Drug safety relies on people like David tackling the Goliaths of big pharma

10th June 2013

By Edwin Gale, University of Bristol

In 2001 I met David Graham, an official from the US Food and Drug Administration, in a car park in Washington. I wanted him to shed light on why the diabetes drug troglitazone, or Rezulin, had been available in the US and Japan two years after it was withdrawn from the rest of the world. He told me he’d be “driving a dark blue SUV and wearing a fawn jacket”. Not the conventional way to discuss drug safety with an FDA official.

Graham was already too outspoken for the FDA and is one of a handful of people to have taken on big pharma and challenged them on the transparency of their research.

Another, Dr Peter Butler, is taking on big pharma over another class of drugs, used to treat diabetes.

These agents, known as the incretins, work by imitating or enhancing the action of a natural hormone called GLP-1, and are used by millions of people with Type 2 diabetes to control their blood sugar level. They are worth over £6 billion in annual sales.

The issue is the subject of Diets, Drugs and Diabetes, a joint BMJ and Channel 4 Dispatches. Some of these drugs also suppress appetite and so could be used even more widely as a treatment for obesity. But the investigation reveals unpublished data that points to serious safety concerns.

Butler, chairman of endocrinology at UCLA, is convinced the whole class may pose dangers. He started his crusade in 2008 after he conducted a Merck-sponsored study with their drug Januvia, and found that the drug was causing damage to the pancreases of rats. Later studies in animals and humans raise the possibility that this group of drugs might even lead to a higher risk of pancreatic cancer.

Butler’s assertions have been challenged by Merck and the American Diabetes Association’s chief scientific and medical officer, who has called the data “inconclusive”.

Januvia is by far the biggest drug in its class, but others such as Byetta are also in the spotlight. In the US, hundreds of people are suing manufacturers alleging these drugs caused pancreatitis and 43 suits against Januvia allege it caused cancer.

The power of vested interests

But drug safety is dangerous territory for clinicians who dare to challenge vested interests. A new drug can already represent some £500m in investment when it reaches the market. By that time its safety will only have been tested in a few thousand people, and its long-term effects will generally be entirely unknown. However, the makers are obliged to market aggressively because the countdown to expiry of their licence for the new drug has already begun.

The result? Millions of people are now exposed to agents whose safety has not been fully established. No wonder that severe adverse effects are found in 20% of drugs following launch (30% in drugs receiving fast-track approval), often many years after they were first approved.

This being so, you might imagine that those who investigate drug safety would receive every encouragement to do so. But history shows otherwise.

You don’t have to sign up to a clinical trial to be a guinea pig. Flickr/Mad_m4tty

The story of Rezulin

In 1997, when Rezulin pills hit the market, they were billed as a way to reduce blood glucose levels. But questions had already been raised about their safety. John Gueriguian, the first FDA official to work with the drug before its launch, was taken off the case.

Side effects of Rezulin included weight gain and fluid retention, sometimes resulting in heart failure. In some people – for no clear reason – it also produced acute liver failure and death. By October 1997, when it was launched in the UK, it had already caused 135 cases of serious liver toxicity and six deaths. Sir Richard Sykes, then chief of GlaxoWellcome (now GSK) in the UK, saw the data and withdrew the drug only six weeks after launch.

Most of the world followed suit. But not the US, where it remained on sale until March 2000 while the death toll steadily mounted. Graham, who wrote the summary report for the FDA, estimated that at least one in 1000 users had developed severe liver damage and hundreds had died.

Amazingly enough, neither the FDA nor the company did anything about it apart from issuing further warnings. It came off the market because of the courage and persistence of isolated individuals. These included the actions of Pulitzer-winning journalist David Willman and “termites”, FDA staffers who sent internal FDA emails concerning the safety of Rezulin to members of Congress. One of these, Robert Misbin, was warned of disciplinary action and later resigned.

Deja vu

Avandia, one of the drugs that took over from Rezulin, didn’t cause liver injury, but it did cause a worrying increase in bad LDL cholesterol. It also greatly increased the risk of a heart attack.

At its height Avandia was the top-selling diabetes pill and worth more than £2 billion in sales.

Concerns initially raised by Dr John Buse of the University of North Carolina had him labelled as a “renegade”, though a US Senate hearing later concluded that his allegations concerning GSK’s attempt to silence him through his superiors and a threat to sue were true.

It seems likely that the company were aware of the heart risk by 2003 and did tell the FDA, who took no action. When GSK were, quite coincidentally, obliged by another misdemeanour to publish all their clinical trial results online, it was the cardiologist Steve Nissen who spotted the heart risk in the data.

Nissen published an independent report in 2007, and three years later Avandia was eventually withdrawn by the European Medicines Agency (EMA), while the FDA opted to place severe restrictions on its use.

Extrapolation of the FDA data suggests that the drug caused more than 83,000 extra heart attacks between 1999 and 2004.

Wrestling Goliath

As these stories testify, action on drug safety has too often been delayed by institutional inertia, even when thousands of lives have been placed at risk. With both drugs, removal from the market was due to the actions of individuals, sometimes at the cost of their career.

You might imagine that clinicians who conduct their own investigations into drug safety would be encouraged to do so. Far from it. Their behaviour challenges commercial interests worth billions, backed by powerful political lobbies.

It also seems to offend the regulators, whose actions sometimes suggest that defence of their own turf takes precedence over patient safety. Whistleblowers also often encounter surprising hostility from doctors who are prescribing the drugs.

Butler’s current case shows scientists are still locked in battles with big pharma. “I knew some stuff that I thought was a worry and I was obliged to pursue it,” Butler recently told the New York Times. Based on his concerns, the FDA and the EMA have begun investigations.

And what about Graham? He became too big to sack, and is now director of the FDA’s Office of Drug Safety. In 2004 he testified before a Senate committee that the FDA was incapable of protecting US citizens against other similar scandals after another Merck drug, the painkiller Vioxx, was withdrawn.

Do the benefits of drugs outweigh the negatives? Mostly they do. But we should surely not be kept in the dark about potential risks when we agree to take them.

Drug safety still relies on lone individuals, ranging from chief executives of pharmaceutical companies to FDA officials, journalists and doctors prepared to wrestle with Goliath – and will continue to do so until a better system comes along. The first step towards this is open access to all clinical trial documents.

Edwin Gale has provided expert testimony with regard to exenatide (an incretin) and received a fee for so doing.

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