Tuesday, July 03, 2007

A Risk in Cholesterol Drugs Is Detected, but Is It Real?


Data Crunching Hints At Tie to Lou Gehrig's; FDA Isn't Concerned
July 3, 2007

As he examined data on a computer one day last fall, drug-safety reviewer Ralph Edwards saw something that concerned him: Of 172 people in his database who developed Lou Gehrig's disease or something similar while taking prescription medicines, 40 had been on statins, the huge-selling cholesterol drugs.

Dr. Edwards, director of the World Health Organization's drug-monitoring center, has amassed about four million reports of medical problems experienced by people taking prescription drugs. His job is to sift through these so-called adverse events, looking for "signals" of potential side effects.

The number of Lou Gehrig's cases associated with statins struck Dr. Edwards as high. He would have expected a number in the single digits, judging from how often other drugs in the database were linked to the disease. Still, the analysis didn't prove anything. Dr. Edwards hesitated to publicize his finding, wary of creating a drug scare and mindful that statins have been shown to reduce heart attacks significantly.


Read excerpts from Dr. Edwards's conversations with The Wall Street Journal.
It's an increasingly common dilemma nowadays. Sophisticated software allows health authorities to troll through huge databases looking for possible drug dangers. The data mining can detect rare side effects that didn't show up in clinical trials. But it can also raise false alarms and force regulators to divert time and money from more pressing dangers.

"People reach different judgments on when to shout and when not to shout," says Robert Temple, medical director at the Food and Drug Administration division that evaluates drugs. "It's the hardest single thing -- the value and danger to screaming early."

The issue is likely to grow as regulators expand access to their databases. The FDA and other national drug regulators used to keep a tight lid on the adverse-event reports they collected, but now the WHO can freely disseminate them. Also, since 2004, the FDA has posted its quarterly data files on the Internet, and anyone can download them free of charge. Some companies have started offering software to crunch the data for side-effect patterns.

Adverse-event reports are a major way to identify side effects after a drug is on the market, but the data can be flawed or misleading. The reports can be turned in by anyone -- patients, doctors, even plaintiffs' lawyers. Media coverage or Internet postings claiming dangers in a particular drug may lead doctors and consumers to report more problems with that drug. Meanwhile, many problems never get reported.

Determining causation is another issue. If people taking a drug are older or more overweight than usual, an adverse-events database may show more links to heart attacks. That wouldn't necessarily point to any problem with the drug -- it would just reflect the less-healthy state of the people taking it.

Clinical trials in which patients randomly receive either a drug or a placebo are usually the best way to identify side effects, because any significant difference between the two groups is likely to be a result of the drug. However, trials are often too small or too short to identify unusual side effects, and they don't necessarily reflect how patients take a drug in the real world.

Drug Monitoring

The WHO, a United Nations body, set up its collaborating center for drug monitoring in 1968 after the thalidomide scandal, in which pregnant women who took the medicine for morning sickness gave birth to children with stunted limbs and other malformities. Now based in the Swedish university town of Uppsala, the center pools adverse events from 83 countries, including the U.S.

Dr. Edwards, a 64-year-old Briton with a background in internal medicine and clinical pharmacology, took the center's helm in 1990. His first experience with puzzling side effects came during a stint at the University of Zimbabwe almost 30 years ago. There, he noticed some patients with a rare skin condition, and tracked down some antibiotics they were taking as the cause.

In the mid-1990s, Dr. Edwards's team developed a software program to mine data with the help of artificial-intelligence Ph.D.'s from a local university. The software made it easier to analyze adverse events for one drug in the context of all event reports and fish out signals of problems.

At first, Dr. Edwards needed permission to publish from the national drug regulators on whose data he relied. Then, at a conference in Hong Kong in 2002, national drug agencies including the FDA loosened their grip, allowing the WHO to publish without permission. Dr. Edwards also received the right to share his data with anyone who requested it, he says.

He gets about 200,000 new adverse-event reports and pinpoints about 60 serious signals a year. Usually he notifies national health authorities and goes no further. Only rarely does he publish his concern. One such case involved babies getting withdrawal symptoms when their mothers took certain antidepressants. That report appeared in 2005 in the Lancet.

Last fall, Dr. Edwards decided to see what his database could tell him about statins and Lou Gehrig's disease, known medically as amyotrophic lateral sclerosis or ALS. The progressive neurodegenerative disease is almost always fatal. He had heard from an American doctor about an ALS-like case that was seemingly related to statins. Dr. Edwards himself had a friend who developed another serious nerve disease, called peripheral neuropathy, after taking a statin.

With a few clicks, Dr. Edwards came upon the 40 cases of ALS in people taking statins, and his software told him the number was much higher than expected.


• The Issue: An analysis by a drug-monitoring group suggests a link between cholesterol-lowering statins and Lou Gehrig's disease, but U.S. regulators say they don't believe there's a risk.
• The Background: Scientists are increasingly using data-mining software to sift through reports of adverse events involving drugs.
• What's Next: More studies to figure out what's happening.
Reviewing scientific literature, Dr. Edwards came up with a theory about the cases. All statins carry a warning on their label about a rare disorder that causes muscle pain or weakness, a long-known side effect of the drugs. More recently, studies have linked statins to peripheral neuropathy. Dr. Edwards speculated these diseases and ALS might be connected, since they involve some kind of neuromuscular degeneration, and he thought all might be triggered by statins in unusual instances.

Yet Dr. Edwards also learned that pharmaceutical companies and other researchers are studying statins as potential treatments for brain or nervous-system diseases such as Alzheimer's, multiple sclerosis and even ALS. Some believe the anti-inflammatory effects of statins may be useful in these diseases.

As Dr. Edwards reflected on whether to publish his findings, one point weighed heavily. ALS is rare -- it strikes about five in 100,000 people and affects some 350,000 people world-wide. By contrast, heart attacks are a leading cause of death, and statins have helped millions of people reduce their heart risk. Dr. Edwards didn't want to raise unwarranted fears about drugs whose value is well-documented.

"We were on the horns of a dilemma and it wasn't easy to resolve," Dr. Edwards says.

Behind the scenes at the FDA, officials were facing a similar dilemma. Ana Szarfman, an agency official who pioneered statistical analyses of adverse events, had noticed the ALS-statin signal in March 2006, about six months before it caught Dr. Edwards's attention. She was using the FDA's database, which overlaps with the WHO's but isn't identical. The FDA says that through the end of last year, about one-third of the ALS adverse-event reports in its database -- 99 of 298 -- involved people on statins.

Dr. Szarfman was known at the FDA for her sleuthing into unexpected side effects, such as the odd link between a Parkinson's-disease medicine, Mirapex, and isolated cases of compulsive gambling. She also helped confirm in 2001 that Baycol, a Bayer AG statin later withdrawn from the market, was linked to an especially high number of muscle-disease cases.

Dr. Szarfman took the ALS signal seriously and considered publishing an article about it. But she held off while the FDA took a closer look. The agency didn't want to jump to any conclusions about a life-saving class of drugs, officials say. Unlike the WHO, the FDA has the ability to press drug companies for more information. That's what it did in this case, asking Pfizer and other statin makers for all their clinical-trial data.

Statin Trials

Taken together, the long-term statin trials involved 120,000 patients. The number of ALS cases came to 20, spread equally between statin takers and those on placebo.

"The result of the analysis was very reassuring," says Dr. Temple, who takes a statin himself. "I personally was relieved because I like my statins."

Dr. Temple says a close look at the FDA's adverse-event data suggested some reports might be unreliable. Slightly more than half of the adverse-event reports in the FDA's database about statins and ALS were submitted by consumers, which is unusual because doctors usually account for the lion's share. Also, some of the ALS cases were reported soon after the patients had started taking statins, raising doubts about whether the drug could have been the cause. Officials noted that the incidence of ALS in the general population hasn't risen since statins became popular.

The FDA plans to publish an academic paper about its statistical findings soon, says an agency official. But based on the analysis of clinical trials, it decided it didn't need to issue any caution about statins.

Dr. Edwards came to a different conclusion. He talked the issue over with his staff and P. Murali Doraiswamy, an expert in neurodegenerative diseases at Duke University who has done research on statins and the brain. Dr. Doraiswamy agreed that the ALS signal was worrisome and should be investigated.

After months of hesitation, Dr. Edwards came across a study by Greek researchers that helped make up his mind. Typically, ALS leads to death within three to five years, usually because the lungs fail when the neurons that send instructions to the respiratory system stop working. But in some rare cases, ALS-like symptoms could be halted or even reversed, the study said. Dr. Edwards decided his finding might help some patients prevent their disease from deteriorating. He wrote a paper and submitted it to two prestigious journals.

Both journals, the British Medical Journal and the Lancet, rejected it, he says. Fiona Godlee, the BMJ's editor, says she can't comment on specific papers, but she calls adverse events hard to interpret. "You only have a record of the people who developed problems, without knowing how many people took the drug and didn't develop problems," she says. The Lancet declined to comment.

Dr. Edwards pitched his paper to Drug Safety, a little-known journal based in New Zealand, which rushed it into print last month.

The paper acknowledges that some Internet sites have been discussing an ALS-statin link for at least a year, raising the possibility of skewed reporting of adverse events. But it notes that the number of events was also high earlier in the decade, before the majority of the Internet postings. The paper calls on patients using statins to talk to their doctor about stopping if they experience severe neuromuscular symptoms.

Pfizer, which brings in nearly $13 billion a year from Lipitor, says it too noticed the ALS signal last year in adverse-event reports, but concluded there was nothing to it after examining all its data. The company says Dr. Edwards has the right to publish what he found, but signals derived from adverse events can unnecessarily alarm the public and create needless headaches for drug companies.

Manfred Hauben, a Pfizer medical director, has long specialized in analyzing adverse events, and several years ago started using sophisticated software adopted by Pfizer. A math junkie who jokes that he suffers from an impulse-control disorder and stays awake at night studying statistics, Dr. Hauben says his enthusiasm for data mining has cooled.

He says with so many drugs and diseases, mere coincidence will create some worrisome-looking links. "Especially when you're looking for rare events, most positive results are going to be false positives," he says. Also, data mining presents "a lot of opportunities to retrofit an analysis to pre-existing expectations," he says. "Two different vendors' software can give two different results."

Prompting Research

Dr. Edwards says his paper is merely intended to prompt more research into the matter -- not cause millions of heart patients on statins to panic and stop the drugs.

But he hopes it will be useful to some patients. "Suppose you started to get symptoms and your doctor said, 'Now you have two years to live,' " he says. "Wouldn't you want to know that there's some possibility that the disease is linked to the drug so you could stop taking the drug?"

Dr. Edwards isn't persuaded by the clinical-trial data collected by the FDA. The signal wouldn't necessarily show up there, he says, because ALS is so rare.

Sheila O'Donovan, a 62-year-old retired journalist who lives in Delray Beach, Fla., wishes the signal had been publicized sooner. Ms. O'Donovan was on Lipitor when she started losing control of her right thumb in 2005. Soon, she was limping and slurring her words. After going off the drug in April of last year, she suddenly felt "brighter," her muscle cramps stopped and she was able to swallow more easily, she wrote in an email. But the improvement was short-lived. Her neurologist diagnosed her with ALS last September and she's gone downhill since. Her voice is now almost gone and she needs a wheelchair to get around.

More evidence could be available in a year or two. Beatrice Golomb, an associate professor of medicine at the University of California, San Diego, is analyzing case reports of people who developed ALS-like symptoms after taking statins. And researchers at Stanford University are looking at patient records in Northern California kept by Kaiser Permanente, a big health-maintenance organization, to see whether people who developed ALS were more likely than control subjects to have used statins.

Write to Avery Johnson at avery.johnson@wsj.com