pharmaceuticals
Getting it to the streets
Drug development flourishes despite medicinal failures, says Laurie Wiegler
Worldview, practices
Andrew Penman, vice-president of drug
development at Southern Research in
Birmingham, AL, US, points out that the drug
approval process in Europe has the advantage
that for such things, Europe is considered as
“one state.” For example, if a drug is approved
in the UK it will also be saleable in Italy.
The European Medicines Agency (EMEA)
regulates drugs, as it conducts the final
scientific evaluation of applications for
European marketing authorisation for
medicines. Companies submit what is called a
“single marketing authorisation application“
to the EMA; once granted, the European
Commission makes that authorisation valid
in all EU and EEA-EFTA states, with the
exceptions of Iceland, Liechtenstein and
Norway, which are European Free Trade
Association (EFTA) members.
The EMEA draws on its six scientific
committees, composed of members of all EU
and European Economic Area-European Free
Trade Associations states (EEA-EFTA) as well as
some doctors and other concerned parties – to
conduct its main scientific work: committees
for medicinal products for human use,
veterinary use, orphan medicines (drugs used
to treat more rare diseases), herbal medicinal
products, paediatrics and for advanced
therapies.
In Canada, drugs must be approved by
Health Canada, monitored by the country’s
Minister of Health. Also, in 2004 the SARS
crisis prompted the formation of a new
government body, the Public Health Agency
of Canada, which largely functions to control
disease outbreak.
44 tce june 2009 www.tcetoday.com
PHARMACEUTICAL makers know
that getting a drug approved is an
endeavour littered with difficulties
and pitfalls. Not only do you have to
identify your drug candidate, prove it
works and show it’s safe, you then have
to get it past the regulator. For most
pharmaceuticals, approval by the US Food
and Drug Administration (FDA) is the
final and most important step in getting
tomorrow’s blockbuster to market.
But any ideas that once a drug’s
launched, pharmaceutical companies can
just concentrate on marketing and rely
on the money coming in are far from the
truth. Recent years have seen a flurry
of drug recalls – for Heparin, Fen-Phen,
Baycol, Ephedra, Vioxx and hundreds
more – over safety concerns with drugs
that were previously approved by the
FDA.
The question is, then: is the FDA
approving drugs too hastily? Have efforts
to ease the development and approval
process helped shareholders while risking
patient’s lives? With an arduous review
process that involves a series of pre-
clinical and clinical trials that consist
of carefully-monitored phases, first with
rats and then with humans, the answer
would appear to be no. Yet, that hardly
calms the families of those who’ve lost
loved ones to bad drugs.
rooting out the problem
Asked to comment for this article, the
FDA first said it must be allowed to
review quotes and later, that questions
be sent in advance. Ultimately, an
interview was not granted because, a
spokesperson claimed apologetically, it
was simply too busy.
The FDA also declined to comment
on allegations that it may be unduly
influenced by the interests of ‘big
pharma’. Some critics fear that such
interfererence could have allowed drug
companies to hide negative test results
and bribe doctors and scientists on the
FDA panel.
For example, in a recent case the
Massachusetts anaesthesiologist Scott
Reuben was accused of fabricating
21 studies that purportedly show the
benefits of painkillers such as Merck’s
Vioxx and Pfizer’s Bextra, which have
since been withdrawn. Reuben called on
the FDA not to restrict the use of these
drugs, citing his own data as evidence.
At the same time, Reuben was being paid
as a corporate speaker by Pfizer, and
the company also supported some of his
research financially.
Frost & Sullivan research analyst Sylvia
Miriyam Findlay, says that while she
regards such accusations as “baseless”,
the FDA needs to address the perception
that it is doing less than it could. “It’s
high time that the FDA looks into its
processes and reduces the approval of
unsafe drugs.”
An impartial observer, a corporate
communications expert who’s followed
pharmaceuticals for years – and asked to
remain anonymous – pointed out that in
light of current bad press, the FDA may
indeed be trying to control the story.
still the only game in town
However, one would have to look no
further than disease-stricken Third
World countries to find good reasons to

continue supporting the FDA. After all,
the agency approves hundreds of drugs
annually, all of which must be proven
both safe and efficacious. The road
to approval is a long and bumpy one,
though, and the outcome is that most
drugs are not approved.
Drugs research has to pass through
three formal phases of human research
before the FDA can put a stamp of
approval on a new treatment. But
before they even get to the three
phases, researchers must be awarded
an investigational new drug application
(IND). This proves that tests on
laboratory animals indicate that it’s safe
to move forward on humans – or at least
to the best of researchers’ knowledge.
If FDA issues the green light, an IND
must pass the following rounds:
• Phase 1 studies are conducted with
healthy volunteers. FDA literature states
that “the goal here is to determine what
the drug’s most frequent side effects are
and, often, how the drug is metabolised
and excreted. The number of subjects
typically ranges from 20 to 80.”
• Phase 2 studies begin only if Phase
1 doesn’t reveal unacceptable toxicity.
“While the emphasis on Phase 1 is on
safety, the emphasis in Phase 2 is on
effectiveness.” This phase is designed to
prove whether the drug works in humans
with a certain disease or condition.
Researchers use about 300 subjects in
these types of studies.
• Phase 3 studies begin only once
Phase 2 has shown the drug works for
the given indication. These studies
gather more information about safety
and effectiveness, studying different
populations and different dosages and
using the drug in combination with
other drugs. The number of subjects
usually ranges from several hundred to
about 3000 people.
Andrew Penman, vice president of
drug development for Southern Research,
who has worked on developing medical
devices and other areas of discovery
throughout the world, points out that
unmet medical need is a key driver
for drug development. “If you develop
a drug to cure lupus, for example, or
multiple sclerosis, you would have a
license to print money.”
conflicts of interest
Yet pharmaceutical companies can spend
millions delivering drugs that we strictly
speaking don’t need, while others are
approved too hastily.
Ruth Merkatz, director of clinical
development and reproductive health
with the Population Council at the
Center for Biomedical Research in New
York, says: “There’s no question that
www.tcetoday.com june 2009
there’s a bit of conflict in the whole drug
development process.”
Merkatz points out that the
pharmaceutical companies have a limited
time to recoup their investment and to
turn a profit, which is their responsibility
if they are a publicly-traded company.
“So because of patents, the sooner they
can get their drug approved while it’s
on patent, the longer they will have to
be able to own the marketplace for that
particular drug.”
As Frost & Sullivan’s Findlay says,
though, oftentimes drug approval
can actually be held up despite best
intentions. “Pharma companies are
facing huge delays for drug approvals
from the FDA, which can be attributed
to various factors [such as] staff
shortage[s] and delays at the [FDA’s]
advisory committee.“
marketing the message
Yet another conflict is occurring in
prime time. Turn on the US TV, and one
is immediately struck by the multitude
of commercials for all manner of drugs.
Lipitor, Humira, Cymbalta, Levitra,
Treximet and Nexium – pharmaceuticals
tackling high cholesterol, arthritis,
depression, erectile dysfunction,
migraines and heartburn – were just
a few of the drugs advertised within a
few hours on two separate US television
stations during prime-time one February
night.
According to Merkatz, it’s not an
accident that Americans may notice
more commercials. “Back in the mid
to late 90s the FDA changed its ruling
and permitted the advertising of drugs
[on television]. Before it was just in
periodicals – in journals and magazines.”
Nowadays the ads are infiltrating
the airwaves – from TV to radio to,
no doubt, the myriad forms of mobile
broadcasting. Even so, she points out:
“They [advertisers] have to disclose
safety risks. All advertisements have to
be reviewed very carefully in the US. It’s
a division within the FDA called DDMAC
(Division of Drug Marketing, Advertising
and Communications.)”
Of course, it would take psychologists
and sociologists, perhaps, to accurately
address the issue of whether clever
marketing – couples running through a
meadow to advertise erectile-dysfunction
improving drugs or supermodels popping
cholesterol-lowering meds – contributes
to a rise in recalls.
Yet, Findlay isn’t shy in
acknowledging the problem, stating
that direct-to-consumer (DTC) marketing
has an impact on the patient-physician
relationship since patients aren’t fully
able to understand the implications
pharmaceuticals
“Even in a country where they may
not make the same amount of profit
from drugs as they do in the US, they
still will make something and will still
have exclusivity in the marketplace
until the generics can come in”
Ruth Merkatz, Center for
Biomedical Research, New York
of these messages. She even draws a
link between the Vioxx recalls of 2004
and direct marketing. Going forward,
“DTC marketing should undergo serious
changes, especially from advertising
drugs to promoting disease awareness,”
she says.
generic prevalence major
difference
While a thorough examination of the
entire drug development industry would
take several months, a briefer glimpse
punctuates some of the similarities
between US drug development and that
of the UK, Europe and Canada.
A marked difference in the UK and
Canada versus the US, at least, is the
prevalence of generic drug use. “The
majority of the medicines in the UK
would be generic medicines provided by
generic manufacturers,” says Mike Murray,
manager of technical services with
London-based ABPI. The reason would
appear to be fairly straightforward: both
nations enjoy free national healthcare,
which puts pressure on healthcare
professionals to prescribe the cheapest
effective treatment.
However, a prevalence of generics
does not equal free: one in five people in
the UK pay a flat fee of £7.20 ($10.99)
per item for their medicines.
“The majority of medicines in the UK
are dispensed free of charge because
there are a number of exempted
categories of patients: the elderly, people
on income benefit/income support,
people suffering from various disease
types and categories, and children
obviously,” says Murray.
One should not jump to conclusions,
though, and assume that socialised
medicine means a socialised
pharmaceuticals industry. As Merkatz
says: “Even in a country where they may
not make the same amount of profit as
they do in the US from drugs, they still Laurie Wiegler
will make something and will still have is a US-based
exclusivity in the marketplace until the freelance
generics can come in.” tce journalist
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