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Worldview, practicesAndrew 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 scientificcommittees, 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 countrys

Minister of Health. Also, in 2004 the SARScrisis 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

pharmaceuticals

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 its 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

tomorrows blockbuster to market.

But any ideas that once a drugs

launched, pharmaceutical companies can

just concentrate on marketing and rely

on the money coming in are far f rom 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

patients 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 whove lost

loved ones to bad drugs.

rooting out the problem

Asked to comment for this article, theFDA 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 Mercks

Vioxx and Pfizers 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. Its

high time that the FDA looks into its

processes and reduces the approval of

unsafe drugs.

An impartial observer, a corporate

communications expert whos 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

Getting it to the streetsDrug development flourishes despite medicinal failures, says Laurie Wiegler

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pharmaceuticals

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 its 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 drugs 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 doesnt 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 inthese 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 dont 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: Theres no question that

theres 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 its

on patent, the longer they will have to

be able to own the marketplace for that

particular drug.

As Frost & Sullivans 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 [FDAs]

advisory committee.

marketing the message

Yet another conflict is occurr ing 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, its 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 tobe reviewed very carefully in the US. Its

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 isnt shy inacknowledging the problem, stating

that direct-to-consumer (DTC) marketing

has an impact on the patient-physician

relationship since patients arent fully

able to understand the implications

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 majordifference

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 UKwould 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 maynot make the same amount of profit as

they do in the US from drugs, they still

will make something and will still have

exclusivity in the marketplace until the

generics can come in. tce

Laurie Wiegler

is a US-based

freelance

journalist

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