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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

    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.
                                                                                                       Graham single-handedly
                                                                                                       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
                                                     mathematical model.
  Bextra: a pain reliever made                                                                         Graham’s testimony has
  by Pfizer
  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

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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

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

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