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JANUARY
2008
on DRUG DEVELOPMENT
DRUG STORE: A toxin from a marine
snail is the source of a treatment
for chronic pain.
Dr George Gornacz/SPL
Medicine or poison?
The term ‘pharmaceutical’ derives from the
Greek ‘pharmakon’, meaning medicine or poison.
FUTURE FACE: It might seem odd that a word countries, there are no drugs
What will we
use drugs for
can cover such opposites. available or they are too
in the future? But medicines and poisons are expensive. Even in the UK,
closely related. Both act in the some patients find they cannot
same way – by interfering with obtain drugs.
Dan Bayley/iStockphoto
STORY
We live in a pharmaceutical age. When we are ill,
14 000
The estimated
number of pills
prescribed over
an average
lifetime.
A sense of humour
Our medicine, like our politics and philosophy, NEED TO KNOW
owes its origins to Ancient Greece. Pharmaceutical company: large
company researching and making
The roots of modern Western medicine lie in Ancient
new drugs (collectively often
Greece, around the 6th century BCE. Before then, disease called ‘pharma’).
and healing were seen in a supernatural context: healing
and religion went hand-in-hand. Illness was often seen Biotechnology company: smaller
company researching new drugs,
as divine punishment.
often using new technologies
By the time of Hippocrates (left), around 400 BCE, Greek (often referred to as ‘biotech’).
medicine had come to focus on the body and on natural Target: the molecule that a drug
explanations for sickness and health. The Greeks believed acts on.
that the body was made up of four humours or fluids –
Metabolites: the chemicals
blood, phlegm, yellow bile and black bile – and that the
produced by metabolism of
balance of these humours was central to health.
a drug within a cell.
Ill-health was thought to stem from an imbalance of the Medicines and Healthcare
humours, so treatments aimed to restore balance. This Products Regulatory Agency
could mean use of pepper to induce sneezing fits, bleeding (MHRA): the body that licenses
people, or subjecting them to enemas or potions to trigger new drugs in the UK.
violent vomiting.
Food and Drug Administration
Later, Ancient Rome embraced Greek medical thinking. (FDA): the US version of the
Their best physicians were nearly all Greek, including MHRA.
Galen, the most celebrated Roman medical man. Making Clinical trial: study of the effects
Education editor: Stephanie Forman the most of nature’s bounty was core to Roman medicine: of a drug in people.
Editor: Ian Jones, Isinglass Consultancy Ltd
dock for paralysis of the legs (possibly scurvy), St John’s Adverse reaction: a harmful
Writers: Ian Jones, Lisa Melton,
Helen Carmichael
wort to expel bladder stones, fenugreek as an enema and side-effect of a medicine.
Illustrator: Glen McBeth
to treat pneumonia, figs for cough remedies.
Placebo: dummy treatment used
Advisory board: Nicky Britten, Nan Davies, The balance of the humours was an enormously influential during clinical trials.
Alan Fairlamb, Ray Hill, Jackie Hunter, Munir
Pirmohamed, Michael Reiss, Roland Wolf.
idea. Only in the past century or so has its popularity Blockbuster: a drug generating
All images, unless otherwise indicated, are from
waned. Even now, however, echoes appear in popular very high sales.
Wellcome Images. thinking – detoxification, phlegmatic personalities and so on.
The Wellcome Trust is a charity whose mission is to
foster and promote research with the aim of improving
human and animal health (a charity registered in
England, no. 210183).
Reflecting the profound impact today’s research will MEDIEVAL MEDICINE
have on society, the Wellcome Trust also seeks to
raise awareness of the medical, ethical and social
Ill-health was seen mainly in a religious context in the Middle
implications of research and promote dialogue Ages. People could turn to healers of various kinds, and kept
between scientists, the public and policy makers. ‘recipe books’ of herbal remedies. With the Renaissance
© The trustee of the Wellcome Trust 2008.
in the 14th century, academic medicine gradually spread
This is an open access publication and, with the
exception of images and illustrations, the content may
from Italy through Europe. Observation and experiment
unless otherwise stated be reproduced free of charge superseded rote learning of ancient documents. Medicine
in any format or medium, subject to the following became a specialist field, but in reality doctors could
conditions: content must be reproduced accurately;
content must not be used in a misleading context; the do little for patients.
Wellcome Trust must be attributed as the original author
and the title of the document specified in the attribution.
DC-3976/20K/12–2007/BC Find out more at www.wellcome.ac.uk/bigpicture/drugdev.
2 | BIG PICTURE 7
Pharma is born
CULTURE CLASH
The Victorian era saw
the beginnings of the
pharmaceutical industry.
By the end of the 19th century,
medical doctors had become
established pillars of society. They
would diagnose illness and write
prescriptions. The medicines
themselves would be prepared
by apothecaries – the dispensing
chemists of the day. This conventional
system coexisted with a flourishing
trade in ‘patent medicines’ or
quack cures.
The Victorian era saw a series
Western medicine sees disease as a disruption
of profound changes. Firstly, the
to our body’s physiology, which treatment aims to
modern scientific disciplines began
correct. But there are other medical traditions – such
to emerge, and science began to
as traditional Chinese medicine and the Ayurvedic
move into specialist facilities such
tradition of India. Like the humours, these share
as laboratories. With the emergence
the idea of balancing life forces.
of germ theory, it became clear that
microbes were responsible for many of Non-Western and Western traditions differ
the killer diseases of the day. significantly. A crucial distinction is the way they
Paul Erhlich and others proposed the idea of ‘magic bullets’ – chemical answer the question ‘does it work?’: Western
compounds that attacked and destroyed only infectious organisms. medicine argues for evidence from scientific studies;
other traditions rely more on the ‘test of time’.
Chemists began to purify the active principles from plants to provide a supply
of drugs. Morphine was isolated from the opium poppy, atropine from the See www.wellcome.ac.uk/bigpicture/drugdev.
deadly nightshade, colchicine from the autumn crocus.
Making medicines
But yields were low. Chemists began to explore ways to make useful
compounds by chemical synthesis. In the 1850s, 18-year-old prodigy TABLOID TALES
William Henry Perkins tried to synthesise quinine from coal tar. Instead he
produced the first synthetic dye, mauvein (mauve). This colour, associated In the late 1800s, Burroughs,
with royalty and privilege, was difficult to obtain by natural means and highly Wellcome & Co. introduced
prized. Perkins made a fortune and also helped create a successful synthetic machine-made compressed
dye industry, which Germany came to dominate. medicines or ‘tabloids’ into Britain.
This was the key to Henry
In a neat twist of fate, the chemicals produced by the dye industry turned Wellcome’s business success.
out to have medically useful properties, leading to the appearance of many It introduced an era of drug
famous pharmaceutical company names, including Hoechst, Bayer, mass-production, though the term ‘tabloid’ later
Sandoz and Ciba. came to be associated with ‘compressed news’
and hence popular newspapers.
Postwar expansion
In the past 50 years, no exception. The drugs had side-effects or were addictive.
the pharmaceutical Bacteria developed resistance. Progress in tackling
industry has become a some diseases has been disappointingly slow. Doctors are
huge global enterprise. accused of dispensing medicines with little thought for patients’
greater wellbeing.
After World War II, drug
companies led a At the same time, concerns have grown about the tactics of
therapeutic revolution. pharmaceutical companies – their marketing muscle, their political
Key discoveries of the early influence, their activities in developing countries and their alleged
20th century – notably manipulation of clinical trial data to support their own products.
insulin, vitamins and Pharma is said to be more profitable than any other business.
antibiotics – were mass In 2006, global spending on prescription drugs topped
manufactured and US$600 billion (£300bn).
available to all.
Are such sums excessive? One could argue that drug discovery
New compounds were is a risky and expensive business and, in return, pharmaceutical
ushered in: cortisone for companies provide life-saving medicines. But some people have
inflammation, drugs to treat voiced concerns over how the industry operates. They accuse
heart conditions, antibiotics to cure syphilis and tuberculosis, and drug companies of spending huge sums promoting their
psychiatric drugs to treat, rather than lock up, the mentally ill. products directly to doctors and lobbying politicians.
Yet the ‘white heat of technology’ that inspired the 1960s has
given way to a more sceptical mood, and pharmaceuticals are
JANUARY 2008 | 3
MAKING A DRUG
Developing a new drug is a long process.
What are the key stages, and who does
what during them? By way of illustration,
YEAR
2014
2012
in drug development. Professor Workwell considers
next steps. One possibility
would be to set up a
‘spin-out’ company, where
university researchers
leave to work in a commercial
environment.
But Professor Workwell enjoys
working in the University. Instead,
she teams up with a small
biotech firm, FlexiBioTher.
This firm is run by Dr Graham
Gogetter, a former university
researcher who left academia
to run his own company.
At this point, it is too early for large pharmaceutical companies
to be interested. The chances that a useful drug will emerge are,
unfortunately, very small. Instead, Professor Workwell and Dr
Gogetter apply for ‘seed’ funding to test their agent further.
YEAR
2012
original agent and painstakingly analysed its effects on bone cells.
2008
It has raised several million pounds from venture capitalists –
Professor Felicity Workwell leads a group of researchers investors who put money into high-risk projects. It’s looking good,
at the University of Chortlington. She is studying but there is still less than a one in ten chance that this agent, now
Huntinzheimer–Parks disease (HPD), a common and codenamed FBT1000, will make it to market.
painful bone condition affecting people in middle age.
She doesn’t work alone. As well as her team of 20,
she has several collaborators: YEAR
YEAR
2016
• Dr Hamish Bedside-Manor, a clinical scientist who runs
a clinic for HPD at Chortlington General Hospital
Enter pharma 2014
Professor Workwell and
• Professor Randy Beckhamburger III, an HPD expert
FlexiBioTher have gone as far as
in the USA
they can. The firm is too small to
• Dr Pierre Souris, a French researcher who studies undertake the expensive research
HPD in mice. and clinical testing that will now
be needed.
With funding from the Huntinzheimer–Parks Disease
Foundation, Professor Workwell’s group is studying the But FBT1000 looks promising,
basic science of HPD, in an attempt to identify possible new and there would be a large
therapies. After five years, they have made great progress. market for a new therapeutic.
They have: So FlexiBioTher enters into
a partnership with a large
• worked out how the disease affects people
pharmaceutical company,
• studied disease mechanisms in more detail in the Merphizoglax.
mouse, and identified the main type of cell affected
Merphizoglax brings its
• found a growth factor that binds to a specific receptor mighty drug discovery skills
on this cell to bear, running many tests
to find out how FBT1000
• shown that genetically engineered mice lacking this
behaves in the body, checking in
receptor do not display the symptoms of HPD.
animal studies for signs of toxicity and characterising further
These exciting findings, published in the scientific its effects on bone cells. The company’s scientists assess how
literature, suggest that the receptor could be a target FBT1000 is metabolised, how long it stays in the body and
for new therapeutics. where it goes.
They have also patented their antibody – essential After more chemical refinement, FBT1000 is finally ready
for later commercial development. to be tested in people.
4 | BIG PICTURE 7
YEAR
2020
2016
FBT1000 has passed its toxicity tests, and the data
from animal studies suggest that it should tackle the
disease in people.
Merphizoglax engages a specialist company to organise phase I
clinical trials on its behalf. Before these can start it has to get
approval from the Medicines and Healthcare Products Regulatory
Agency (MHRA).
The trials involve six healthy volunteers who are given doses much
lower than have proved safe in animals. The drug is given by
medically qualified staff in a facility linked to Chortlington District This is another critical ‘go/no-go’ decision point for Merphizoglax.
Hospital. The volunteers are monitored carefully. The company cannot afford late failures. Fortunately, the phase II
The news is good. The volunteers have suffered no ill-effects. trial has gone well – FBT1000 gets the green light.
The company can move on to phase II trials – the first time actual Now it is time for large, phase III trials. Dr Bedside-Manor and
patients get the drug. Professor Workwell are involved in the trial, which recruits patients
The phase II trials involve a small group of patients and are from a series of hospitals in the UK, as well as in the USA and
designed to check that the drug is safe in people with disease France. In all, almost 5000 patients volunteer to take part.
and that it does have beneficial effects.
YEAR
YEAR
JANUARY 2008 | 5
WHAT DRUGS DO We are used to seeing pharmaceuticals in their blister packs, or medicines in brown bottles.
Less common treatments might call for injections or use of a drip in hospital.
But what’s in those anonymous pills and fluids? And what do they actually do inside our bodies?
Small wonder?
SMALL
SMALLCHEMICALS
CHEMICALS
Most drugs are small organic Sir James Black was behind two
CH3
Most drugs are small chemicals. major drug families: beta-blockers
N
CH3 to treat coronary heart disease and
organic chemicals. H
Many drugs are small molecules drugs that blocked histamine
These drugs are aspirin that latch onto specific structures receptors, which are used to treat
(left) and Tamoxifen in or on our cells. Our cells have
(right). stomach ulcers. He introduced a
numerous specialist functions, new way of thinking to drug
CH3 regulated by instructions from development. Black’s approach
genes. The drug molecules alter involved understanding how cells
PROTEIN ANTIBODY-BASED DRUGS these processes, subtly changing use messenger molecules to
Compared with Monoclonal antibody cell biochemistry. communicate with each other. By
a typical drug technology enables large
(approximate quantities of identical Herbs and minerals were used adapting these natural processes,
size arrowed antibodies to be produced. in ancient cultures. During the he was able to develop analogues
for comparison), Antibodies are large European Renaissance, that bound to the same targets but
protein Y-shaped proteins and apothecaries experimented with stopped them working.
therapeutics are bind very specifically
huge. This is to their targets.
plants retrieved from the Americas Small is beautiful
etanercept, a by explorers, such as the bark of Drug companies have preferred to
modified version the quina tree. This contains create drugs from small molecules.
of a cell surface quinine, used to treat malaria.
protein, which This should make them easy to
is used to treat Even when an active ingredient had synthesise, to modify and to
rheumatoid been identified, doctors rarely knew characterise, as well as more likely
arthritis. to reach their targets in the body.
how it actually worked. A profound
change came when researchers They can generally be given in pill
began to use an understanding of form. A small, stable molecule is
the molecular basis of human easier to quality assure, and scaling
physiology to develop new drugs – up to full production is more
ROBOTS TO THE RESCUE so-called rational drug design. straightforward.
Imaginative new approaches
are being used to increase
the numbers of new drugs A true magic bullet?
in development. Automated, Monoclonal antibodies are becoming a more common
high-throughput approaches
therapeutic tool.
are one trick – see
Big Picture Online for others. A critical part of drug development is getting a therapeutic agent binding
specifically to its target. But, as usual, nature is several steps ahead of us,
and has already created highly targeted molecules: antibodies.
Monoclonal antibodies, in effect cloned antibodies all recognising the same
www.wellcome.ac.uk/ structure, are now entering the clinic in increasing numbers.
bigpicture/drugdev Many monoclonal antibody therapies have been developed for cancers,
as cancer cells have distinctive structures on their surfaces that can be
specifically recognised by an antibody. If a toxin is attached to the antibody,
ON THE WEB it can be delivered directly to a tumour.
Other monoclonal antibodies are similar to small-chemical drugs, in that
they target receptors or ligands, blocking biochemical signalling. Trastuzumab
(Herceptin), for example, recognises a mutated receptor on breast cancer
cells carrying a HER2 mutation. Infliximab (Remicade) and adalimumab
(Humira) block a molecule that promotes inflammation (tumour necrosis
WHAT HAVE POTATOES,
ON THE WEB factor-α, TNF-α) and have made a major impact on the treatment of
rheumatoid arthritis.
GOATS AND RICE IN COMMON?
They are all being used to produce pharmaceuticals.
David Meharey/iStockphoto
www.wellcome.ac.uk/ www.wellcome.ac.uk/
bigpicture/drugdev bigpicture/drugdev ON THE WEB
6 | BIG PICTURE 7
3 LINES OF DEFENCE:
Drugs (blue) can act in
several ways. Some (1)
may prevent a target
molecule (red) reaching
a cell (the castle).
Others (2) occupy the
4
places (receptors) that
the target would bind
to on the cell/castle.
If a target does get
to the cell (3) a drug
may prevent it sending
a signal to the DNA
in the nucleus (4).
A disastrous phase I trial (see page 5) The likely explanation is that the
/Observ
in 2006 raised questions about the drug acted in unexpected ways in the
safety of drug testing. volunteers, triggering a massive immune
er 6-3-
taking part in a phase I drug trial at previously, even though they have a very
Times 26-7-06
Northwick Park Hospital, London, were similar version of the target molecule.
given small doses of a new drug being
developed for rheumatoid arthritis. The So, should the trial have been approved?
Times/Sun, © NI Syndication; Observer/Guardian, © Guardian News & Media Ltd 2006
drug, a monoclonal antibody known The drug targeted a key component of the
as TGN1412, had been through animal immune system. Was it too risky to be
testing; the trial had been approved by trialled in people? Extra safeguards are now
the Medicines and Healthcare Products being put in place for agents that target the
© Sunday Telegrap
Within an hour of receiving the drug, the The case is a reminder that clinical trials
first volunteer reported a headache and are risky. Mercifully, extreme reactions like
began to complain that he was ‘burning up’. this are very rare. It also emphasises why
h 30-7-06
8 | BIG PICTURE 7
Holistic hullabaloo Dangerous drugs
Despite the years of research roughly 5 per cent of hospital
and clinical trials, a drug may admissions. They are responsible for
still turn out to have harmful around 5000 deaths annually (more
side-effects. than the number of people killed on
the roads). In the USA, the number
A 78-year-old man prescribed an
of adverse reactions – and related
antifungal agent after treatment for
deaths – nearly tripled between
leukaemia began to hear music in
1998 and 2005. Five of the top
his head. It was so realistic that he
six killers were painkillers.
wrote to his hospital to complain.
He compiled a list of the song titles, Such numbers have to be set
which included ‘Do You Hear What against the enormous benefits that
I Hear?’ Doctors changed his pharmaceuticals bring, but they do
medication and the music stopped. illustrate that drugs are powerful
agents. As well as discovery of new
In another unusual series of cases,
Where do complementary and alternative agents, pharmaceutical companies
patients using a particular drug for
medicines fit into modern medical practice? also work to reduce the unwanted
Parkinson’s disease turned into
side-effects of existing medicines.
Arnica for bruises, Echinacea (above) for colds: for compulsive gamblers. One female
millions of people the answer to the evils of modern life, patient lost US$100 000. ‘Safety’ is not an absolute: it
from constipation to migraine, lies in complementary involves a cost–benefit analysis,
These cases illustrate extremely
and alternative medicine (CAM). weighing up the risks with the
rare side-effects, but adverse drug
benefits. These will depend on
The list of treatments is long and varied – Ayurvedic, reactions as a whole are surprisingly
the drug, the nature of the illness,
Chinese and Tibetan herbs, acupuncture, chiropractic common. About 250 000 people are
the availability of alternatives – and
and reflexology. For some practices, there is scientific admitted to hospital each year in the
individual choice.
evidence of positive effects; for most, there is not. UK because of adverse reactions –
A popular but controversial approach is homeopathy,
founded 250 years ago by a German doctor, Samuel
TALE OF TWO DRUGS: VIOXX MEETS THALIDOMIDE
Hahnemann. He conceived the principle that ‘like cures
like’. For example, onions, which produce streaming,
Russell Kightley/SPL
itchy eyes, might, in minute doses, relieve hay fever. Safety is much improved, but
not infallible, as the case of
But critics are scathing. Homeopaths dilute a substance Vioxx illustrates.
so many times that the final remedy is unlikely to contain
a single molecule of active substance. Although some Vioxx
have proposed that water may maintain a ‘memory’ Vioxx and related drugs were
of the active substance, there is no known mechanism supposed to be good painkillers
by which homeopathy might work. with fewer side-effects than
existing drugs. It was launched
In addition, put under scientific scrutiny, homeopathy in 1999, but almost immediately
fails to measure up. A recent analysis of well-conducted some researchers questioned
studies of homeopathy found no evidence that it was whether it was really safe. In
better than a dummy medicine (placebo). 2004, with global sales exceeding
The placebo effect should not be rubbished, however. 1953: Thalidomide is synthesised US$2.5bn (£1.2bn) a year, Merck
In any clinical trial, typically around 30 per cent of people by German company Chemie withdrew the drug after a cancer
given a placebo will respond positively. The success rate Grünenthal. trial revealed a doubling of risk
of many drugs is not much better than that. of heart and stroke.
1955: Despite lacking supporting
But does it work? evidence, the company distributes What happened? Vioxx is
A source of dispute is whether CAM remedies work – thalidomide to German doctors as estimated to have caused
and how this can be judged. Support for CAM tends an epilepsy treatment. Patients 88 000 –139 000 heart attacks,
to be anecdotal evidence – a patient given a medication report a deep soothing sleep. 30–40 per cent of them fatal.
improves, therefore the medication works. This is not Some critics accused the FDA,
1957: Grünenthal launches it as the USA’s drug-licensing body,
accepted as valid evidence by the scientific community. an over-the-counter drug mainly of not doing enough to protect
Conventional medicine uses randomised controlled for morning sickness. patients. Merck was accused of
trials as a stern test of effect. CAM practitioners respond 1961: Australian researcher massaging data (which it denies).
that individualised treatment cannot be tested in this way. William McBride publishes a BMJ It recently agreed a settlement
Some herbal medicines have passed stringent tests. paper linking hundreds of cases of nearly US$5bn (£2.5bn) for
There is now evidence that St John’s wort is of malformations (see above) Vioxx lawsuits – without
effective for mild depression, and Echinacea to thalidomide use. admitting liability.
can protect against colds. In all, 8000–12 000 babies Yet both drugs may rise again.
were affected, only about 5000 Thalidomide is used to treat
surviving beyond childhood. After leprosy and cancer. Vioxx could
SHOULD A DYING GIRL GET ACCESS
thalidomide, the regulation of drug be made available in the USA
TO AN EXPERIMENTAL DRUG?
testing was tightened considerably (with warnings), as it works well
See Big Picture Online.
ON THE WEB and systems introduced to report for some patients; but Merck
has not relaunched it.
www.wellcome.ac.uk/ adverse reactions.
bigpicture/drugdev
JANUARY 2008 | 9
DRUGS AND
PEOPLE
We talk about ‘drugs for high blood pressure’ rather than ‘drugs for
FAST
FACT
A recent survey
of GPs
suggested
that £2bn
Mrs Smith’. What is given to Mrs Smith is also given to Mr Smith is wasted every
year because
and Mrs Jones. patients do not
follow their
But this one-size-fits-all model is beginning to undergo a radical change. People are different prescriptions.
and what works for Mrs Smith may not work for Mrs Jones. As the genetic and molecular
understanding of disease mechanisms and drug responses become clearer, so medicine
is getting closer to tailored therapeutics.
But what do we really think about drug taking? Some people might want to restrict their Eugene Bochkarev/iStockphoto
pharmaceutical intake but others are keen to take them even though they are in good health.
10 | BIG PICTURE 7
Tailoring medicines
What are the prospects for
personalised medicine?
One of the main justifications for human
genetic research is the prospect of
medicines tailored to a patient’s individual
make-up – pharmacogenetics.
The idea is that a patient would be
diagnosed with, say, heart disease and a
doctor would do a quick test to find out
which drug would work best on them or
which they should not take because of its
likely side-effects. It’s an appealing vision,
but how realistic is it?
Pharmacogenetics may well be the future
but it is likely to be some time arriving.
There are some applications: Many different forms of CYP enzyme
exist, and each form may have many
• Trastuzumab (Herceptin) is prescribed
only for breast cancer patients with variants. The way an enzyme metabolises
AN INDUSTRY VIEW
HER2 mutations. a drug may therefore differ significantly. How is industry responding to
Duplication of CYP2D6 has been linked the pharmacogenetic challenge?
• Imatinib is given to chronic myeloid to poor response to antidepressants;
leukaemia patients with a specific other variations underlie limited response Drugs targeted at only a subset
chromosome abnormality. to painkillers such as codeine. One of the population could spell the
potential use is to screen people for end of the blockbuster model.
• The anti-HIV drug abacavir causes
a rash in 5 per cent of patients with CYP2C9 variations, which predict how Ruling out non-responders could
a particular gene variant. Patients can well people respond to warfarin, a drug reduce market size by
be screened before medication is given. used to prevent blood clotting but which 30–40 per cent.
can also cause excessive bleeding.
Among the most significant factors in A better understanding of disease
pharmacogenetics are the cytochrome Unfortunately, although the promise is will suggest new drug targets.
P450 (CYP) enzymes mainly found great, the translation of pharmacogenetics
into clinical practice is likely to be slow. Clinical trials could be streamlined –
in the liver, which metabolise drugs. only responders would be included.
The identification of a variant linked to
a particular drug response is only the Pharmacogenetics could identify
beginning. Many factors are likely to groups at risk of an adverse
influence the body’s response to a drug, reaction. This might mean new
and clinical trials will be needed to life for drugs that work but are
confirm that patients actually benefit from too risky to use.
targeted treatment – something that so far So pharmacogenetics is a challenge
has rarely been done. And even then the for industry, but also a likely source
The blood thinner warfarin, originally used as a rat practicalities of changing healthcare of benefits.
poison, is metabolised by liver enzymes. It can delivery will have to be tackled.
prevent blood clotting, but the correct dose for a See more at www.wellcome.ac.uk/
patient will depend on which liver enzyme genes bigpicture/drugdev.
they have.
Attitudes to drugs
We can’t seem to make up our mind about drugs. intensively, rarely have
any track record of
In 1979 author M N G Dukes described “the love–hate relationship
success, and may contain
which exists between the public and its drugs – substances which
a whole host of bioactive
are hailed one moment as the solution to every problem and
chemicals. Paradoxically,
castigated the next as the cause of every ill”.
the word ‘clinical’ has
We are consuming more medicines than ever before. We take for come to mean something
granted that they will cure our headaches, see off infections, lower cold, logical and uncaring.
our blood pressure. We give enthusiastically to medical research How has it come to this?
charities and see health-related research as a positive thing.
The shift in attitude could be
But we are terrible at taking medicines as instructed: around a half inflamed by a growing unease
of people being treated for chronic diseases do not stick to their about conventional medicine. Pharmaceuticals-based medicine
prescriptions. We worry that we are overmedicating, giving young is based on treating disease, not patients, in a highly mechanistic
children a ‘chemical cosh’ (as Ritalin has been described) at the way. A quick consultation and here’s a prescription. Next.
first sign of hyperactivity. Our final years are spent consuming a
In contrast, complementary therapies can seem caring and
colourful cocktail of daily medications.
focused on the patient not just the disease. Remedies may seem
We have concerns about what drugs might do to us, and don’t more ‘natural’ and kinder, a relatively safe way to improve one’s
take them unless we absolutely have to. And yet we are happy health (whatever the reality).
to turn to ‘natural remedies’ that have been studied far less
JANUARY 2008 | 11
REAL VOICES
Big Picture on Drug Development
Sarah uses homeopathic medicines. Roger is a volunteer who has taken
part in drug trials.
What conditions do you take
homeopathic remedies for? How did you hear about the
S I took them for eczema. They reduced drug trials?
my symptoms dramatically and gave far R There was a small advert in a local newspaper,
better results than anything else I tried – and someone pointed it out to me.
including conventional steroid creams,
organic creams made by other complementary What made you
healthcare practitioners, and Chinese medicine. want to volunteer?
R The arrival of my two
Would you take them for all your health daughters, around 15 years
problems? ago. My wife had stopped
S No. Some conditions are life-threatening, like septicaemia. working, and I can’t deny
the money was a big
What encouraged you to try them out? issue. You get between
S Partly because I felt that it might address the causes, not just the £500 and £3000 per trial.
symptoms. My eczema started 12 years ago, during work stress.
Another benefit is the
It disappeared completely whilst I was pregnant with each of my
thorough medical checks
two children. Then it got much worse after they were born.
you get before and
After talking to me, the homeopath prescribed tablets that were linked during the trials.
to cravings I had during pregnancy. First of all she gave me a course
of Sepia. Then she treated the eczema, with lycopodeum. How was the trial run?
R If you’re an inpatient, you go in the night before,
There is no doubt that since the first five-day dose there was a dramatic
and sign all the documentation with witnesses.
improvement in my hands – greater than I had ever seen.
The next day, you get your dose of the drug at timed
What effect do they have on you? intervals, and they start taking your blood samples,
S My skin is much less dry and feels more resilient, and I feel well also at regular intervals. You can see the results if
and fortified in general, more than I usually do, despite having had you want. Some people don’t like needles, but you
a cold recently. have to have a canula. That’s as invasive as it gets.
How do you think they work? There are often restrictions on what you can eat and
drink, but they don’t tend to be harsh. They might
S I don’t know because I’m not a homeopath.
say no grapefruit and no poppy seeds, for example.
I do know they offered me a real solution. I think precise diagnosis of the
cause is probably key: a qualified homeopath can listen and give you How concerned were you about
exactly what you need for your individual case. I also think they give possible side-effects?
you stronger tablets than the ones you can buy at the chemists. R People have been nervous since Northwick Park.
But I’ve never had any lingering effects.
What do you say to people who question whether
they work? My attitude is that I’m more likely to get killed on the
bike on the way over there, than during the trials.
S You can question anything. Homeopathy is easy to undermine because
of its nature. It’s worked for me, that’s all I can say. It’s in the company’s interests to look after me, and
they are loath to release anyone with any effect,
Do you think they should be provided however small. You’re very well monitored – both
on the NHS? for your individual benefit, and for their statistics.
S Yes. But people expect too much of the NHS anyway. Homeopathy I may have been affected long-term and not realised
Background: Marcelo Wain/iStockphoto
might be another burden. it. But I’m confident that I won’t be, and I feel well
If the Government paid for it, great. But patients would have to be very looked after.
cooperative, have the right expectations and attitudes, and do what they
are told. You can’t drink tea or coffee whilst you are having homeopathy,
for example, and you can’t use menthol toothpaste.
12 | BIG PICTURE 7
HOW DO YOU THINK HOW CONCERNED WERE YOU ABOUT
HOMEOPATHY WORKS? POSSIBLE SIDE-EFFECTS?
S I think precise diagnosis of the cause R People have been nervous since Northwick Park.
is probably key: a qualified homeopath but I’ve never had any lingering effects.
can listen and give you exactly what you My attitude is that I’m more likely to get killed
need for your individual case. on the bike on the way over there, than during
the trials.
FAR LEFT
Arnica montana,
Daniel’s wife Susan speaks Should all drugs should be a homeopathic
for Daniel, who was denied remedy.
available to patients? Garo/Phanie/
the drug Lucentis, in this Rex Features
S Yes, definitely. Whatever you need, breast
interview. cancer drugs or eye injections, if you’ve got the MIDDLE LEFT
disease, they should give it to you. Testing drugs
What drug did you on volunteers
want access to? What if they only provide small in France.
Sipa Press/
S Daniel’s got wet age- benefits? Rex Features
related macular degeneration (AMD) in S Yes, because you don’t know until you’ve tried NEAR LEFT
one eye, which is caused by blood vessels leaking how it will work, especially for something as Daniel and Susan.
behind the retina. It’s the biggest cause of blindness important as eyes or cancer. You deserve a chance.
Surrey and Berkshire
Newspapers Ltd
in the UK and the USA.
We wanted access to Lucentis, made by Genentech, How could the NHS keep on top
which shrinks the blood vessels behind the eye. of costs?
It’s licensed in Europe, the USA, Scotland, but S If Daniel had had the injections quickly, there would
not England. be fewer costs in the long run. If he goes completely
blind, there’ll be his benefits claims, hospital visits,
Who decided that you could and my attendance allowance. It’s a false economy,
not have it? thinking of the here and now, rather than tomorrow.
S Our local Primary Care Trust (PCT).
How can we decide between
What reasons were given? different deserving causes?
S They said it’s not available. Then they said they S You can’t pick some people to be treated and
would only fund it if it spreads to the second eye. leave the others. It shouldn’t be like that.
You have to go blind in one eye first.
If they’ve got the drug, they should give it to you.
What did you do? We’ve worked all our lives, paid taxes and national
S We fought the PCT for three to four months. insurance all our lives.
We paid for one injection of Lucentis privately. We need to divert more funds to the NHS.
It cost £1560. But one injection didn’t give any Something else has to go.
improvement: you could need 20 to 24 injections,
which would be too expensive for us. How good a job is NICE doing?
S It’s not. It’s a bureaucracy, with people sitting in
Do you know of other people little offices, giving patients no help or advice. They
who did gain access? should ask the Government for more money.
S Yes. Some PCTs do give Lucentis. It’s a
postcode lottery.
Power to prescribe
This issue’s activity is based around a simulation of a
pharmaceutical company planning future spending. It gives ONLINE ACTIVIT
students the chance to role-play various characters working Y
for the company and to consider which pharmaceutical they
should develop.
Three different drugs – tackling obesity, HIV/AIDS and heart disease
respectively – have had successful phase II trials but the company can only
afford to run expensive phase III trials on one of them. Which one will it be?
Students will review each of the proposals, take part in a debate to discuss the
issues at stake and vote on the drug they think the company should invest in.
Role-play cards, teacher notes and activity sheets are provided. Full details can
be found at www.wellcome.ac.uk/bigpicture/drugdev.
Mustafa Deliorman/iStockphoto
JANUARY 2008 | 13
YOUR MONEY
OR YOUR It is impossible to discuss healthcare and pharmaceuticals without
PhekThong Lee/iStockphoto
LIFE?
The pharmaceutical industry is
considering money. UK healthcare is a huge and increasing strain
on resources. In developing countries, lack of money means no
access to the medicines we in the West take for granted.
14 | BIG PICTURE 7
Drug costs The market decides
How much does it cost to About 40 per cent of the cost Pharmaceutical development is based on free-
develop a new medicine? reflects expenditure on clinical market economics. This significantly shapes
failures. Around half the cost the nature of the industry.
Several figures are bandied about,
of drug development is classed
but the generally accepted figure For some, the idea that money can be made out of
as ‘opportunity cost’ or ‘time value
is produced by a US body, the ill-health is distasteful. But we live in a free-market
of money’ – reflecting the long time
Tufts Center for the Study of Drug economy, and the economic rules that apply to, say,
periods and intensive efforts needed
Development, which uses data food production, also hold for healthcare. By some
to develop a new drug.
supplied by the pharmaceutical tokens, it is a highly successful model: we have drugs
industry. In 2001 it put the cost The figures refer to entirely new we can rely on for many conditions, and research is
of developing an entirely new drug drugs – which are relatively rare actively being carried out to develop new therapies.
at US$800 million. A more recent (20–30 are launched each year).
Many drugs are refinements But the way that the market operates has some
study from another US group
of pre-existing agents, and unfortunate consequences.
suggested a range from US$500m
to US$2bn, depending on the drug. hence cheaper to produce. For a start, there is a strong focus on the diseases
of the rich industrialised world. There is little incentive
A biotech product, such as a
to develop medicines for diseases affecting developing
protein or monoclonal antibody,
is more expensive to produce FAST countries, as companies would find it hard to recoup
(US$1.2bn) and takes longer to
bring to market; however, fewer fail
FACT development costs.
Even in rich countries, the emphasis tends to be on the
It is estimated
during development (success rates that the global treatment of chronic diseases – where people have to
are around 30 per cent compared healthcare take medication for long periods. From a financial point
with 20 per cent for traditional marketplace of view, a drug such as an antibiotic or a vaccine, which
pharmaceuticals). will be worth generally needs to be used just once, is a less attractive
US$1.3 trillion option. Nevertheless, vaccine development in industry is
by 2020. growing.
Another common feature is that of ‘me-too’ drugs –
minor variations on existing products. Companies fight
each other for a slice of a profitable cake. Development
costs will be substantially lower, but benefits to patients
may not be great.
As patents are crucial to the industry, compounds
not protected in this way – even if effective – are not
attractive for investment. Why put millions of pounds
into developing a drug that your competitor can make
TOP 5 BLOCKBUSTERS as soon as it is approved?
The modern pharmaceutical industry pins most of its hopes on ‘blockbusters’
– drugs for common diseases generating millions (even billions) of pounds THE FUTURE IS NOW
in profits. Technically, a blockbuster is a drug that generates more than
US$1bn sales a year. Around 100 blockbusters exist. Drugs are supposed to be for when we
The upshot is that firms concentrate heavily on a small number of products. are ill – but they can also make us ‘better
Extremely large sums are spent marketing the drugs (typically more than than well’.
30 per cent of revenue and at least twice what is spent on R&D; the
industry’s total annual marketing costs have been estimated at US$60bn). A drug to boost brain power? It sounds far-fetched but
it already exists. Drugs intended for medical use may
The days of the blockbuster may be numbered, however. The trend for have applications outside the clinic, raising challenging
more targeted medicines is leading to a fragmented marketplace. ethical questions:
Modafinil (Provigil), a treatment for sleep disorders,
can boost mental powers, by increasing alertness
Annual sales Drugs and the ability to concentrate on a task.
1 Lipitor (atorvastatin) for Methylphenidate (Ritalin), used to treat attention deficit
high cholesterol hyperactivity disorder (ADHD), improves concentration.
2 Nexium (esomeprazole) Donepezil (Aricept), a drug for Alzheimer’s disease,
for heartburn may improve normal memory.
3 Seretide/Advair None of these drugs is licensed for use in normal
(fluticasone/salmeterol) people. They have side-effects and the impact of their
for asthma long-term use is unknown.
4 Plavix (clopidogrel) for There is growing evidence that such drugs are being
heart disease used by healthy people, including students preparing
5 Norvasc (amlodipine) for exams. Is this cheating or much the same as
for hypertension getting a kick from caffeine in coffee or Red Bull?
For more on this, and how a drug called propanolol
may help us lose unwanted memories, see
www.wellcome.ac.uk/bigpicture/drugdev.
JANUARY 2008 | 15
DRUG DEVELOPMENT
THE BIG PICTURE
• Modern medicine is based mainly on a biochemical • Although some
model of disease. pharmacogenetics-
based approaches
• Drugs interfere with biochemical processes.
are used in medicine,
• Drugs were originally selected for their ability to treat their introduction is
symptoms, with little understanding of how they worked. likely to be
• Drug development is increasingly based on known disease slow and gradual.
mechanisms – rational drug design. • The economics of
• Most drugs are small chemicals, though protein therapeutics drug development
are becoming more common. is dominated by
‘blockbuster’
• Drug development is a lengthy and expensive process – medicines with very high sales; this is likely to change as
many drugs never make it to market. pharmacogenetics becomes more important.
• Drug development aims to maximise safety and efficacy. • The pharmaceutical industry is strong in the UK,
• Clinical trials will not pick up rare side-effects, so the use contributing to employment and national wealth.
of new drugs is monitored. • Critics of the industry argue it has too much influence,
• A drug will rarely, if ever, work for everybody. promoting drug-based approaches and being too focused on
economic rather than medical priorities.
• All drugs have side-effects; these have to be weighed
against the benefits a drug provides. • New medicines have to be approved by the MHRA, the
Medicines and Healthcare Products Regulatory Agency.
• Adverse drug reactions are a common cause of hospital
admission and a leading cause of death. • To be used in the health service, medicines usually also need
to be recommended by NICE, the National Institute for Health
• There is a trend towards personalised medicines, and Clinical Excellence, which assesses value for money.
including drugs matched to patients’ genetic background
(pharmacogenetics). • People are often reluctant to take medicines and commonly
do not take them as prescribed.