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(The Delta 8,9 DHES Factor)


The Philadelphia Inquirer Monday, January 20, 1997

(A small pill is in the center of a big fight. Wyeth-Ayerst is the original producer of Premarin, the most-prescribed U.S. drug. The firm claims a rival's proposed generic version lacks a key estrogen.)

By Donna Shaw INQUIRER STAFF WRITER

They don't look like such a big deal, these little pills in maroon, green, white, purple and gold. But, oh, the war they've spawned -- over medicine, money, politics and power.

The main combatants are two pharmaceutical companies, one gargantuan and one small, each with its own version of the pill. Lined up behind the big company are a host of women's groups, medical organizations, and female members of Congress. On the other side are proponents of cheaper drugs, animal-rights activists, and several male members of Congress. Scientists at major medical institutions are divided as well.

At stake is the future of the nation's most-prescribed drug, Premarin, a hormone-replacement product whose sales approach $1 billion a year. It is used daily by eight million American women, who are supposed to take it for the rest of their lives.

And that's what has prompted the war.

After a half-century of having the market pretty much to itself, Wyeth-Ayerst Laboratories, the Montgomery County pharmaceutical firm that makes Premarin, is facing competition.

Leading the charge is Duramed Pharmaceuticals Inc., a Cincinnati manufacturer that is seeking U.S. Food and Drug Administration approval to make a cheaper, generic version of the drug. A decision from the agency is expected soon.

No one disputes that a less expensive version, with the FDA seal of approval, would become an overnight success. Every prescription benefit plan in the nation would most likely steer, if not yank, its customers to the new product in order to trim costs.

Both sides sound confident. "I would be just dumbfounded if it went against us,'' said Michael Dey, president of ESI Lederle Inc., the Wyeth-Ayerst unit that makes Premarin.

"We're going to win, we expect to win, and we're not going away,'' countered E. Thomas Arington, Duramed's chairman and chief executive.

Prescribed as a treatment for night sweats, hot flashes, osteoporosis and other ailments related to menopause, Premarin for decades has been a mainstay for Wyeth-Ayerst and its parent firm, American Home Products Corp., of Madison, N.J. Although there are synthetic hormone-replacement drugs on the market, none has come close to overtaking Premarin, which is made from the blended estrogens found in the urine of pregnant horses.

Analysts say that as women baby boomers approach menopause, the demand for hormone-replacement therapies can only grow, reaching perhaps $3 billion in five years.

No wonder, then, that Duramed and others would like a piece of the action. But their undoing may be a substance called delta 8,9-dehydroestrone sulfate.

When it received FDA approval in 1942, nobody knew exactly what was in Premarin or how it worked.

Over the ensuing years, as scientific knowledge and techniques advanced, researchers identified at least 10 distinct estrogens, or female sex hormones, in the product. But no head-to-head studies ever were performed to determine the relative merits of each component.

Pregnant mares were chosen as the source over pigs or other mammals because they were easy to keep in large numbers and excreted large amounts of urine.

Scientists eventually concluded that Premarin's two most prevalent estrogens, estrone and equilin, were the active ingredients. Those standards were updated in the early 1990s, with three more of the 10 estrogens added to the FDA's list of substances that must be included in generic versions of Premarin.

Among the other five estrogens was delta 8,9-DHES, which the government classified as an impurity.

Following those guidelines, Duramed spent more than $33 million to develop and test a vegetable-based copy, called Cenestin, that contains nine of the 10 estrogens -- all but delta 8,9-DHES. Its absence didn't seem to matter because the FDA didn't require that it be included. The company filed for product approval in September 1994.

Two months later, Wyeth -- which had been conducting additional research on Premarin's components -- formally petitioned the FDA to make a significant change: It wanted delta 8,9-DHES reclassified as a required ingredient.

In other words, it wanted the FDA to declare that the one ingredient missing from Duramed's pill was absolutely essential to the drug.

Wyeth said scientific advances had allowed researchers to examine the effects of the drug's individual estrogens, down to the cellular level, and the research indicated that delta 8,9-DHES was a key therapeutic ingredient. The substance appeared to help prevent menopausal symptoms and osteoporosis, a disease that causes bones to become frail and break, Wyeth said.

Under the federal Waxman-Hatch Act of 1984, a generic drug must contain the same active ingredients as the original medicine, or the FDA cannot approve it. Wyeth argued that, without delta 8,9-DHES the proposed generics simply weren't equivalent.

Duramed officials were furious. In a letter to the FDA, they claimed that Wyeth deliberately had performed experiments "designed to yield more questions than answers'' in an attempt to subvert the process. They noted that the FDA had approved other synthetic hormone-replacement drugs that did not contain delta 8,9-DHES; none of those, though, was a generic form of Premarin.

Duramed also sought to enlist the backing of women's groups, only to find that Wyeth had beaten them to it, Arington said in an interview at his offices in Cincinnati.

Duramed officials said the implications of a Wyeth victory go beyond Premarin. They said other big drug companies would use similar tactics to ward off generic-drug firms, costing consumers billions of dollars.

"There would be no generics, period,'' said John R. Rapoza, Duramed's head of regulatory affairs.

Wyeth officials said Duramed is missing the point.

"Delta 8,9 has specific effects on the cardiovascular and [ central nervous systems ] that we don't see with the other estrogens,'' Dey said. ". . . This is clearly a very potent estrogen.''

The generic firms could add delta 8,9-DHES to their product -- one company has told the FDA it's willing to do so -- but it would cost more time and money.

Premarin costs about $12 per month. Duramed said its product would run about $3 per month.

There have been suggestions, too, that the FDA team that had been reviewing the Premarin matter was replaced because it was perceived as anti-Wyeth.

Last month, U.S. Sen. Mike DeWine, who is from Duramed's home state of Ohio, asked FDA Commissioner David Kessler to investigate whether key regulators, including those who had final approval authority on a generic Premarin, "may have been removed or transferred from the review process.''

A spokesman for DeWine said Thursday that the senator had not received a response to his Dec. 20 letter, but hoped to hear something soon.

Sen. DeWine wants to be reassured that it is the scientists and the medical community making this decision,'' said the spokesman, Charles Boesel. "If not, that's certainly very troubling.''

Letters in 1992 and 1994 to Wyeth from Roger Williams, director of FDA's Office of Generic Drugs, show that Williams' staff repeatedly had rejected the notion of reclassifying delta 8,9.

Since then, there has been a divisional reorganization at FDA, and Williams is no longer as directly involved in the Premarin matter. The final decision is now in the hands of another top official, physician Janet Woodcock.

An FDA spokeswoman said the agency would not respond to questions about DeWine's letter until it replied to the senator. Wyeth officials said they had nothing to do with any changes at the FDA.

In the end, it's the science that's supposed to prevail. But that's where there's still much division.

In July 1995, the FDA asked advice from its Advisory Committee on Fertility and Maternal Health Drugs. The panel concluded there was insufficient data to determine whether to reclassify delta 8,9.

In November 1996, the FDA issued its preliminary analysis, but didn't clear things up: Delta 8,9 might or might not be important, but the evidence was "incomplete or conflicting.''

The FDA asked for public comment on the issue. By its Dec. 7 deadline, the agency had received a mountain of replies.

Women's and medical groups rallied behind Wyeth, saying women could become guinea pigs for an unproven medicine and not realize the downside for years. At particular risk were poor women and those in managed-care plans that required patients to use generic drugs, they said. Experts at Duke University, Sweden's Karolinska Institute and Baylor College of Medicine backed Wyeth, too.

"There is the risk that, over extended time . . . the generic will not deliver benefits equivalent to the original,'' officials from the Association of Professors of Gynecology and Obstetrics wrote.

"As a cardiologist, I am aware that researchers are identifying almost daily the previously unrecognized effects of conjugated [ blended ] estrogen on the cardiovascular system,'' said Debra R. Judelson, president of the American Medical Women's Association.

Betty Smith Williams, president of the National Black Nurses Association, added: "The realities of our health-care system are such that many lower-income minority women who are on Medicaid or in managed-care programs will have access only to the generic, whether they want it or not, and whether their doctors feel comfortable with it or not.'' Forcing women to use the generic "would be the equivalent of doing unplanned, uncontrolled research on how these women respond to the product,'' she wrote.

Other letters supporting Wyeth came from U.S. Sen. Barbara Mikulski, U.S. Sen. Patty Murray, the American College of Obstetricians and Gynecologists, the Women's Legal Defense Fund, and the National Osteoporosis Foundation.

Duramed accused Wyeth of unleashing "a well-organized letter-writing and lobbying campaign.'' Transcripts show that, at the 1995 advisory committee meeting, five of the seven nonprofit organizations that testified for Wyeth acknowledged they had received funding from the company.

In response, Wyeth spokeswoman Audrey Ashby said her company "has a long tradition of working with third-party organizations whose goals are allied with our own corporate mission to enhance women's lives through science and education. Their support on this issue is unrelated to Wyeth-Ayerst's financial support.''

Duramed, too, had many backers.

"From the perspective of a practicing physician, Wyeth-Ayerst appears to be manipulating the American legal system and the FDA review process in order to maintain their monopoly and increase health costs,'' wrote Robert C. Sergott, a physician and researcher from Philadelphia's Wills Eye Hospital. ". . . The medical, scientific and legal charade of delta 8,9 must be terminated. The credibility of the FDA is at stake.''

"FDA has no scientific or legal basis for changing its approval requirements,'' said Robert S. Milanese, president of the National Association of Pharmaceutical Manufacturers, a trade group that represents independent drug manufacturers and their suppliers. Wyeth's tactics allowed the company "to reap monopoly profits at the expense of American consumers and taxpayers,'' he added.

Other Wyeth critics included People for the Ethical Treatment of Animals, HorseAid, and the Humane Society of the United States, which said the mares used as the source of Premarin's estrogens were subjected to cruel living conditions. Wyeth repeatedly has denied those allegations.

Richard Hochberg, a Yale University professor, and Bruce Ettinger, of the Kaiser Foundation Research Institute, wrote that studies showed delta 8,9 did not contribute to Premarin's effectiveness.

Several lawmakers, including U.S. Sen. John Glenn of Ohio, Rep. John D. Dingell of Michigan and Sen. Ron Wyden of Oregon, all Democrats, demanded that the FDA explain the delays in decision-making and noted that consumers would save money should the generic be approved.

The two companies, meanwhile, await the final word.

At Wyeth labs in St. Davids, teams of scientists at the company's new Women's Health Research Institute are busily figuring out the roles of specific estrogens. The company is in the midst of a $40 million, five-year study on the effect of hormone-replacement therapy on postmenopausal women with heart disease.

Duramed posted a loss of $18.2 million for the first nine months of 1996, laid off 94 workers -- 26 percent of its staff -- in October, and cut executives' salaries. Arington said that, one way or another, they would keep moving forward, borrowing more money if they must.

His company's gleaming, state-of-the-art manufacturing facility stands ready, rows of Cenestin labels already loaded in the assembly line's machinery.

"Even if we lose, we're going to grow and prosper and do extremely well,'' he said. "We're committed to moving ahead.''


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