http://www.washingtonpost.com/wp-dyn/articles/A62671-2004Sep4.html

Herbal Remedies Turn Deadly for Patients

Suits Fail to Bring Tougher Rules

By Justin Gillis

Washington Post Staff Writer
Sunday, September 5, 2004; Page A01

When a medical checkup indicated trouble with his prostate gland, John Meyer decided to try a natural remedy. Ignoring his wife's skepticism, the southern Arizona man went out and bought an herbal supplement promoting "prostate health."

Murray Berk, a Long Island garment buyer, did the same thing when he was diagnosed with prostate cancer. "I thought it was great there was a natural product available," said his daughter, Shelley Martin.

The two men wound up taking the same herbal remedy, a substance called PC-SPES. Today both men are dead.

Their relatives blame the herbal supplement and the California company that made it. Batches of PC-SPES, it turned out, had been improperly mixed with pharmaceuticals, including an anti-inflammatory drug, an artificial estrogen considered so dangerous it was pulled from the market years ago, and a blood thinner that in high doses is used as rat poison.

The company, operating under the name BotanicLab, sold at least eight other herbal supplements that eventually proved to contain undisclosed prescription drugs. Those products are now off the market, and BotanicLab has closed. The company pleaded no contest to a felony charge for selling contaminated goods and three owners pleaded no contest to misdemeanor charges. Company executives declined to discuss the adulteration.

While BotanicLab may be history, the regulatory system that allowed the company to go into business with little oversight has not changed much. The government subjects herbal remedies to far less scrutiny than pharmaceuticals, a hands-off policy that has allowed the $20 billion supplement industry to flourish, growing to 1,000 manufacturers shipping 29,000 products.

Polls show most Americans think the products are safe and assume the government is testing them to be sure. In fact, strapped regulators at the Food and Drug Administration said they have typically conducted only 100 or so inspections a year, though they hope to step that up.

Congress mandated a light regulatory touch in the mid-1990s, after industry lobbyists stoked public concerns that the government was going to put new restrictions on common vitamins and natural remedies used for generations. Lawmakers have since begun to reassess that approach after the Food and Drug Administration last year moved to ban the use of the herbal stimulant ephedra and the bodybuilding supplement androstenedione in response to rising health concerns.

The BotanicLab disaster offers a detailed case study in how dangerous herbal remedies can be hyped on the Internet, embraced by desperate patients and legitimized by research institutions in ways that put lives at risk.

Many of the most exaggerated health claims about PC-SPES were made not on the bottle's label, where they would be subject to federal regulations, but on the Internet, where free-speech laws give people wide latitude to discuss the virtues and drawbacks of any issue. The glowing commentary apparently hit home with people reluctant to rely on traditional treatments, or for whom those had failed.

PC-SPES also gained popularity after some of the nation's premier cancer centers backed BotanicLab's flagship product and recommended it to patients. Top medical journals published studies touting the potential benefits of the remedy, studies they have yet to retract.

The adulteration was ultimately rooted out not by the major cancer centers endorsing PC-SPES, but by suspicious patients scraping up money to run their own tests.

Research on PC-SPES received critical financing from several outside sources, including $2.1 million in U.S. government money. Early funding also came from a prostate-cancer foundation created by Michael Milken, the convicted junk-bond financier who has become an influential voice in cancer politics in Washington.

Though BotanicLab shut down two years ago, new details about the disaster continue to emerge as a string of lawsuits in California and New York unfold against the company, its distributors and other parties.

Thirty-five people or their estates have come forward to claim harm, including men whose breasts grew so large they had to have them surgically removed, and others who inexplicably bled to death. Lawyers for the injured claim there may be hundreds of other victims in North America and Europe.

Whether any injuries can be linked to intentional adulteration remains to be seen. BotanicLab has at various times asserted that the adulteration of its products occurred among the Chinese suppliers of the raw ingredients and it should not be held responsible. Attorneys for the company and several defendants have also said in court that the purported victims are exaggerating their injuries.

This account of the BotanicLab saga is based on a review of more than 11,000 pages of documents that have surfaced during the legal action, and on interviews in Washington, New York and California. Newsday and several major newspapers reported some aspects of the story as it evolved, and significant details were first reported in the Cancer Letter, a Washington publication. Its editor, Paul Goldberg, and publisher, Kirsten Boyd Goldberg, made some of their files available.

David Markham, a San Diego attorney representing some victims in the case, estimated that BotanicLab may have taken in as much as $50 million before it was shut down.

"The big question," Markham said, "is why did it take five years for law enforcement in the United States to figure this out?"

Early Promise

The scientific brain behind BotanicLab was Sophie Chen, an immigrant from Taiwan who went to college in the United States and then pursued a conventional career in chemistry, working at several large drug companies. In the early 1990s, she struck out on her own, telling people she wanted to try to marry Western medicine with Chinese herbal remedies.

Her scientific collaborator was Xuhui "Allan" Wang, an herbalist who liked to tell people he was a descendant of the doctor who served the last emperor of China. As Chen told the tale, the pair drew on the ancient wisdom of Chinese herbologists to combine Asian and a few American herbs into proprietary mixtures to treat conditions like prostate cancer, arthritis and others. They won U.S. patents on at least two blends.

The remedies became the core products of International Medical Research Inc., which did business under the name BotanicLab. Chen and associates in California, including her brother John Chen, set up the company in the Los Angeles suburb of Brea. Their timing was good: American interest in alternative medicine was rising in the 1990s.

What's more, the products could be put on the market relatively quickly. The herbal supplements did not have to undergo tests in humans because the company was not promoting them on the label as treatments for specific diseases.

Instead, the labels on various remedies touted support for "healthy joints" or offered "immune system enhancing properties." The Chens hit upon their biggest success with a supplement they called PC-SPES, labeled for "healthy prostate function."

Spes is the Latin word for hope, and the buzz on the Internet was that "PC" stood for prostate cancer. The product was billed as a combination of six Chinese herbs, one Chinese mushroom and an American herb.

PC-SPES showed early promise. Men with slow-growing prostate cancer pay close attention to the levels of a protein in their blood that may indicate whether their disease is spreading. Those who took the remedy reported that levels dropped sharply. True, it was quite expensive for an herbal remedy, as much as $500 a month, but many patients saw PC-SPES as worth it.

Chen told people she wanted to seek FDA approval to label the supplement as a prostate-cancer treatment, making it the nation's first formally sanctioned herbal remedy. That meant tests would be required, even though the product was already being sold in stores. Milken's prostate-cancer foundation provided Chen with two grants.

Other doctors launched small-scale studies. Then in 1998, the New England Journal of Medicine published a study led by Robert DiPaola, a researcher at the Cancer Institute of New Jersey, that suggested there really was something to the herbal formula. Leading institutions, including Johns Hopkins University, began gearing up for larger trials.

The National Center for Complementary and Alternative Medicine -- a unit of the National Institutes of Health, created at the behest of congressmen who support alternative medicine -- was looking for herbal remedies that might have some merit, and PC-SPES seemed like a top candidate. The agency began awarding grants.

BotanicLab's treatment was even featured in a 1999 book, "The Herbal Remedy for Prostate Cancer," by James Lewis Jr., a prostate cancer survivor and education professor who wrote several books about his personal battle and the disease. The book is still listed on Amazon.com's Web site, which features glowing reviews.

A Troublesome Mix

To all outward appearances BotanicLab was a roaring success by the year 2000. But behind the buff concrete walls and smoked-glass windows of the company's office in Brea, trouble was brewing.

The company was churning through a string of chief executives. One of these was a Harvard Business School graduate, Reed M. Benet, with special expertise in founding and expanding young natural-products companies. Hired in 2000, he said he was drawn by the company's sales growth of 40 percent a year and by the buzz he heard about BotanicLab's products and their promise against cancer. He said he was particularly impressed that the product was being tested in the laboratory of Eric Small, a top prostate-cancer researcher at the University of California at San Francisco.

Benet said he didn't entirely realize what he had taken on until he moved to Southern California. On one of his first days on the job, he said, he walked into a room where bulk herbs were stored and mixed. He found none of the paraphernalia of a modern company producing a consumer product -- no bar codes, no quality-control manual.

"It was a room full of boxes with mahogany-colored slats bound together with twisted wire, with Chinese letters on the boxes," Benet said in an interview in San Francisco, where he lives now. "Everything looked like it could have been carried in there by a camel 100 years ago on the spice road. I started realizing, 'Oh, my God -- what have I gotten myself into?' "

Benet said he went into the job knowing standards in producing nutritional products were less rigorous than those used in pharmaceuticals, but he still worried about the origin of the bulk herbs, which came from an array of Chinese suppliers. BotanicLab had bought a machine for its Brea site to help test product ingredients, but Benet said he could never get approval and funding to operate it.

Benet said that he advocated strict quality control and other measures, to no avail. After repeated clashes and growing doubts of his own, he said, he finally resigned in 2001.

Benet said he never saw anything at the company to suggest it was spiking its products with pharmaceuticals. But tests that the company itself ordered, after Benet left and the company came under pressure from California regulators in 2002, showed that bulk herbs coming into the country were free of pharmaceuticals, while packaged products leaving the Brea facility were adulterated with them. In addition, tests conducted after BotanicLab shut down have shown changes in the pharmaceutical ingredients over time that the people suing BotanicLab regard as evidence of a conscious effort to manage troublesome side effects.

Stephen H. Smith, a Los Angeles attorney representing multiple defendants, including the company, John Chen and Wang, pledged in an e-mail message on July 8 to answer queries about BotanicLab, but then failed to respond to multiple follow-up calls or to a set of written questions sent to him by fax and e-mail.

In two brief telephone interviews, Sophie Chen declined to discuss BotanicLab, the product adulteration or issues related to quality control in detail. But she did assert that she was not personally involved in mixing the company's products, saying she spent most of her time doing research in New York. She accepted no responsibility for the problems some patients now attribute to BotanicLab products. She said she pleaded no-contest to a criminal charge because she didn't have the money to fight it.

"I am just a scientist," Chen said. "I am only trying to find a cure for cancer."

Serious Side Effects

From the outset, doctors noticed that for an herbal remedy, PC-SPES had some odd properties.

Published studies showed that some of the men who took it got enlarged breasts, their nipples grew tender, their penises shrank, and they developed other problems. To some doctors, the side effects bore a curious similarity to the effects of another prostate cancer treatment: Users of PC-SPES showed signs of being on artificial estrogen therapy.

Prostate cancer arises in a male sex organ and grows under the influence of testosterone, the male hormone. It can therefore be suppressed, to a degree, by suppression of testosterone (a standard treatment today) or by administration of artificial forms of the female hormone, estrogen (an older, less popular form of treatment).

As part of his early study of PC-SPES, DiPaola, the New Jersey cancer doctor, tested the product for artificial estrogens. But any herbal mixture potentially contains thousands of chemical compounds, and analytical chemists said that finding an artificial drug among them can be difficult. DiPaola and his collaborators got results strongly suggesting an estrogen in the mix, but they couldn't figure out what it was.

The DiPaola group included the test results in their paper and urged caution in using PC-SPES, but in practice, it appears, other cancer doctors overlooked the lingering mystery and took the paper as a green light to recommend PC-SPES to their patients. DiPaola initially agreed to an interview about his testing of PC-SPES, but subsequently canceled it and declined to take questions; an aide said that administrators at his institution had ordered him not to talk because of the pending lawsuits.

Problems like enlarged breasts in men were strange but manageable. But then doctors began publishing comments in their studies about a more worrisome side effect: blood clotting. This, too, is a classic side effect of treatment with artificial estrogen, and a potentially deadly one. A clot in, say, a leg can break away and lodge in a vital organ, killing the patient.

JoAnne Meyer of Sonoita, Ariz., suspects PC-SPES caused the clot that killed her husband, John.

Meyer was a relatively healthy 64-year-old in 1998 when he learned he had an enlarged prostate gland. That's a benign condition, treatable with standard medical care, but John Meyer wanted to try natural remedies first. His wife had always scoffed at his interest in herbs, figuring he was wasting money, but she never imagined they would hurt him.

Though PC-SPES was mostly used by men with prostate cancer, it wasn't labeled that way, and Meyer apparently took the product's claims -- for "prostate health" -- at face value. Soon after starting the product, he contracted a serious leg problem that JoAnne Meyer now believes was a large blood clot. He was laid up for months, but felt well enough on Sept. 14, 1998, to try to get some yard work done while his wife was out.

"When I came back I found him dead over at the barn," Meyer said. An autopsy showed that blood clots had broken loose and lodged in his heart and lungs.

Echoes of Another Error

While PC-SPES was widely touted on the Internet, a few prostate-cancer patients who posted regular comments there were wary. In particular, some of them said in public postings, the side effects of PC-SPES struck them as resembling the side effects of a cheap artificial estrogen called diethylstilbestrol, better known as DES.

DES was at the center of one of the great medical disasters of the 20th century. The drug was given to pregnant women in the United States for three decades, beginning in the 1940s, to prevent miscarriages. Not only was it ineffective, later studies showed, but it caused cancer in the daughters of mothers who took it, and it caused genital abnormalities in both their daughters and sons. The drug was pulled from the market in 1971.

The drug was also tested as a prostate-cancer treatment, but it produced so many side effects, including blood clots, that most doctors concluded it would do more harm than good. It was largely discarded, but interest in it has cropped up from time to time because of scattered research showing it might work at low doses.

Public suspicions that PC-SPES might be contaminated with DES prompted the FDA's office in California to test the product in August 2000. But an e-mail from an FDA chemist that has come to light in the lawsuits showed that the agency used a protocol capable of detecting only high doses of DES, and none was found.

Elizabeth Keville, director of the FDA laboratory in California that conducted the test, said her scientists looked for relatively high levels of DES based on information they received from a consumer who had filed a complaint with the agency. If the scientists had known to look for lower levels, they would have conducted the test differently, she said.

"You've got to make certain assumptions" when running a test, Keville said. "We certainly would not have been looking at those higher levels had we been told it's trace contaminants. . . . When we look back, yes, perhaps things could have been done differently."

The FDA's failure to find DES became marketing fodder for BotanicLab, which posted the results on its Web site. Then, in 2001, some men noticed the PC-SPES suddenly stopped working for them -- levels of the indicator protein started rising to worrisome levels. Moreover, a few men taking the drug started to turn up in hospital emergency rooms, bleeding profusely beneath the skin and from various orifices -- the very opposite of the earlier blood clots.

Communicating over the Internet, patients tried to link various medical problems to specific batches of PC-SPES. One of the key figures in assembling this jigsaw puzzle was a Connecticut woman named Susan Domizi.

Her husband, David, had taken PC-SPES with good results. But it inexplicably stopped working for him in 2001, and she wanted to find out why. With a manufacturing background, she knew to ask about product lot numbers and quality control.

She decided to have various batches of the remedy tested for DES adulteration. The Domizis were vacationing at a family home on Maryland's Eastern Shore when she learned the results: The effective lots of PC-SPES had tested positive for DES adulteration at low levels, and the more recent, ineffective lots had tested negative.

Domizi knew she had to go public, but she feared the reaction, since PC-SPES had acquired a passionate following among men with prostate cancer.

"I didn't sleep for about 24 hours," she said. "I knew that any accusation would be greeted by the majority of men with horror and anger."

Added Evidence

She was right. Domizi posted her results, then linked up with men in California who paid for a second study, by Rocky Mountain Instrumental Laboratories, that confirmed her test. She was bombarded by e-mail, including death threats, from PC-SPES fans, but doctors couldn't ignore the accumulating evidence.

That October, a serious bleeding case came to public attention when two doctors working in Seattle, Mark Weinrobe and Bruce Montgomery, published a case report in the New England Journal of Medicine. Their patient, a traveling salesman, had turned up in an emergency room in Idaho bleeding from every orifice, and the hospital had barely saved him.

The state of California launched an investigation in January 2002 and eventually found DES in the same lot studied by the FDA. Meanwhile, Small, the University of California at San Francisco researcher who had been testing PC-SPES in patients, ordered separate tests in early 2002 that confirmed DES adulteration, and he halted a human study of PC-SPES. Soon afterward, the state announced that it also had found another drug, warfarin, in certain lots of the herbal supplement.

Warfarin, also known by the brand name Coumadin, is an exceedingly powerful blood thinner -- so powerful, in fact, that it was first developed and sold as rat poison. Rats that eat it bleed to death.

The drug is used in patients prone to clotting, but cautiously. It interacts with many other drugs, and taking aspirin with it can kill some people who are particularly sensitive.

The California health department ultimately forced a recall of PC-SPES and another product called SPES, billed as an "immune system enhancing formula." The latter was found to contain undeclared alprazolam, better known as Xanax, a powerful tranquilizer that can cause numerous side effects.

In the end, the state found adulteration with some pharmaceutical agent in every BotanicLab product that it could test, including several discontinued ones, and a laboratory in Switzerland also found contamination.

'Simply Too Sophisticated'

Robert Nagourney, a California cancer doctor who was originally a supporter of PC-SPES but grew wary as problems cropped up, conducted his own analytical tests, finally coming up with a definitive explanation for all the strange side effects the supplement had produced over the years.

His tests, on lots going back to 1996, showed the product had been spiked with low doses of DES and with an anti-inflammatory drug from the very beginning. The tests also suggested that after complaints about side effects began, someone repeatedly tweaked the PC-SPES formula, lowering the amount of DES, adding a less dangerous form of estrogen, and then eventually adding warfarin to the product in an attempt to counteract blood clotting from the estrogens.

"Obviously, some intelligent mind was orchestrating this thing," said Markham, one of the California lawyers suing BotanicLab and dozens of defendants accused of aiding the company. "This cocktail was simply too sophisticated."

Once the full scope of the product adulteration became known and the lawsuits began, BotanicLab shut down. Lawyers suing Sophie Chen have accused her of absconding with large sums, a charge she has denied.

Sophie Chen, John Chen, Xuhui Wang and the company itself were prosecuted in Orange County, Calif., accused of felonious conduct in selling dangerous products to the public.

But the state's case against them was circumstantial. A person close to the investigation, who would speak only on condition of anonymity because of the ongoing lawsuits, said the state had a relatively weak hand: no eyewitness testimony about who adulterated the products and no proof that BotanicLab had bought DES or other pharmaceuticals in bulk. At times BotanicLab has claimed that any product adulteration must have happened among bulk-herb suppliers in China. Moreover, this person said, the state got little help from the FDA and, at the time the criminal case was filed, had tests showing product adulteration only over a brief period.

In the end, the three individuals pleaded no contest to misdemeanor charges. All three said in court filings that they "had no preconceived design to injure other people."

Only the company, by then a defunct shell, pleaded no contest to a felony. The defendants were barred from the dietary supplement business in California and forced to pay nearly $500,000 in penalties.

In the telephone interview, Sophie Chen said that while she could not discuss details, she hoped that "truth and justice" would prevail and people would understand her side of the story. "In due time hopefully we will have more information out to the public, when my lawyer thinks it's time," Chen said. "I feel very badly because I would very much like to talk about it, but I can't."

A Weak Regulator

The policies that allowed BotanicLab to operate for five years with little government supervision are rooted in decades of political struggle in Washington. The FDA has intermittently tried to tighten rules on dietary supplements, only to be fought to a standstill by industry lobbyists.

The biggest of these battles occurred in the early 1990s. After more than 30 deaths and numerous illnesses were attributed to a contaminated supplement called L-tryptophan, the FDA proposed a broad crackdown on supplement makers.

That effort backfired.

Prodded by industry publicity, huge numbers of Americans became convinced the government was about to take away their vitamins. "It was Armageddon as far as we were concerned," recalled Annette Dickinson, president of the Council for Responsible Nutrition, a Washington group that represents many supplement makers.

Moved by public protests, Congress passed the Dietary Supplement Health and Education Act of 1994. Supplement makers hailed the arrival of an era of "health freedom."

Drugs, the most stringently regulated category of consumer goods, must be proven safe and effective by their manufacturers before they can be put on the market. The 1994 law effectively prohibited the FDA from applying a similar standard to dietary supplements, even though they are often billed on the Internet and in store pamphlets as treatments for disease.

The FDA does have the power to ban some supplements if it can show "a significant or unreasonable risk of illness or injury." However, the burden of proof falls not on manufacturers to prove supplements are safe, but on the FDA to prove they're dangerous. Industry groups say that's a reasonable standard for a category of products that includes vitamins and minerals people have used for generations. Consumer groups contend that with 29,000 products on the market, the law effectively paralyzes the FDA.

"People cannot assume the FDA is minding the store, because it's not," said Marion Nestle, a nutritionist at New York University who has long followed the issue. "It can't. And they can't blame the FDA because Congress took away the ability of the FDA to do that."

The FDA's field force of inspectors, whose main job is to safeguard the food supply, in recent years conducted roughly 100 inspections a year to police the dietary supplement industry. The agency plans about 300 inspections this year. Susan Walker, who has held the job of enforcing supplement rules at the FDA for the past two years, said she was committed to "full implementation" of the 1994 law, including stricter manufacturing rules. "We are moving diligently, and we want to get it right," she said.

Others, meanwhile, are assessing their roles. Stephen E. Straus, director of the National Center for Complementary and Alternative Medicine, a unit of the National Institutes of Health that funded PC-SPES research, said that in the late 1990s, scientists held the "somewhat naive" view that the label on an herbal product was an accurate description of what was in the bottle. His agency didn't require detailed ingredient testing of herbal products in studies it funded. It is revising that policy, yet finding adulterants in a complex herbal mixture remains difficult.

"This is a substantial analytic problem that remains a work in evolution," Straus said.

Shattered Trust

In the civil suits claiming harm from BotanicLab products, numerous parties stand accused of aiding the company. Lawyers in the case have learned that Chen gave small amounts of company stock to collaborators she recruited at New York Medical College, where she held an unpaid adjunct faculty position, and they have asked whether that largesse tainted the scientists' judgment.

Several of the researchers in question have denied under oath that their judgment was altered, and the college itself has said it played little role in supervising Chen's work. She remains on the faculty there. "At no time has New York Medical College owned any interest in PC-SPES or its manufacturing or marketing entities, nor has it engaged in . . . distribution or marketing of the product," spokeswoman Donna E. Moriarty said in a written statement.

Milken's Prostate Cancer Foundation has also been sued. It has acknowledged awarding $150,000 in grants to Chen and another $500,000 to other researchers testing PC-SPES, but said these were small sums in a large research portfolio.

The victims' lawyers have turned up evidence that a Prostate Cancer Foundation executive traveled with Chen to China, that another published a paper with her, and that the group provided a venue for a conference on PC-SPES.

Leslie D. Michelson, chief executive of the foundation, said the group had done nothing wrong. "It's wonderful to look back with 20/20 hindsight and say 'you should have known' " about the product adulteration, he said. "Nobody did know."

The lawsuits could take years. Meanwhile, some people who took the products said their illusions about natural remedies have been shattered. One cost of the PC-SPES debacle, some families said, was that faith in the herbs kept some people from undergoing more conventional medical treatment that might have saved their lives. That may be the case with Murray Berk, the Long Island garment buyer. By the time PC-SPES was pulled from the market he had been on it for years, and his daughter said doctors advised them that the DES in the supplement had rendered his cancer resistant to more conventional treatment. He died last year.

"Giving people prescription drugs without their knowledge is insane," said his daughter, Shelley Martin, who once sold herbal products but has grown wary of them. "I just cannot believe it. It's total fraud."

A California woman named Tatiana Palma was one of the people who took BotanicLab products and is now suing.

She said she thought taking natural products would be safe and might help with her rheumatoid arthritis. But she and her husband, Charles Pell, now believe the pills contained prescription drugs that worsened several of her medical problems and caused a blind spot in one eye.

Sitting in a Santa Monica restaurant, she recently gazed toward a sunset over the Pacific Ocean and said she had learned a hard lesson. "The only herbs I am ever going to trust again," she said, "are the ones I grow in my own back yard."