For Emma Brooks, Ex-Lax is a trusted old friend. "I've been buying it for my husband and me for a long time," says the 67-year-old Washington, D.C., resident, sounding a bit like an actress in a commercial. So she was dismayed to learn that the laxative, first sold in 1906, was yanked from the shelves last month because it poses a cancer risk. "After all these years, they think there's a problem?" she asks. "How did they come up with that?"
As it turns out, the bolt out of the blue for Mrs. Brooks and millions of other consumers actually was the culmination of a protracted scientific odyssey, carried out in government offices and laboratories by researchers who toil far beyond the view of most Americans.
Scientists first raised safety questions about phenolphthalein, the main ingredient in Ex-Lax and several other laxatives, two decades ago. Since then, bureaucrats, scientists and laxative makers have debated everything from gene-deficient mice to television attack ads.
Voluntary Recall
But the Ex-Lax debate didn't hit home for most consumers until it was essentially over. On Aug. 29, the Food and Drug Administration proposed banning phenolphthalein, warning that "animal studies indicate a potential cancer risk to people," especially if used excessively. Ex-Lax's manufacturer, a unit of Swiss-based Novartis AG, immediately announced a voluntary recall and plans to reformulate the product with a different ingredient.
A close look at the Ex-Lax episode sheds light on how the government comes to decree what is good and bad for Americans and how a popular product nearly a century old came to be linked to cancer. It also reveals how scientists working at a little-known federal facility can knock off one of the most established names in the over-the-counter drug business.
One thing is clear: Americans place great emphasis -- too much, many doctors say -- on regularity. Consumers in the U.S. spend at least $600 million a year on laxatives. More than half of that is for stimulant, or quick-acting, laxatives -- a category Ex-Lax led last year with sales of $41 million. Correctol, made by Schering-Plough Corp., was a close second.
Grandfathered In
Ex-Lax has been a mainstay in the industry, famous particularly for its chocolate-covered version found in many medicine chests and a number of fraternity-house pranks. But the origins of its active ingredient, phenolphthalein, are unclear. One theory is that its laxative qualities were discovered accidentally in 1902 by Hungarians considering using it as an additive for wines.
Ex-Lax Inc. began selling its product in 1906, the same year the FDA's predecessor agency, the Bureau of Chemistry, was created. The regimen for evaluating drugs was far different than it is today; medications simply had to meet certain standards for strength and purity. The FDA wasn't created -- and didn't set stringent testing requirements -- until much later. Even when it did, many old, widely used drugs such as Ex-Lax were effectively grandfathered in without testing.
That began to change in the 1970s. The FDA launched an exhaustive review of over-the-counter drugs that is still going on. At the time the review began, there were hundreds of thousands of such drugs, but the products involved only about 700 active ingredients. Some were eventually restricted, including hexachlorophene, once common in deodorant soaps but now available only by prescription because it may damage the central nervous system; and zirconium, still safe in most antiperspirants but removed from aerosols because it could cause lung nodules.
Safe and Effective
As part of the review, a panel examining laxatives concluded that phenolphthalein was safe and effective for occasional, short-term use for constipation, a conclusion the agency tentatively endorsed in 1985 but never officially ratified.
Around the same time, another agency began moving on a different track. During the 1960s and 1970s, the National Institutes of Health's National Cancer Institute prepared a large-scale animal-testing project, called the National Toxicology Program, to scrutinize an array of substances for cancer-causing potential. The idea was for scientists at various agencies to "nominate" compounds that were in widespread use but that never had undergone adequate cancer screening. The cancer institute nominated phenolphthalein in 1978, but it got a low priority for testing.
There matters stood for years. It wasn't until the early 1990s that the toxicology program, by then located at NIH's National Institute of Environmental Health Sciences in Research Triangle Park, N.C., got around to testing it. Several scientists worked on the compound, but the research of two veterans, June Dunnick and John French, would prove decisive.
Subdued by nature, Dr. Dunnick and Dr. French relish the low-key atmosphere of the institute, located on a verdant campus near Raleigh. Dr. Dunnick transferred to the institute 17 years ago after working on antiviral treatments at NIH's main campus in Bethesda, Md. At first, she recalls, "I thought you had to wear a plaid shirt" because the relaxed dress code there was such a stark contrast to Bethesda's shirt-and-tie crowd.
Scientists at the institute have scrutinized the safety of everything from fluoride to sugar substitutes to industrial compounds. Under director Kenneth Olden, they also have worked to make their research more understandable -- and credible -- to other agencies and to consumers. "The public is skeptical if we publish one week that something causes cancer and two years later that it doesn't," Dr. Olden says. A case in point: Saccharin, which has been listed by the National Toxicology Program as an "anticipated" human carcinogen since 1981, may be taken off the list because of questions about whether data showing increased bladder cancer in rats can be extrapolated to people.
For the phenolphthalein study, Dr. Dunnick ordered the standard two-year test regimen, which calls for giving rats and mice copious amounts of the compound, then killing them and examining them for tumors. (One scientist not affiliated with the institute calls the method "stuff and snuff.")
The data from the study were compelling. Phenolphthalein caused "carcinogenic activity" in rodents' ovaries, thymus glands, kidneys and adrenal glands. "We were as surprised as anybody else that it came through with this kind of cancer signal," says John Bucher, Dr. Dunnick's boss and deputy director of the toxicology program.
But as is often the case with animal studies, a crucial question loomed: Was the information relevant to human beings? "Here was something that had been on the market for ages, and there had been no indication of a problem in humans," Dr. Bucher says. "We had to ask ourselves: Are we making a fundamental mistake?" The scientists concluded that they weren't, and that they had identified a previously unknown potential cancer risk for humans. The toxicology program, which has no regulatory authority, notified the FDA and released a draft report in December 1995.
Ex-Lax wasn't the only brand-name laxative that contained phenolphthalein. Schering-Plough's Correctol, which at the time was outpacing Ex-Lax as the best-selling stimulant laxative, also contained the compound, as did the Bayer Corp.'s Phillips" Gelcaps.
The FDA's panel of cancer experts, which includes agency pharmacologists, toxicologists and statisticians, swung into action. It asked the North Carolina scientists to do studies using lower doses and enlisted the help of Sandoz, Ex-Lax's manufacturer at the time, in researching how the compound is metabolized and affects genes.
At the same time, some Sandoz top managers huddled to review the data. They decided then, as they would at key points over the next year and a half, that a change wasn't necessary. They suspected that the North Carolina scientists had used excessive doses that simply couldn't be translated to human use. "We knew the compound better than anybody else, and it had an excellent safety profile," says spokesman Eric Jackson.
But if Ex-Lax wasn't headed for changes, its maker was. Sandoz and Ciba Geigy were making plans to merge and become Novartis, a drug giant based in Basel, Switzerland. Throughout the changes, officials kept a close eye on the Ex-Lax situation but still "decided there wasn't a problem," Mr. Jackson says.
Schering-Plough was handling the issue in a very different way. While it initially defended phenolphthalein to the FDA, it abruptly switched gears in December 1995 and decided to replace the compound with a chemical cousin called bisacodyl. "Correctol has been specifically marketed to women as a product they can trust," says Steven LaMonte, senior vice president of marketing for Schering-Plough. "So when there was a question, we decided to take the high ground." The reformulated product began appearing in January 1996.
For its part, the FDA was choosing its course carefully. The agency's cancer experts met in April 1996, and they were asked to keep in mind a special group: people who overuse stimulant laxatives. While the medications are designed for short-term use, they are often abused, especially by bulemics and anorexics trying to lose weight. And the products" over-the-counter status means it is difficult to control their use. Dr. Dunnick then outlined the toxicology-program findings. Sandoz scientists countered that the rodent tumors resulted from extremely high doses that resulted in blood levels at least 30 times higher than what humans would get from the maximum recommended dose.
In a crucial victory for Sandoz, the carcinogenicity committee found that Dr. Dunnick's data, while establishing that the compound caused cancer in rodents, didn't provide evidence to conclude it was a cancer risk for humans. The panel recommended more tests. A month later, Ex-Lax overtook Correctol as the best-selling stimulant laxative in the country.
Special Mice
But more bad news for Ex-Lax already was brewing. Dr. Dunnick had taken the next big step: enlisting Dr. French's help in using genetically altered mice for another round of phenolphthalein tests. They decided to test the compound on mice lacking one copy of the tumor-suppressor gene, p53. Mice (and people) normally have two copies of the gene, which helps protect DNA-damaged cells from becoming cancerous. Mice with only one copy of the gene respond to carcinogens much more quickly than mice with two copies, says Dr. French, who has worked with p53-deficient mice for four years. And the scientists used doses much closer to those taken in daily use, particularly by people who use laxatives excessively.
The new studies took six months, and the results were striking: The rodents had tumors, along with significant genetic damage consistent with the development of cancer, Dr. French says. The information turned the FDA committee around. In April 1997, it determined in a 15-to-1 vote that "human cancers are known to be associated with alterations in the p53 gene. Thus there appears to be a potential risk for humans" from phenolphthalein. The committee also recommended additional testing of other stimulant laxatives, including bisacodyl (the new active ingredient in Correctol), and plant derivatives aloe and senna.
Novartis scrambled to reassure the public and appease the FDA. In letters to the agency, company officials repeated, correctly, that there had never been any human studies that question the safety of phenolphthalein, nor any reports of such adverse effects in humans. Novartis also disputed the FDA's reliance on the p53-deficient mouse and proposed a long-term human study to determine whether Ex-Lax's main component actually causes cancer in people. And the company recommended a public-education campaign to curb laxative abuse.
Battle of the Ads
The spring also brought a slugfest between Novartis and Schering-Plough. Novartis ran television ads showing two sisters discussing the fact that Correctol officials had "changed their medicine" and suggesting that it didn't work as well. Schering-Plough ran newspaper ads pointing out that "a government panel has determined that some laxatives may cause cancer," and suggesting that Ex-Lax might need to be recalled. It also provided a toll-free number for confused consumers. Bayer, meanwhile, pulled Phillips" Gelcaps off the market and suggested consumers use its Milk of Magnesia instead.
On Aug. 29, the FDA proposed banning phenolphthalein and said it would accept public comment for 30 days; final action will occur within weeks. Novartis, meanwhile, has announced plans to use senna as the new active ingredient for Ex-Lax, and plans to roll out a massive advertising campaign to promote it. (The firm already has one product, called Ex-Lax Gentle Nature, that uses senna.) And while Schering-Plough has run ads reminding consumers that Ex-Lax is being withdrawn from the market, Novartis is putting out the message, "We want to keep your trust."
But what about the continuing FDA review of the replacement ingredients, senna and bisacodyl -- a review that could take years to conclude? Officials at Novartis and Schering-Plough say they are confident the ingredients are safe, and that they have the studies to prove it.
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