1. What role does technology play in the pharmaceutical industry?
A Identification of new targets for drugs
Technological developments enable research that permits the
identification of new therapuetic targets and approaches.
A number of examples are available in the PhRMA Industry Profile 2003,
which is available at
NB. The above URL leads to a page with links to individual chapters,
which are in pdf format
From Chapter 1:
A variety of new psychoactive drugs are undergoing testing for mental
illnesses such as schizophrenia, depression, and various forms of
dementia such as Alzheimers disease. Computerized brain scans, DNA
probes, and other advanced diagnostic techniques have given
researchers new tools to understanding the inner workings of the brain
at a molecular level and how chemicals affect them
From Chapter 2:
The report quotes Jurgen Drews, a pharmaceutical researcher as saying
that the recently completed map of the human genome could increase the
number of molecular targets for drug intervention from the current 500
or so to as many as 10,000.
More precise medicines are the aim of the growing field of
pharmacogenomics, which focuses on differences in drug effects due to
slight genetic differences in patients that can, for example, affect
the way an individual metabolizes medicines. Well define disease
more specifically and be able to get at the underlying causes and
create new personalized medicines, says researcher Dr. Lee Babiss.
Genetic technologies: transgenic organisms can provide new model
systems that not only allow the identification of disease mechanisms
and new therapeutic targets
Mouse model could identify new antipsychotics
[Published: 01 July 2003 Source: CNS Drug News from Espicom]
Howard Hughes Medical Institute researchers have produced a
genetically-altered mouse that exhibits behavioural abnormalities that
are similar to those observed in humans with schizophrenia. The
scientists report that they have already used insights from studying
the mouse to identify a genetic variant associated with schizophrenia
In their latest studies, scientists built on their earlier research on
a genetically-engineered mouse, which had been specifically altered to
knock out the gene for calcineurin only in the animal's forebrain.
Calcineurin is an enzymatic switch that plays regulatory roles in both
the immune system and the brain. Until a brain-specific knockout mouse
was developed in the Howard Hughes laboratory, it had not been
possible to pinpoint the enzyme's function in the brain
A leading theory about schizophrenia posits that it originates from a
disorder of the brain-signalling pathways involving dopamine
researchers have [identified] a new target for antipsychotic drugs
that is not directly related to dopamine receptors.
B. Drug design and development
While yesterdays scientists relied on a combination of persistence
and serendipity to find compounds that might work against diseases,
todays scientists are supplementing the old approaches by using new
technologies that increase efficiency and enable researchers to create
new medicines. They use gene chips, combinatorial chemistry, robots
that screen more compounds in an hour than an army of technicians can
screen in a month, high-speed computers that point to likely drug
targets, laser microscopes that capture individual cells, and x-ray
crystallography to help produce medicines that bind more tightly to
their cellular-level targets and work more effectively.
From Chapter 2, PhRMA Industry Profile 2003 (URL given above)
Example: Use of increased computer power and capability in drug design
The input of biocomputing in drug discovery is twofold: firstly the
computer may help to optimise the pharmacological profile of existing
drugs by guiding the synthesis of new and "better" compounds.
Secondly, as more and more structural information on possible protein
targets and their biochemical role in the cell becomes available,
completely new therapeutic concepts can be developed. The computer
helps in both steps: to find out about possible biological functions
of a protein by comparing its amino acid sequence to databases of
proteins with known function, and to understand the molecular workings
of a given protein structure.
In all cases, the aim of using the computer for drug design is to
analyse the interactions between the drug and its receptor site and to
"design" molecules that give an optimal fit.
The techniques provided by computational methods include computer
graphics for visualisation and the methodology of theoretical
chemistry. By means of quantum mechanics the structure of small
molecules can be predicted to experimental accuracy. Statistical
mechanics permits molecular motion and solvent effects to be
Even if the structure of the receptor site is unknown the computer
may help to figure out how it might look by comparing the chemical and
physical properties of drugs that are known to act at a specific site.
Moreover, if the amino acid sequence of the receptor site is known,
one can try to predict the structure of the unknown site.
From: Biocomputing and Drug Design by Wolfram Altenhofen
One of the best known examples of the application of computers in drug
design was in the development of HIV protease inhibitors, which are
now a key component of AIDS therapy.
More information on the use of computers in drug design is available
on the web site of Drug Design Methodologies
Example: Combinatorial chemistry
Increasing pressure to identify, optimize, develop, and commercialize
novel drugs more rapidly and more cost-effectively has led to an
urgent demand for technologies that can reduce the time to market for
new products. Molecular diversity, of both natural and synthetic
materials, provides a valuable source of compounds for identifying and
optimizing new drug leads. Through the rapidly evolving technology of
combinatorial chemistry, it is now possible to produce libraries of
small molecules to screen for novel bioactivities. This powerful new
technology has begun to help pharmaceutical companies find new drug
candidates quickly, save significant dollars in preclinical
development costs, and ultimately change their fundamental approach to
From a description of the book Combinatorial Chemistry and Molecular
Diversity in Drug Discovery edited by Eric M. Gordon and James F.
Imagine a biologist collecting leaves from exotic rain forest
. Perhaps one leaf contains a heretofore undiscovered
antibiotic, while another tree yields an antitumor agent. Never mind
that each extract may contain hundreds of different leaf components.
If the assay proves positive, the chemists will be able to discern the
formulae of the critical components. Now picture a modern organic
chemistry lab. The chemist appears to be carrying out a standard
reaction: A + B yields C. But now A is actually a mixture of five
components while B may be a composite of 10. Instead of a single
product C, the chemist deliberately produces a mixture of 50 different
In the not-too-distant past, the second scenario might have been the
trademark of a somewhat sloppy chemist or the consequences of a set of
very impure reagents. But today, such mixtures of
products--combinatorial chemistry--are being heralded as the future of
Some laboratories are deliberately preparing (and successfully
decoding) mixtures as large as 200 billion separate compounds in each
product vial. Meanwhile, analytical chemists are busy improving both
the sensitivity and the resolution capabilities of their diverse
groups of hyphenated instruments (GC-MS, LC-MS, MS-MS, CZE-MS, etc.)
in order to keep up with the demands of mixture analysis
From What is Combinatorial Chemistry? University of Louisville
Peptide Research Laboratory
Example: High-throughput screening
High Throughput Screening (HTS) refers to a modern process whereby
thousands of samples can be screened each day, against a given (known
or unknown) target (disease). This process has led to a significant
improvement in Lead Identification those samples which may
eventually become candidate drugs by firstly improving the spectrum
of sample structures believed to have some possible effect and
secondly by quickly eliminating those samples which have no effect.
HTS is usually involved in the first phase after a target has been
identified and is currently one of the few areas in the whole drug
discovery process where significant time savings can be made in
finding candidate drugs. For this reason HTS has seen widespread
adoption amongst all of the major pharmaceutical companies.
. As a highly automated process, the computing requirements within
the HTS discipline are all pervasive
From Technical Update 2003 on High Throughput Screening by Tessella
Support Services plc. (this has a lot of detail on the IT aspects of
Today, while Pharmacopeia is fully enabled in 96-well microplate
technology for carrying out assays, its screening facility uses
predominantly higher density (384- and 1536-well) reduced volume (1-10
uL) plates that maintain the footprint of the 96-well plate. The
acceleration of sample processing that results from this
miniaturization leads to peak sampling rates in excess of 100,000 per
http://www.pharmacopeia.com/dd/techno/tech_hts.html (web site of
HTS methods can be based on cell lines (cultures of cells which can be
maintained indefinitely), bacteria, yeasts, on subcellular components
such as mitochondria, membrane fragments, etc. or on biochemical
compounds such as enzymes and their substrates. The cells and
microorganisms that are used can be genetically modified, using
appropriate technologies, so that they produce specific enzymes or
carry desired receptors on their surfaces.
Even greater miniaturization is possible through the application of
gene technology to develop the laboratory on a chip concept:
One such example:
The labs on a chip are the brainchild of Infineon Technologies in
Munich, http://www.infineon.com the world's sixth largest
semiconductor manufacturer by sales
the chips are 500 microns thick, and patterned into an array of 10
micron holes, each a tenth of the diameter of a human hair. There are
a million of these per square centimetre
Infineon has teamed up with Gettysburg USA based MetriGenix to seed
the arrays with up to 400 samples of DNA strands [which] attach
themselves to the walls of the channels. Each gene sample is
distributed across around 100 holes. Three reagents are then pumped
through in sequence. The first is a blocker, the second the tissue or
blood sample under test and the third, a fluorescing reagent dye. Some
of the genes in the fluid under study bind to some of the immobilised
genes. The others are washed off. The bindings are detected by means
of a marker, such as a luminescent dye that is split up by an added
enzyme, which causes it to release light, detected by a CCD camera. If
the pattern of light regions matches that of healthy tissue, medical
treatment is judged to be effective. Unhealthy patterns can be matched
against patterns arising from known diseases or known organisms.
From: Chip devices give boost to medicine Eureka Magazine, May 2003
C. Improvement of drug delivery systems
Drug delivery is used mostly with small molecules, such as individual
peptides. Cutting-edge technologies tackle the real challenge: how to
package and deliver proteins and other large complex molecules so that
delivery will be accurate, modulated, and effective.
Competition is so intense in the pharmaceutical marketplace that
companies look to drug delivery as a way to gain a competitive
advantage. The value that drug delivery adds can be improved safety,
efficacy, convenience, and patient compliance.
Drug delivery product sales in the U.S. are expected to reach $30
billion by 2005 and should continue to increase, driven by new product
launches across all technology platforms.
The Impact of Drug Delivery in the Pharmaceutical Industry:
. Drug delivery extends the profitability lifetime of existing
marketed products as their patents approach expiration.
Drug delivery systems are the cornerstone of successful drug
development as the pharmaceutical industry discovers challenging new
compounds that require sophisticated, targeted delivery systems.
. Drug delivery systems improve patient compliance and enhance
quality of life by more convenient dosing and mitigated side-effect
. Drug delivery represents the "next step" in genomic and proteomic
From Drug Delivery Technology
2. How is technology driving the pharmaceutical industry?
Adoption of new technologies is seen by pharma companiesto be a matter
of sheer survival:
The average cost to develop a new drug has grown from $138 million in
1975 to $802 million in 2000.
From Chapter 1 of the PhRMA Industry Profile 2003
Speeding up the process of drug design and development makes all the
difference, although the introduction of new methods will have an
impact on work practices.
The benefit of being the first to market with a new drug can be as
much as $1bn revenue in the first year, with 75% market share for the
lifetime of the drug. Being first to market is an essential obective
for modern pharmacuetical companies to survive in this high risk
What are the consequences of introducing HTS?
Introduction of a
highly automated system into a largely manual environment has a number
of business and IT challenges:
* The working practice on the ground may need to change to accommodate
the new system i.e. new protocols, standards, training.
Business Process changes such as these represent challenges
somewhat beyond the IT infrastructure required to implement them, they
may very well require cultural changes within the company. However,
they are likely to be necessary.
From Technical Update 2003 on High Throughput Screening by Tessella
Support Services plc
Despite the recent trends for pharma companies to merge into ever
larger entities, small is increasingly becoming more beautiful again,
at least with respect to the impact of genomics on pharmaceutical R&D:
Millennium Pharmaceuticals, a genomics-centered company with the
potential to become a major player in the pharmaceutical industry,
hopes to cut in half the time and cost of developing new drugs. Along
with other contenders, it stands to become a leader in the biotech
industry, assuming genomics shifts the balance of power from
traditional drug companies to biotech companies.
Big pharmaceutical companies, meanwhile, are trying to modify their
huge internal research programs to exploit the potential of genomics.
However, the technology is so new and so different that small biotech
firms and academic labs are seen as more likely to achieve
breakthroughs in identifying disease targets. To offset this
disadvantage, many large companies are establishing alliances with
small biotech firms. Bristol-Myers Squibb is spending more than 50% of
its genomics research budget on collaborations with small companies.
Pfizer has agreements both with Celera and with Incyte Genomics, a
Celera competitor. It's a perfect example of large, established
companies realizing their disadvantage in the development of new
technology and joining forces with the young upstarts to avoid being
rendered dinosaurs in the industry.
From The Seismic Impact Of Technology by Jagdish N. Sheth and
Rajendra S. Sisodia
Optimize Magazine, February 2002 (the extract is on page 2 of the web
Are there any ethical issues relating to technology in the
A. The Rich/Poor divide
As new technology permits the development of ever more sophisticated
drugs geared towards ever smaller groups of patients (Well define
disease more specifically and be able to get at the underlying causes
and create new personalized medicines, says researcher Dr. Lee
Babiss.-Chapter 2, PhRMA Industry Profile 2003, see above for
reference), it is likely that prices will increase. There will be a
smaller customer pool from which the pharma company can recoup its
investments and derive a profit. This means that these drugs will be
out of the reach of poorer nations.
This has already been happening in the case of AIDS drugs:
"The new drugs will help the yuppies of the world," said Thailand's
Mechai Viravaidya, a parliament member and leading advocate of AIDS
prevention in Bangkok in a recent Time magazine article, "but for most
people with AIDS, it's like a dog looking up at an airplane: he can
see it, but he can never get a seat"
The call for affordable AIDS/HIV drugs is growing. Simultaneously,
the number of clinical trials testing these drugs in impoverished
nations has exploded as developed countries have established more
effective treatments and stricter regulations.
The likelihood that these poorer nations will see the benefits of
these studies tested on their people is remote. Public health services
in Africa, overwhelmed even before the AIDS crisis, have crumbled in
the face of providing treatment for the flood of AIDS victims. The
average African worker would exhaust his annual income within a few
days for drug treatments available in the West, many of which cost
more than $3,000 per month
From AIDS ethical implications by Michael Coren (Hybrid Vigor, a
discussion of bioethics. Emory University)
However, they will also be out of the reach of poorer individuals in
rich nations without a comprehensive system of social security.
Donna Ignatavicius, MS, RN, a certified gerontological nurse in
Hughesville, Md., has heard stories of older Americans who resorted to
eating dog food, who subsisted on bread and water, who became
malnourished so they could afford prescription drugs.
"Its not uncommon," said Ignatavicius, president of DI Associates
Inc., a health care consulting firm. "We hear the older adults say,
Im either going to have to not eat so I can buy my medicines or buy
food and give up my medicines. "
Annual prescription drug spending per elderly person has grown from
$559 in 1992 to a projected $1,205 for this year, according to a
report by the PRIME Institute at the University of Minnesota College
of Pharmacy. The institute studies economic and policy issues related
to pharmaceuticals. By 2010, seniors will spend an average $2,810 a
year on prescription drugs, the report predicts.
From: Back-breaking drug costs : Rising prices of prescriptions force
older patients to make trade-offs by Cathryn Domrose, Nurse Week,
October 30, 2000
Not only is it a question of price. The new types of drugs that are
developed will be more likely to target the needs of rich societies
rather than poor societies. Michael Coren also gives an example of
this in his article:
Most AIDS experts agree that only an effective vaccine will call a
halt to the rapid spread of the epidemic. Yet, only 10% of the
National Institute of Healths budget is allocated to research on an
AIDS vaccine, typically a product with lower profit margins than the
therapeutic drugs marketed in wealthier industrialized nations
Pharma companies will have even less incentive to use expensive
technology in order to develop drugs for the numerous parasitic and
other infectious diseases that plague the developing countries. when
it can be focused on diseases of rich countries with ageing
populations, for example, Alzheimer disease, cancer, heart disease.
Geneva, 9 Oct 2001 - A new report by the international medical aid
NGO, Medicins Sans Frontiers (MSF), says that there are now virtually
no new drugs being researched and developed for fatal diseases that
mainly affect the poor.
The report, titled Fatal Imbalance: The Crisis in Research and
Development for Drugs for Neglected Diseases, surveyed the R&D
activities in drugs of 20 top-grossing pharmaceutical companies in the
[from] 11 of these companies, which together account for
combined sales of nearly $117 billion
only one new tuberculosis drug
emerged on the market in the last five years
MSF points out that people in developing countries, who make up about
80% of the population, only represent about 20% of worldwide medicine
This acute lack of drug R&D into unprofitable diseases can be
illustrated in new data that reveals that of the 1,393 new drugs
approved between 1975 and 1999, just 13 or 1% were for tropical
From: No new R&D on drugs for diseases affecting poor, says new
report by Kanaga Raja (Third World Network)
The problem is further compounded by the fact that local
pharmaceutical companies in developing countries will not have the
money to invest in the equipment and training required by the new
technologies, and thus will not be able to use them to solve local
B. Exploitation of indigenous resources
The difficulties of technology transfer to developing countries also
means that they will not be able to compete in researching and
profiting from the therapeutic possibilities of local plants, since
they will lack the high-throughput technologies to screen many
thousands of compounds. Pharma companies from rich countries can jump
in and patent their discoveries, and then make the poor countries pay
for something that originates from their own environment. Moreover,
companies might even be able to patent the plants themselves if they
use genetic technology to modify them:
The European Parliament has controversially endorsed a directive that
makes it legally possible to patent life forms and their genetic
material under European law. The approval, given Thursday, could clear
the way for European multinationals to patent varieties of indigenous
plants and seeds for private profit -- but endangering livelihoods in
developing countries, especially those of its farmers.
"The European parliament clearly placed commercial interests over
ethical values," said Magda Aelvoet, co-president of the parliament's
Green group. "'Biopiracy', the unauthorised patenting of genetic
resources taken from developing countries by mighty Western
multinationals and institutions will not be stopped," she said.
Under the directive, bioengineers could carry out minor genetic
alterations to plants used in traditional medicine in the South, claim
it as a original 'invention', and patent the plant itself for
profitable exploitation in the North.
The definition of invention has been further stretched to cover the
patenting of 'discoveries'. Representatives of the country from which
the source plant originally came from will have to challenge these
claims in courts of law. Such 'patents on life' are already legal in
the United States and in Japan, where the gene or sequence of genes
patented become the 'intellectual property' of the researcher,
institution or a private company which 'discovered' it.
The European Federation of Pharmaceutical Industries and
Associations (EFPIA), which represents large pharmaceutical companies
such as Rhone-Poulenc, Pfizer and Glaxo Wellcome, says that their
members suffer "systematic disadvantage" as a result of the U.S. and
From: Parliament Clears 'Biopiracy' Directive May 14, 1998 (SUNS:
South-North Development Monitor)
C. Ethical issues of pharmacogenomics
The issues that arise from the production of drugs tailored to
individuals is covered in an article by Dr. Carol Isaacson Barash,
founder and principal of Genetics, Ethics & Policy Consulting, Inc.
She makes the following points:
Is it a misuse of scarce resources?
Many believe that pharmacogenomics, like other new fields spawned by
the Human Genome Project, represent a misallocation of resources.
Rather than embark on learning how genes indicate a predisposition to
disease and developing cures and enhancements, or experimenting with
ways to change the human germ cell, global efforts should be spent on
solving more urgent problems facing humanity, such as global famine or
accessibility to potable water.
Others argue that the economic and social benefits provide sufficient
Who pays and who benefits?
The availability of this new technology may be costly initially, and
thus accessible only to those wealthy enough to pay for both the test
and the designer drug best suited to them. Yet, the cost will likely
diminish so as to become affordable to most. However, will lower costs
influence a person to submit to the required genetic testing, thus
creating threats, if not violations, to one's autonomy (the basic
tenet of bioethics)?
Under this question she also raises the issue of conflicts of
interests arising in researchers
A recent study found that policies governing conflicts of interests
at major medical institutions varied considerably in both disclosure
requirements and the nature of permitted academic-industry
relationship, thereby opening a door to the possibility that an
interest in financial gain could overpower an interest in either
achieving valid research or protecting the well-being of subjects.
And she mentions that patients who contribute to drug development by
participating in trials do not always benefit when the drugs finally
appear on the market:
Numerous sufferers of Gauchier Disease, who helped companies
developed safe and effective treatment (clinical research), were
denied access to treatments by insurance companies by refusing to
cover the high cost therapies. The patients couldn't afford to pay
costs out of their own pocket.
Will these drugs be used ethically?
Under this question, Carol Isaacson Barash discusses whether doctors
will always ensure patients have the appropriate genetic tests first,
or whether they will be prescribed a designer drug because the
physician is enthusiastic about it for one reason or another.
Whose rights will take precedence?
The father of a research subject opened a letter addressed to his
child and learned that his child had enrolled in a genetic research
The letter indicated that for the purpose of research the research
facility had obtained some of the father's medical records. The father
objected to what apparently was non-consensual disclosure of his
medical information, even for the purpose of obtaining an informative
family history to be used to provide optimal care for the
From Ethical issues of pharmacogenomics by Carol Isaacson Barash
The Nuffield Council on Bioethics has produced a discussion paper on
the ethical issues of pharmacogenomics, which is available in pdf
A further issue is the question of whether these drugs will be used by
people unwilling to confront their own problems and unwilling to
change negative lifestyle choices (diet, smoking, alcohol, exercise,
D. Animal welfare issues
The use of computers and high throughput methods in early stages of
drug discovery and development has certainly reduced animal use. The
statistics on the use of laboratory animals published by the UK Home
Office show that the main actor responsible for the decrease in animal
use since the mid-1970s has been the pharmaceutical industry.
However, there is still the issue that every new drug that is produced
will have to be tested on animals. In the UK, in recent years, there
has been a dramatic increase in the use of transgenic animals, which
might soon even start to reverse the decline of the last 25 years.
This is primarily because of the explosion of the use of transgenic
animal models in medical research. Are all new drugs being developed
thanks to new technologies sufficiently important to justify the use
of animals in their development and testing?
The UK statistics are available at:
I hope this has given you sufficient leads to follow, but please do
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Search strategies: 1. new technology pharmaceutical industry 2.
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numerous side searches following leads in the retrieved documents.