R e g u l a t o r y & L e g a l U p d a t e
nternational pharmaceutical companies have been reeling ever since
One of the regulatory changes Graham proposed was granting the
Dr David Graham testified before a US Senate Committee on the Office of Drug Safety independent regulatory authority. Currently,
FDA’s approval procedures. What Dr Graham said on 18 November safety officers are faced with a conflict of interest if they have to
2004 propelled him onto the front pages of US newspapers, punctured convince the Office of New Drugs that a licensed drug produces
the stock prices of several major pharmaceutical companies and made damaging side effects. The conflict arises because the group that
him the poster boy for whistle-blowers across the world. Dr Graham’s approves the drug in the first place is also responsible for taking
testimony dealt a major blow to the hitherto spotless reputation of the regulatory action against licensed drugs.
FDA. Graham, who has worked for the FDA for 20 years, claimed that
it had ignored evidence from its own scientists about several drugs it Widening the net
had licensed for general use which subsequently proved to be as Dr Graham was an associate director in the FDA Office of Drug
dangerous as they were effective. Safety when he testified, and his stinging criticism of the FDA
meant that he was subsequently moved to an unspecified role,
A testimony for change working for the FDA commissioner. His research has been
Dr Graham told the senate committee that the FDA had ignored unprecedented in marshalling large samples of data collected
warnings that a particular pill, Vioxx, could cause heart attacks and by healthcare providers using new drugs.
strokes. Manufactured by Merck and marketed as an anti-arthritis
treatment, Vioxx had to be withdrawn, wiping $30bn off the company’s What Graham’s system revealed was very different from the results of
stock market capitalisation. At the time of its withdrawal, two million the carefully controlled clinical trials, which compare the effectiveness
people were already taking the drug. Since it has been licensed, 84 of two medicines in treating a specific condition and invariably ignore
million people have taken it. Graham’s testimony did not just hit any wider effects. Merck’s trials of Vioxx, for example, showed that it
Merck and Vioxx. He also highlighted major safety concerns over caused fewer ulcers than its competitors. Graham’s analysis showed
five other popular drugs in the USA (see Figure 1). that Vioxx also caused more heart attacks, especially once users had
been taking it for more than 18 months. In fact, he believes that
In less than three hours, Graham single-handedly destroyed the Vioxx caused 140,000 heart attacks. It also caused more strokes.
FDA’s reputation as a thorough investigator of treatments and a
diligent protector of the interests of US patients. Instead, the FDA
was exposed as a patsy of the big pharmaceutical companies. Industry
commentators and politicians were quick to attack these companies In less than three hours,
as powerful interests driven solely by greed.
destroyed the FDA’s
reputation as a thorough
COVER STORY investigator of treatments
and a diligent protector of
the interests of US patients
Watch out for whistle-blower, David Graham
Former FDA associate director, Dr David Graham, has shaken up the pharma industry with his
disclosure of the FDA’s approval inaccuracies. Ignoring the side effects of such drugs as Vioxx has
led to several fatalities, and there are now calls for big changes to the international drug business.
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R e g u l a t o r y & L e g a l U p d a t e
One major issue thrown up allegations about Prozac, the big pharmaceutical companies have
The five drugs in question by Graham’s testimony and agreed to provide more comprehensive data about their clinical trials
his subsequent high public and studies, based on the GSK model. This is a deliberate attempt
profile was the blinkered way to head off the threat of legislation forcing changes in the way
Meridia: a weight-loss drug in which the FDA approved companies develop new drugs. This move towards providing more
made by Abbott Laboratories the wording of the labelling information, both positive and negative, is a tacit admission that in
Graham: It raises blood pressure on drug packets. In the case the past drug developers have been tempted to cut corners to get new
and increases the risk of strokes. of Vioxx, for example, the drugs onto the market – whether the ultimate aim is to help patients
labelling minimised the or to provide the revenues to keep other research projects going.
Crestor: a cholesterol-lowering cardiovascular risks while
drug made by AstraZeneca emphasising a benefit for The temptations are huge; Merck, for example, knows that the market
Graham: It has been linked to ulcer. In her senate for analgesics (or painkillers) is worth $10bn a year in the USA alone.
kidney failure. testimony, the FDA’s Sandra The market for anti-depressants is even bigger. Getting a drug approved
Kweder, deputy director of that can grab a slice of that market appears to be the drug companies’
Accutane: an acne medication the Office of New Drugs, overriding ambition. To get approval, they simply had to show that
made by Roche said that the deaths Graham their product was effective.
Graham: It causes birth defects indicated were just the
when used by pregnant women. predictions of a
Bextra: a pain reliever made Graham’s testimony has
Graham: It increases the risk of
The Spitzer effect
In the wake of Graham’s
changed the dynamics of the
heart attacks and strokes. testimony, there were calls international drug business
for changes in the law and
Serevent: an asthma medication regulations covering clinical
made by GlaxoSmithKline trials. The impact of In the USA, public trust in drug companies has dropped dramatically.
Graham: The drug has actually Graham’s testimony was Investors have taken a hard look at their portfolios and sold companies
caused death from asthma and enhanced by the fact that it with questionable products. Already the drug companies face class
people have been found dead followed a high-profile actions from patients, who argue that companies knew the risks of
holding their Serevent inhalers. campaign by the New York certain drugs but failed to inform the public and the regulators.
State Attorney General, Eliot
Spitzer, to force pharma Big pharma responds
companies to provide more Initially, the response of the big pharmaceutical companies to
information on the data they accumulate during clinical studies and Graham’s testimony was inadequate. It took until January 2005 for the
trials. This culminated in a settlement at the end of August 2004, industry to come up with the idea of providing more information,
when GlaxoSmithKline (GSK), the UK’s largest drug company, along the lines of GSK’s agreement with Spitzer. In the immediate wake
agreed to disclose information on clinical studies of its drugs. of Graham’s testimony, several big pharmaceutical companies did little
to help themselves, with ill-advised advertising claiming that some of
The GSK settlement ended the debate, on whether the company the drugs cited by Graham were, in fact, safe. This attempt at business
had been economical with the truth over clinical data accumulated as usual was too much for the FDA. It publicly criticised AstraZeneca
during trials for an anti-depressant, marketed as Paxil in the USA for misleading advertising that suggested the FDA had confidence in
and Seroxat in the UK. Spitzer showed that although GSK had Crestor, an anti-cholesterol treatment.
carried out five studies into the effects of Paxil/Seroxat on
children and adolescents it had released only one of these studies. Steven Galson, acting director of the FDA’s drug division, was
The four studies that produced negative results from GSK’s point quoted as saying that the FDA had been worried about the dangers
of view were suppressed. of Crestor ever since it was approved. AstraZeneca all but admitted
that the adverts had been a mistake and said that they would not
The corporate blood drawn by Spitzer and Graham has tempted others be repeated.
to look for scandals, perhaps where none exist. At the end of December
2004, the British Medical Journal (BMJ), published an article alleging that Global consequences
adverse clinical data related to Prozac, a blockbusting anti-depressant, What the Graham testimony has done is to change the dynamics of the
had gone missing ten years ago during a product liability lawsuit. This international drug business. Global drug companies are already
lawsuit arose after Joseph Wesbecker, a Prozac patient, went on a noticeably more cautious about their boasts for drugs under
shooting spree and then killed himself. Eli Lilly, Prozac’s manufacturer, development. The damage caused to these companies’ share prices and
rejected the BMJ’s allegation, which was based on evidence from an global reputation by Graham has resulted in the widely held belief that
anonymous source. The BMJ claimed that the missing documents it is better to forego the revenues from a potentially risky drug than to
allegedly showed that patients taking Prozac were twice as likely to suffer the embarrassment and expense of withdrawal.
display symptoms of psychological activation, such as nervousness and
aggression, as those patients who were taking the placebo. AstraZeneca, for example, had applied to the EU for approval to sell
the drug in the Europe (the drug is already licensed by the FDA and by
The aftermath the Japanese authorities). On 4 January 2005, Astra Zeneca announced
As a result of the Graham testimony, the Paxil/Seroxat case and the that it was withdrawing its EU application after the release of clinical
World Pharmaceutical Frontiers • Providing a global perspective on the pharmaceutical industry • www.worldpharmaceuticals.net Page 32
R e g u l a t o r y & L e g a l U p d a t e
data from new trials in December 2004, which showed that, although Under Canadian law, prescription drugs can only be sent to a US
the drug shrank tumours, its harmful side effects prevented it from applicant if the prescription is counter-signed by a Canadian doctor.
significantly increasing the life expectancy of its users. The fee for doing this was US$12 per prescription, but the Canadian
doctors’ insurers are threatening to withdraw cover if they are sued for
Parallel imports malpractice in the USA.
Dr Graham’s testimony altered the balance of power in the
international pharmaceutical business. The FDA is no longer seen as This issue is equally important in Europe. In the UK, one in five of all
the toughest hurdle for a new drug. The FDA’s failure to weigh the medicines sold in high street pharmacies are parallel imports. The
benefits of a new drug against its potential dangers means that its pharmaceutical industry argues that the trade does not lower costs for
authority in other areas has been undermined. One crucial area is the NHS, but it does threaten jobs in the UK pharmaceutical industry.
parallel imports. Increasingly, many US healthcare providers are
ignoring scare stories from the pharmaceutical companies, endorsed by The big issue
the FDA, and buying cheaper versions of common drugs from Canada. Drug companies rarely look into the effects that newly developed drugs
might have on patients when combined with other common drugs they
This is another area where Spitzer has been active; he has set up a might be taking for a different condition. As anybody with elderly
website to monitor the price of drugs in various pharmacies across the relatives knows, old people are often taking four or five different pills a
state of New York. Other US states have gone further and allowed some day. Some commentators claim, perhaps exaggeratedly, that older,
of their healthcare providers to import cheaper versions of US licensed proven pharmaceuticals can become deadly when they are combined
drugs from Canada. The FDA, under pressure from the drug with newer drugs.
companies, which claim that manufacturing standards are lower in
Canada, has threatened to prosecute states and cities that allow However, the big issue for the drug industry over the next six months
healthcare providers to import cheap drugs from Canada. However, the will be facing the changes initiated by Spitzer and Graham regarding
FDA has always stressed that it will not prosecute individuals who use the publication of clinical trial and study data. These changes are likely
the internet to import the drugs they need from Canada. to open up new areas of research. END
For further information circle 18
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