'This Is at Least a Signal'
WHO's Dr. Ralph Edwards
On Data Mining Over Drugs
July 2, 2007 11:13 p.m.
Dr. Ralph Edwards of the World Health Organization's collaborating center for international drug monitoring spoke with The Wall Street Journal's Avery Johnson about his decision to go public with a hypothesis linking a condition remarkably similar to amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease, to cholesterol drugs called statins.

The move was controversial because Dr. Edwards's group digs around in side-effect reports turned in at random by consumers and doctors -- not the same as scientifically rigorous clinical trials data. But Dr. Edwards stands by his choice, and thinks it offers a lesson to multinational drug companies and regulators. Below, some edited excerpts from a series of discussions. (See related article.)

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On data mining and his methods:

A signal is a set of data constituting a hypothesis that's relevant for the safe and rational use of a drug. It consists of a hypothesis together with data and arguments.

Data mining is just a tool that's used to screen a huge amount of data. It doesn't remove the need for very careful judgment. Just because you come up with a number doesn't mean anything. It's just the start of the process.

There is the potential to misuse numerical data. [In the decision to open up his data to more people and for publication,] there was a real concern that the information would be misinterpreted. If this gets into unscrupulous hands, it could create problems.

Data mining is still really under discussion as a tool. Everyone's saying now, "Forget spontaneous reports [from patients or doctors]. They're unreliable." But if you go to the health-care database with complete patient records, how do you find anything? You have to use data mining. The industry uses the argument that the data is bad and you can't take any notice of it. They say all those reports are poor quality because you don't have the age and the duplication problem.

I've been in debates where you have hundreds of adverse-event reports but they're imperfect. Can you disregard 100 adverse-reaction reports just because of the way the information is transmitted? Someone must have made a link in order to send it in.

On his decision to publish his "signal":

What we have here is 40 case reports. I can't see any other reason why they're reported to us. Other neurodegenerative diseases are not reported in excess. We thought, "This is at least a signal."

All of our reactions were, "If this is true, this is a very important finding. If this is a cause-and-effect relationship, it needs working out as fast as possible."

I'm very aware that anyone who looks at the signal is going to say it's a difficult one. The disease is rare and deadly. Anyone who has it is going to look around and say, "My God, why me? Why should I have this?" And one thing they're going to think is, "Is it the drug?" They or their family are going to report it, and that could be an explanation [for the increased reports]. But if I have Alzheimer's, that could also happen. Why ALS? Why not Parkinson's or MS [multiple sclerosis]? Somehow, this has triggered off a number of reports.

For God's sake, if I had a really high lipid level, the benefit of statins is high and the theoretical risk is trivial. That's the kind of decision to make individually. Maybe you're someone with ALS in the family. If your lipid level is on the border, there's no risk short-term to stopping the drug.

This one is probably the most difficult decision I've had to make. The rarity and yet the severity of the adverse reaction and the possibility that if it turned into a drug scare millions would be concerned about taking the drug, and the risk of stopping it is immense.

On the drug industry and regulators:

I tend to believe that our problems in drug safety are more caused by attempts at secrecy until we have more certainty. The industry's problem is that nobody trusts them, and it's because they don't come out and say things earlier.

The drug industry least of anybody wants a drug scare. So their level of proof is likely to be higher than mine. People have threatened our positions, and tried to stop publications. It can get quite nasty.

The FDA's approach is that they need more information before they go public. One issue regulators point out is if we make data more available, what happens if we [the WHO] draw different conclusions or act sooner than they do? Are we making them look silly?

Anytime this comes up we agonize that it's going to create a drug scare. But whilst we've been sitting on information lots of people could've been damaged by the drug if the signal is correct. At what point should anyone go to the public and say there might be something wrong with this drug?

The bottom line is, what is it that health professionals and the public need to know? I think a lot of our thinking depends very much on what we think the public wants to know and needs to know. We take very little effort to have the public really be on board with this, to really educate them. We don't communicate, and that's upside-down. If we can't explain the problem, we have a problem ourselves.

We give the benefit of the doubt to the drug. Why shouldn't we give the benefit of the doubt to patients? Given the clear sense of concern on the Web, the FDA could've said, "If this is a real risk, it must be very rare." They should say what they're doing. After a plane crash, [the government] says what it's going to do.

On his role and the role of his WHO center:

Our function is to act as a failsafe on drug safety issues.

The dilemma for us in our position is somewhat different than the dilemma drug regulators have, in that a lot of their work is with the pharmaceutical industry. In most countries, any release of information on drug safety follows a negotiation between regulatory agencies and industry.

We have a slightly different philosophy. In this case, ALS is a very rare condition. I think if we can get this out there and say, "Be on the lookout and in individual cases stop the statin for a while" -- we may get more information that way than from setting up a study. It's a matter of very considerable debate and is an issue that I and many people find very troublesome indeed.

I'm a crusader for finding the best way to communicate information. I work very hard for those ideals. We are that little voice, we're not bound by the ties that bind them [regulators].

People should listen to what we have to say, look at the evidence we produce and question it. We're health professionals with a lot of experience in the field. Our knowledge of the data is immense.

On two prestigious journals' decisions not to print his paper:

[I found it] really irritating. The drug-safety sections of both [papers] are very limited -- the maximum is 800 words. I tried to compress 40 cases into 800 words and it didn't work. In both cases, they said this is a matter for a specialist journal.

I was surprised they didn't publish it. The journals have said they haven't changed. But they've had a lot of criticism for publishing the vaccines and autism signal. I suspect that the level of evidence of spontaneous reports is not good enough anymore. They used to like spontaneous reports.

On why he thinks clinical trials might not turn up an ALS signal:

ALS is rare. I think it just wouldn't show up, or wouldn't necessarily show up in clinical trials. [If they did see it,] they'd have no more than a half dozen patients with ALS by chance.

If they saw any patients at all, it could be due to chance. If the drug caused a 20% increase that would only be a couple more patients -- 14 in the drug arm and 12 in the control arm. Would you find that very convincing? No.

I'd imagine that data coming from various studies would also make it difficult. Meta-analyses compare apples to pears.

How were the adverse reactions recorded? You don't know how the patients are selected, whether their age is representative. [The trials are] relatively short term. Because ALS is a progressive disease, its onset might be rather slow.

On whether the signal he's identified will bear out:

I want more information to decide for myself.
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