The Legal Janitor

By Andy Ho

IF YOUR doctor assures you that a new drug is safe because it is ‘FDA-approved’, take that with a pinch of salt. Once upon a time, he could have been right but, now, there is cause for concern. If he seems to be in the dark, shine some light on it for him.

The Food and Drug Administration (FDA) had long been regarded as the world’s gold standard in drug safety review. Thus, the Health Sciences Authority (HSA) here basically takes the American regulator’s tack on most drugs. For example, after the manufacturer’s worldwide recall of the anti-arthritis drug Vioxx last September, the FDA still allowed a similar drug, Celebrex, to remain on the market - and HSA followed suit.

This means that whatever is brewing inside the FDA matters to us here.

The Vioxx recall, followed by serial upsets over similar arthritis drugs, Celebrex and Bextra, then Aleve, in the last quarter of 2004 exposed how lax the FDA had become in passing new drugs. According to a Pulitzer Prize-winning investigation by the Los Angeles Times, in 1988, it approved 4 per cent of all new drugs in the world market. By 1998, it was first-past-the-post in 66 per cent of cases.

Moreover, the LA Times also found that it was approving 80 per cent of all applications at the end of the 1990s, compared to 60 per cent at the beginning of the decade. While it was allowing more new drugs on to the world market much faster, it was also recalling more drugs than it had in its entire history.

In fact, the FDA was the last to recall several drugs that the European health authorities were quick to ban in the late 1990s. The FDA is now the soft underbelly of the system that supplies the developed world with safe pharmaceuticals.

Ill watchdog

HOW long has the once-wary watchdog been ill?

Ever since it was found in the pockets of the huge pharmaceutical companies from 1992, critics say. An indication of how far the FDA has fallen: Even after the manufacturer, Merck, had voluntarily recalled Vioxx, the FDA would take no action on similar anti-arthritis drugs. Instead, it sat on its hands until one of its scientists turned whistle-blower during an open United States Senate hearing last November.

Arguing that Vioxx was implicated in 55,000 deaths in the US alone, FDA reviewer David Graham said he had been forced by agency leaders to water down his findings because of their cosy ties with the pharmaceutical industry.

He was no Lone Ranger either.

A recent US government survey of FDA scientists found that a third had qualms about the agency’s initial approval of new drugs while nearly a fifth said they were under pressure to approve a drug even when they had safety concerns.

The agency’s run of bad media last year began with an uproar in February over its refusal to air a staff scientist’s conclusion that certain anti-depressants, like Paxil, could put children at higher risk of suicide. It even disallowed the expert to present his conclusions about the risk of suicide in children on such drugs.

After contentious hearings, the agency would only change Paxil’s labelling. Last December, the ABC News programme Primetime Live obtained actual internal studies the drugmaker, GlaxoSmithKline, had done which concluded that Paxil had little or no effect in treating depression in children and adolescents.

The New York state government sued the maker, charging that it had repeatedly concealed information about Paxil from doctors. For example, GlaxoSmithKline had conducted five studies in children but published just one. The Paxil lawsuit was later settled with a US$2.5 million (S$4.1 million) fine and a promise from the maker to make all of its research available online.

After the Paxil debacle, half the US flu vaccine supply for last year was found to be contaminated, bringing FDA oversight of the drug supply system into question.

Finally, at the end of the year, Vioxx was recalled.

But even before Vioxx, there had been concern about the way drugs were tested and allowed to go on sale in the US.

For example, in May 2000, the editor-in-chief of the New England Journal Of Medicine, Dr Marcia Angell, wrote a scathing editorial titled, Is Academic Medicine For Sale?, which accused scientists of striking a Faustian bargain by accepting research funds from pharmaceutical companies.

In September 2000, a USA Today investigation showed that experts hired to advise the FDA on new drug approvals were not quite independent: About 54 per cent had a direct financial interest in the drug or topic they were evaluating.

That year too, The Washington Post revealed that the manufacturer of Celebrex, a Vioxx-like arthritis drug, had published six months of favourable trial results, but suppressed data for the following six months. The muzzled data indicated that Celebrex led to stomach ulcers as frequently as people on older medications. Celebrex (and Vioxx) had been heavily advertised as painkillers protective of the stomach.

In 2001, Los Angeles Times journalist David Willman won the Pulitzer Prize for his many exposes on the FDA. Then, last year, Dr Angell, who now teaches public health at Harvard, published The Truth About The Drug Companies, a book based on her 20 years at the New England Journal Of Medicine, from where she witnessed the growing influence of drug companies over top medical journals, doctors and government agencies.

Genesis of a downfall

WHAT pushed the FDA off its pedestal?

In the first instance, it may be traced to pressure from the gay lobby and Aids activists.

One fateful day in 1988, when the FDA was still taking more than two years to carefully review and grudgingly approve new drugs, Aids activists occupied its headquarters, paralysing operations there for a day. They demanded immediate approval of experimental Aids drugs.

The big pharmas pounced on the opportunity afforded by the huge media coverage to pressure Congress for fast-track approval of their new drugs. At first, it was just for HIV and other alife-threatening and serious illnesses like cancer. But they also had drugs in the pipeline for Alzheimer’s, say, and that was a serious illness too. In no time, they were calling many other diseases - like heartburn - ’serious’ as well.

Soon, the floodgates were open.

By 1992, the FDA had been given the discretion to accelerate approval and a law was passed so drug companies could pay a user fee - almost US$500,000 per drug - to start the process of getting a new drug approved. In return, the FDA would complete its review within six to 12 months. This was how the HIV drug, Ritonavir, received FDA approval within 10 weeks in 1996.

But is there really a problem with accelerated approval?

Sadly, it releases new drugs well before traditional FDA clinical testing requirements would have allowed. Traditionally, Phase I introduces a drug to a small group of volunteers for a short time, usually under a year, to assess a new drug’s safety.

If the drug is judged to be safe enough, it goes into Phase II, which lasts two years when hundreds of patients are tested in randomised double-blind studies for efficacy and dosage. If all goes well, Phase II is repeated with thousands of research subjects in Phase III, after which the drugmaker may file for FDA approval.

The agency’s reviewers had always prided themselves on their thorough review of scientific evidence, even though data from studies on one new drug frequently filled the equivalent of 1,000 phone books. Now, instead, they were put under extreme pressure to meet tight deadlines because, with fast track, drugs may be introduced in the market as early as Phase I, totally bypassing Phases II and III.

But six to 12 months are never enough to plough through all the details. Yet, by 1994, according to the FDA’s own testimony in a Congressional hearing in 1997, it was completing 95 per cent of new drug reviews on time. By 1996, it had achieved 100 per cent.

Yes, the lucrative user fees meant that more reviewers could be hired but these highly educated people could not do their job conscientiously. Those who had the temerity to oppose a new drug would be intimidated by their higher-ups.

Funding to monitor the safety of new drugs was unchanged, which meant that the monitoring could not keep pace with the number of new drugs that were coming on the market. The FDA tried to resolve this by requesting drugmakers to conduct post-marketing safety studies themselves but that research, while frequently promised, was rarely performed.

In cases where serious side effects did emerge post-marketing, the FDA resorted to the device of modifying package labels - often in tiny print and lengthy prose - thus shifting the responsibility for managing risks to busy physicians and uninformed patients.

Some experts appointed to the FDA’s 18 advisory committees that decide on the approval of new drugs were also allowed to consult or do research for the very drug companies whose products they evaluated. These included experts who served on the very committees that approved drugs that had to be recalled later, including Propulsid, Lotronex, Lorenza, Rezulin, Posicor - and Vioxx.

Clearly, accelerated approval provides incentives for drug companies under competitive pressures to (ab)use the process: develop new drugs rapidly and bring them to the market regardless.

When the fox guards the hen house

IT WAS under such circumstances that, from 1997 to 2000, seven drugs had to be recalled, almost none needed to save lives: one was for heartburn, another a diet pill, and so on. Never before had so many drugs been recalled in such a short time.

With many of these drugs, the FDA had used fine-print warnings on package labels to keep them on the market for as long as possible. In some cases, the FDA even withheld safety information from label changes so physicians were kept in the dark.

Since the FDA faced the unwelcome prospect of having to explain its original approval decision whenever a withdrawal was contemplated, it is unsurprising that in the 12 years, the FDA repeatedly delayed recalls long after there was irrefutable evidence of risks that outweighed any demonstrable benefits.

In addition to Lotronex, Rezulin and Propulsid, other prescription drugs withdrawn since 1997 have included diet pills Redux and Pondimin; a painkiller, Duract; allergy pills Seldane and Hismanal; blood-pressure pill Posicor; an antibiotic, Raxar; and now Vioxx.

Thus the FDA’s faster but laxer approach did put more new drugs on pharmacy shelves - and more money in the coffers of drugmakers - but also caused more injuries and fatalities.

So what to do when the fox is guarding the hen house?

For those who have lost faith, Vioxx may well have flung open the doors of the world’s leading drug companies to reveal studies they have long buried.

The Vioxx case has led to much criticism about how inept the agency has become. Trial lawyers have accused Merck of hiding information that showed Vioxx doubled patients’ risks of heart attack and strokes. Its 55,000 deaths could have been avoided had the FDA required a clinical trial specifically designed to tease out those risks, given that the drug’s chemistry suggested heightened heart risks.

Under the mounting threat of lawsuits, Merck - not FDA - withdrew Vioxx. Congress has now promised to investigate the agency - and Merck. Public hearings in Congress on issues related to Vioxx and FDA would begin early this year. But if the safety of prescription drugs is to be assured, a more thorough change to the way the agency works is necessary.

The parallels to Big Oil, Big Banking and Big Tobacco are frightening, especially Big Pharma’s practice of muzzling negative drug data, aided and abetted by physicians and scientists who run trials and publish selective data to make their drugs look good. It is scandalous that drug companies may both do the research or fund the trials and also own the results of such studies, which they may bury or use selectively to seek FDA approval.

Meanwhile, what’s the consumer to do?

The good news is that the embattled industry announced in the first week of January that it will publish more data about its drug trials. The International Federation of Pharmaceutical Manufacturers and Associations, as well as three other industry associations in the US, Europe and Japan, said they will post on the Internet, by mid-2005, databases of current and completed drug trials we can all access for free.

The bad news is that this is not mandatory - and some drugmakers have already voiced reservations, claiming they will share data only as appropriate when it doesn’t involve divulging competitive information.

In fact, there are already many such databases online. What would be helpful is a single location where they are harmonised together so doctors - and patients - can access them easily to see if a particular drug of interest reached the market after just Phase I testing.

But don’t hold your breath.