in the first few months
of production, natural leukocyte IFN was being used to treat
a dengue epidemic that broke out in Cuba in early 1981. Such
an approach was facilitated in its early years by a relative
isolation from the market pressures that confront most biotech
start-ups, even if the country itself faced great financial strictures.
Since
then "there
has been continual growth," according to Dr. López-Saura,
with both expansion and evolution into institutes such as CIM
(Center for Molecular Immunology) or CENPALAB (National Center
for the Production of Laboratory Animals) and various other bodies,
based at Cuba's various "scientific poles." These act
as effective science parks, pooling research with production
capacity in a highly integrated network.
Cuban biotechnology
extends far beyond the perimeter of the CIGB. For example, the
West Havana scientific pole, where the CIGB is based, consists
of 51 institutions dedicated to developing biotechnological research
into a range of products from pharmaceuticals to cosmetics. Cuban
IFN has been used to successfully treat 16 different viral infections
in Cuba, including acute and chronic hepatitis C, hepatitis B,
and respiratory papilomatosis.
Basic Research
But an increased
emphasis on broadening basic research in the late 1990s is no
small part of the reason why Cuban biotech today is coming to
fruition in a range of areas. This work takes advantage of combined
research, development, and production facilities at the CIGB
of some 60,000 m2, in addition to 1,500 m2 of hot houses, 2.5
hectares of cultivable land, and 6,000 m2 of production facilities
at Biocen (the National Biopreparations Center; Havana), amounting
to 11.6 hectares of installations in total.
There has also
been what Mella describes as the coming together of experience
and economic drive through fostering a younger generation of
workers with experiences drawn not just from science but also
from all fields of the biotechnology industry, including economics.
A good example
of the integration of different parts of this biotech network
in Cuba is the development of epidermal growth factor as a joint
project between the Centre for Oncology and the CIGB. The resulting
product is currently going through clinical trials (with a view
to marketing) but is already used by the Cuban health system.
Another key area that current work focuses on is transfer factor,
with batches taken from all parts of the country to ensure a
varied source.
IFN Gamma is
the project closest to the international marketing stage. Approved
last year, but still being improved on, it shows promising results
in a variety of uses, such as in the treatment of TB, for example.
However, conducting clinical studies on this product has proved
difficult because of the size of the country; Cuba has few TB
cases to work with.
Applied
Research
The
catchphrase for Cuba's approach to biotech, as Luis Herrera,
general director of the CIGB, notes, is "cooperation and exchange." Accordingly,
the CIGB for example, is structured into three general management
divisions and seven sub-divisions, such as the business group,
biomedical research group, and clinical trials group, which interact
with each other and other institutions in the scientific poles.
Communications
between units is certainly in evidence. The principal lines of
development that this network then feeds into include human vaccines,
biopharmaceutical products, diagnosis, and agricultural applications-all
points of contact for extending the "cooperation and exchange" overseas.
More
specifically, emphasis is placed on bringing all parts of the
life cycle of the products themselves together: from initial
conception through to post-production quality assessments, something
that Jürg
Gysi, Ph.D., general manager of Catalys (Wallisellen, Switzerland),
describes as "an interesting closed circle you don't find
elsewhere." The research network is thereby directly incorporated
into the production process. The explanation for this lies in
the organization and precepts of Cuban biotech at large. Not
only is integration something that occurs spatially, by having
basic products produced on the same site where basic research
is done and with many researchers living on-site, for example,
but it also occurs temporally, with a number of feedbacks being
applied to the process so that quality controls may be maintained
at all sstages, including a post-production responsiveness that
makes their products flexible to market conditions.
As
Dr. López-Saura
points out, "Cuba is neither a large nor a rich country," so
the focus on cooperation becomes all the more important. But
how, exactly, do foreign companies become incorporated within
this? In the case of Catalys, contact with Cuba began with the
exchange of technical information four years ago after representatives
attended a conference in Cuba. Since then, links have developed
with individual researchers and directors. In many ways Cuba
has already formed an overseas extension of the network.
Developing
Foreign Markets
The
first foreign market to be supplied commercially-excluding the
previous availability of products to countries in need-was Brazil
in 1989, shortly followed by China. In the 12 years since then,
commercial relations with foreign companies have grown to constitute
a network based on more than 200 products approved in more than
52 countries. As Miriela Gil, of the CIGB's business development
group, states, "We
have been developing relations with many countries." All
such foreign commercial agreements are controlled through Heber
Biotec, and, as Dr. Gysi notes, "The research that they
[the CIGB] are doing is, in the end, all geared toward what they
are doing in Heber."
The profits
made by Heber Biotec go to the state and are then largely directed
into the health system. A certain amount is fed directly back
into research and product development at the CIGB. In marketing
terms, Heber Biotec's most successful product has been Heberbiovac
HB, its anti-hepatitis B vaccine, of which $180 million has been
sold in 10 years, and 78 million doses of which have been injected
in patients in a number of countries.
IFN Alpha is
the only first-line FDA-approved treatment for hepatitis B. Other
products include Heberon Alfa R, the company's recombinant Alfa-2b
treatment, produced in Escherichia coli. This product has recently
shown efficacy in the treatment of both viral and oncologic infections
in several clinical trials involving BALB/c mice and is used
against hepatitis B and C and malignant neoplasys, among other
uses.
A
number of foreign companies, who were also part of the commercial
stand at the conference, including Catalys, the Mexican firms
Pepra Tech (District Federal) and Grupo Eetisur (Yucatán),
and ItalCaribe, have all developed relations with Cuba over the
last five years and commented on the speed at which these have
developed.
Domestic
Markets
A number of
Cuban companies were present, including Labiofam (Havana) and
Biocen. Labiofam is the domestic market leader in biopharmaceutical
products, supplying 95% of the veterinary medicines used in Cuba.
It has offices in 13 countries, from Argentina and China to Jordan.
Biocen, which has existed for less than ten years, has, according
to sales representative Adalmis Alonso, recently developed a
wider range of products, such as its CromoCen CC fluorogenic
medium, allows detection and count of microorganisms by color
in less than 24 hours and with a greater contrast than other
culture media. Biocen also produces commercial products, such
as Biotrofer, an antianemic and tonic of natural origins.
All production
in Cuban centers must conform to strict quality-control criteria
that have recently been tightened in order to meet Good Management
Practices. Taking the purification process as an example, throughout
the entire process, rigorous quality (viability, purity, plasmid
stability) and process (biomass weight, total protein concentration,
IFN purity by electrophoresis) controls are applied, such that
the final product not only passes the appropriate tests (such
as USP24, regarding sterility, and BP98, regarding innocuousness)
but that it compares favorably to other commercial products in
terms of purity and potency.
Regulation
Compliance
In recognition
of this, and as reported by the registrations and regulations
department of the CIGB, a satisfactory in situ inspection was
carried out by a group of WHO international inspectors in October
2000. The resulting qualification will allow CIGB to sell the
vaccine to U.N. International Agencies.
Similarly, with regard to IPR regulations, Dr. López-Saura points out
that for future products in Cuba, "the principal change that will take
place, and that is currently taking place, is that the new products are patented." This
will affect, for example, the new IFN gamma product, and may inject greater
capital into the development of new products.
Pipeline
There
are currently many projects in the pipeline and at various sstages
from patent applications to clinical trials. Moreover, according
to Dr. López-Saura, "There
are products in the pipeline for the next 15 years," and
it seems that the Cubans are keeping their eye on certain opening
markets. "Latin America will be a key market," confirms
Carlos Mella.
The
most immediate products to emerge from Cuba will include the
liquid injectable IFN, an epidermal growth factor currently undergoing
clinical trials, and transfer factor. In the long term, the Cubans
are confident that they will consolidate their position as the
leading biotechnology center in Latin America and the developing
world, as well as continuing to make the kind of inroads into
the global market of the developed world's biotech companies.
Mella continues, "We
lack money and nothing more."
This suggests that it is not just the facilities in Cuba that have matured
but the country's research and development process more generally. The characteristically
integrated and applied approach to biotechnology remains, but a broader development
strategy, including a greater economic sophistication, has been introduced
alongside. This has in turn produced moves to standardization perhaps most
clearly seen in its attention to quality management and patenting.
The Next
Step
However, despite
the maturing of Cuban biotech, it is clear that a deepening need
to continue if it is to further consolidate its position as a
key biotechnology center, positioned to access both developed
and developing-world markets. And it will need to seek out greater
levels of investment.
But it is also
clear that the Cuban biotechnology industry is determined to
build on the platform of past success so as to be a player in
the emerging phase of global bioscience development. Cuba's joining
of HUGO (Human Genome Organization) last year is perhaps more
than a hint that it wishes to add in silico research to its in
vivo and in vitro experience, and may point to the shape of things
to come.
What is certain
is that Cuba already has the educational and technical resources
to be a part of the next wave of drug production and the commitment
to turn this into a viable development strategy for the next
20 years.
Simon Reid-Henry is based at Jesus College, University of Cambridge, U.K. E-mail:
smr26@cam. ac.uk.
• Biotechnology
exports increase by 42% in 2001
Heber
Biotec S.A., exclusive distributor of the products developed
by the Centre for Genetic Engineering and Biotechnology, wins
National Export Prize in the category of large firms • Recombinant
hepatitis B vaccine leads in sales
BY LILLIAM
RIERA (Granma International staff writer)
THE firm Heber
Biotec S.A., whose exports for last year increased by 42.1% in
comparison to 2000, won the National Export Prize in the category
of large firms, for companies whose annual sales plans exceed
$10 million USD.
The company,
100% Cuban-owned, holds exclusive rights to the international
marketing of all products, technology and projects coming out
of the Genetic Engineering and Biotechnology Center (CIGB) of
Havana.
General
Manager Mayda Mauri told Granma International that the award "demonstrates
the maturity reached by the biotech sector within the Cuban economy," based
on the decision made by the Cuban government in the 1980s to
achieve this scientific branch’s completion of the cycle
of research, development, production and marketing.
She
added boasts "the
work and genius of researchers and producers (from the CIGB and
the National Biopreparations Center) as well as the strict fulfillment
of international norms of quality."
Mauri
indicated that in 2001, "millions of doses of vaccines and hundreds
of thousands of biological products" were exported, constituting "a
record in terms of volume and value," she added.
SALES IN MORE
THAN 35 COUNTRIES
Heber Biotec
exports to more than 35 nations, many of them Latin American,
as well as some Asian, Middle Eastern, and Eastern European countries.
However, the executive highlighted that gradual introduction
into First World markets is an important objective.
He noted that
the recombinant vaccine against hepatitis B (called Heberbiovac
HB) holds the lead in sales and commented that at the beginning
of this year, the firm received certification from the World
Health Organization permitting the CIGB, through Heber Biotec,
to become a vaccine supplier for United Nations agencies like
UNICEF and the Pan American Health Organization.
Similarly,
she highlighted the increase in exports of recombinant streptokinase
(Heberkinasa), used in cases of acute myocardial infarction,
deep venous thrombosis and pulmonary embolism; alpha 2b human
recombinant interferon (Heberon Alfa R), for the treatment of
viral hepatitis B and C, human papilloma virus and infections
among AIDS patients; as well as a creme with recombinant human
epidermal growth factor (Hebermin), which improves scarring by
stimulating the formation of new blood vessels.
Mauri explained
that this year the hepatitis B vaccine without Tiomersal, an
alternative responding to market demand, has already been registered
on the island and is being marketed, along with the recombinant
human gamma interferon (Heberon Gamma R), with antiviral action
and for the treatment of patients with juvenile rheumatoid arthritis.
She added that
they are also marketing a line of products derived from human
placenta, developed by the Placental Histotherapy Center, such
as Melagenina Plus, to combat vitiligo (an illness that provokes
the depigmentation of the skin); Coriodermina, for the treatment
of psoriasis; and other skin cosmetics.
All these are
widely used in the national health care service. In 2000, the
entire Cuban population under 20 years of age was immunized against
the hepatitis B virus.
However, Mauri
also explained that they are not only trying to diversify the
products exported, but also the markets. She indicated that there
has been an increase in the number of countries to which Heber
Biotec has been able to sell more than $1 million USD worth of
products.
Heber Biotec
S.A. was legally constituted in 1991 and has more than 200 health
registrations approved in 52 countries, as well as distribution
agreements signed with companies worldwide. Along with the CIGB,
it forms part of a complex for research, development, production
and marketing, whose mission is to find and apply new solutions
to contribute to improving the quality of life for millions of
people throughout the world.
• Simple
blood test can detect intestinal disease
LONDON,
Mar 15, 2002 (Reuters) - Cuban doctors have designed a simple
10-minute blood test to diagnose people suffering from a common
intestinal disease caused by a protein found in cereals. Instead
of taking a biopsy, doctors at the Centre for Genetic Engineering
and Biotechnology in Havana are using a quick and easy technique
that recognizes antibodies in the blood to detect the disorder. "It is highly
accurate in detection of untreated patients with celiac disease," Dr.
Luis Sorell said in a letter to The Lancet medical journal on
Friday. Celiac disease is caused by an intolerance to gluten,
which is found in wheat, barley and rye. It causes bloating,
diarrhoea, stomach pain, fatigue and weight loss. Damage to the
intestine can lead to vitamin deficiency. The only remedy is
to avoid foods such as breads, cereals and any other products
that contain gluten.
In a test of
90 people the test correctly identified 50 individuals with celiac
disease and produced negative results for those without it. Sorell
said the test, called an immunochromatographic assay, is dipped
in plasma or serum and produces two dots for a positive result
and one dot if it is negative. He added it could be useful for
diagnosing the disease in high-risk groups such as diabetics,
people with Down's Syndrome and autoimmune diseases and close
relatives of celiac sufferers.
• CUBA-GERMANY
Germans interested in selling Cuban biotechnology products
Havana,
Feb 16, 2002 (EFE).- The German state of Hesse is interested
in promoting the sale of Cuban vaccines and biotechnology products
in Europe.Hesse's economy minister, Dieter Posch, who concluded
a state visit to Cuba on Saturday with a meeting with Vice President
Carlos Lage, said such products had spurred the most interest
among members of the delegation he headed. During his stay, Posch
visited a factory in Havana's "Finlay Institute," Cuba's largest
biotechnology center, where "the possibilities were discussed,
what vaccines and other products might be of interest to the
European market in general and the German market in particular.
It's not easy to market a medication produced here in Cuba in
Germany because a very complicated systems of patents and permits
exists," Posch noted. He recalled that Cuba had submitted
a list of products suitable for marketing and of potential interest
to Europe and Germany. "Once we have been able to determine
what products we're talking about, we can begin to work on their
possible marketing," Posch concluded.
• Letter
from the United Nations Development Program
Naciones
Unidas
Oficina del Coordinador
Residente
File: Hepatitis B
21 de Diciembre del 2001
Apreciado Dr.
Herrera:
Asunto:
Aceptación
por la Organización Mundial de la Salud (OMS) de la vacuna
recombinante contra la Hepatitis B desarrollada y producida por
el CIGB.
Ha
sido una muy grata noticia recibir copia de la comunicación por
la cual la OMS, máxima organización del Sistema
de las Naciones Unidas en el campo de la salud, informa que la
vacuna de referencia ha sido aceptada para su utilización
por cualesquiera de las agencias de asistencia del Sistema de
las Naciones Unidas.
La
aceptación
de esta vacuna para su empleo por el sistema de las Naciones
Unidas es, a nuestro entender, un sobresaliente éxito
tanto de la ciencia como de la industria cubanas.
Deseo,
con estas líneas, felicitarlo a Ud. como principal autor del
desarrollo de esta singular vacuna y de su ulterior proceso de
producción industrial, y a los relevantes científicos,
ingenieros y técnicos cubanos que hicieron posible tan
señalado reconocimiento de la OMS, alcanzable solo por
contadas instituciones de países desarrollados.
Me
acompañan
en esta calurosa felicitación la Sra. Elena Martínez,
Directora del Buró para América Latina y el Caribe,
del Programa de las Naciones Unidas para el Desarrollo (PNUD),
el Sr. Carlos Magariños, Director General de la Organización
de las Naciones Unidas para el Desarrollo Industrial (ONU DI),
y todos los colegas que en nuestras Sedes y la Oficina en Cuba
tuvieron el privilegio de apoyar de una forma u otra al equipo
nacional que alcanzó tan colosal éxito científico
e industrial.
Es
para nosotros, funcionarios internacionales de las Naciones Unidas,
reconfortante y muy alentador, comprobar una vez mas, el excelente
y eficiente uso de la cooperación de las Naciones Unidas con Cuba
para el beneficio de su población y, en este caso, también
para beneficio de toda la humanidad.
Le
reitero a Ud. y a sus colaboradores las más cálidas
felicitaciones por tan relevante proeza.
Con mis mejores
deseos,
Luis
Gómez Echeverri
Coordinador Residente
Sistema de la ONU en Cuba.
Dr. Luis Herrera
Director-General
CIGB
Oficina
del Coordinador Residente de las Naciones Unidas
Calle 18, No. 11110, Miramar, La Habana, Cuba, Apartado 4138,
Teléfonos
(537) 204-1512 al 15
Fax (537) 204-1516, E-Mail: registry.cu@undp.org
• ACCEPTABILITY
OF HEBERBIOVAC-HB
11 December
2001
From:
Director, Vaccines and Biologicals.
To:
Mr. Alan Court, Director Supply Division UNICEF Copenhagen.
Subject:
Acceptability in principle of recombinant hepatitis B vaccine,
HEBERBIOVAC-HB produced by the Center for Genetic Engineering
and Biotechnology in Cuba for Supply to United Nations Agencies.
Dear
Alan,
We
are pleased to inform you that after appropiate review of the
Product Summary File, testing of vaccine sample for consistency
of final product characteristics and site visit to the Company,
the recombinat hepatittis B vaccine produced by CIGB in Cuba
has been found acceptable in principle for purchase by UN agencies.
With
best regards,
Dr.
Daniel Tarantola,
Senior Policy Adviser of the Director-General,
Director,
Department of Vaccines and Biologicals.
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