An Expose Revealing How Politics Trumped Science at the FDA

See Article at cagw.org

Introduction
On May 5, 1997, a little noticed news item reported that the U.S. Food and Drug Administration (FDA) had rejected an application for a generic version of the drug Premarin. The FDA approving or rejecting a drug is generally a dog bites man story. But not in this case. Indeed, it appears that in making one of the most important decisions in recent years, the FDA sacrificed science and the public health on the altar of political accommodation. Although the FDA and Premarin's manufacturer, Wyeth-Ayerst, would like the American public to believe that this decision was in their best interests, the reality is that it was driven by hoards of lobbyists, fraught with conflicts of interest, and characterized by questionable behind-the-scenes political maneuvering.

Government waste, fraud, mismanagement, and abuse are marbled throughout the federal government in myriad forms, and the job of exposing them is difficult enough. But it is made even more complicated by the insidious ways it permeates policy and spending priorities. The high-profile, often contentious, battles which play out on the House and Senate floors and in the media over federal spending obscure the fact that each year, countless decisions are made in the dark corners of the regulatory maze of our nation's capital that needlessly cost Americans billions of dollars. They can also have an adverse impact on the quality of our lives.

This report provides a snapshot of how public policy priorities in one federal regulatory agency, the FDA, were bent to serve corporate and political agendas. The lessons drawn from the actions documented here are not unique to this agency. The politicization of the regulatory process has all too often become the stuff of inside Washington chatter and government investigations. It's time to shine the light on this harmful and costly process.

Background
Hormone replacement therapy (HRT) has increasingly become the treatment of choice for women experiencing discomforts associated with the onset of menopause. Most American gynecologists readily introduce this treatment option to their patients. Indeed, it is endorsed by a number of health officials as a safe and effective long-term treatment for menopausal symptoms, such as hot flashes. Besides alleviating menopausal symptoms, HRT has also been shown in studies to safeguard women against osteoporosis, the irreversible thinning of bones which often results in broken hips and injured spines as a result of falls. Clinical studies show that hormone replacement therapy has reduced hip fractures due to osteoporosis by more than 60 percent. In addition, a 1996 Columbia University study found that taking estrogen for ten years after menopause reduced the risk of Alzheimer's disease by 30 to 40 percent.

Though the debate over whether to choose HRT or not continues at the fringes, the reality is that 8 million American women, through their private insurance companies, Medicare, and Medicaid spend an estimated $750 million a year on HRT and that number is growing. By the year 2000, more than 50 million American women will reach menopause and the demand for HRT will explode.

Premarin, a drug made up of conjugated estrogens obtained from the urine of pregnant mares, is the most widely prescribed drug in the United States and the drug of choice for hormone replacement therapy. Wyeth-Ayerst, the sole manufacturer of the drug, is owned by American Home Products (AHP), a company with sales of $14 billion in 1996. A July 23, 1997 Wall Street Journal article reported that AHP's sales of Premarin rose 45 percent in the second quarter of 1997, to $291 million. Wyeth's revenues from Premarin are $1 billion a year.

The rising costs of health care, and the role that drug costs play in compounding that burden, have spawned an enormous demand for safe, effective, and consumer-friendly generics. In recent years, other pharmaceutical companies have identified and sought to fill the need for a generic version of Premarin. A generic version of Premarin would save female consumers approximately $300 million a year.

Cost isn't the only issue. A commitment to HRT means taking the drug every day. Yet, a large percentage of women lapse after only two years. Fears of increased risk of breast cancer has been cited as one reason for the drop off, but there is also significant evidence that many women who take Premarin stop taking the drug for a period of time (known as "drug-holidays") because of its cost. The availability of a lower-cost, generic version of Premarin would result not only in increased access to the therapy for thousands of women who might not be able to afford the name brand, but would also encourage women to stay on their regimens and avoid the expense and suffering caused by hip fractures and other problems associated with a reduction in bone mass and density. The National Osteoporosis Foundation estimates that one out of every two women over the age of 50 will have an osteoporosis-related fracture in her lifetime.

In order to speed up FDA approval of all generic drugs, Congress enacted the Drug Price Competition and Patent Term Restoration Act, (known as Waxman-Hatch after the Congressman and Senator who sponsored the measure) in 1984. In doing so, the authors of the legislation set up straightforward scientific measures of equivalence: it required manufacturers of generic drugs to show that a generic drug's active ingredients (those that deliver a drug's therapeutic benefit) showed up in the bloodstream in the same concentration, using the same dosage form as the brand name drug it was copying. In this way, the public could be assured that they were buying drugs of the same safety and quality at a much lower cost. Many important drugs are being made available at a substantial discount in this manner, such as ibuprofen and acetaminophen.

A Brief History of Premarin: Not from the Horse's Mouth
Premarin was first marketed for menopause in 1942. It's approval was based on clinical studies certifying the safety of the product for its intended use. In 1962, Congress passed a new law which authorized the FDA to certify a drug's efficacy, as well as its safety. Drugs approved before that time, like Premarin, were required to submit a supplemental application demonstrating efficacy to the FDA. Premarin tablets were certified by the FDA as effective for treating menopause in 1972. In 1986, based on studies conducted by Wyeth, the FDA approved Premarin for treatment of osteoporosis.

When Premarin's patent expired, the field was opened up to other pharmaceutical manufacturers interested in developing and marketing a generic version of Premarin. Several smaller companies, including Duramed Pharmaceuticals, were offering a generic in the 70's and 80's.

But in 1990, Wyeth-Ayerst told the FDA that the generic products on the market released estrogens more quickly into the blood stream than Premarin. Relying on the Waxman-Hatch Act's requirement that a generic have the same rate (how fast the drug enters the blood) and extent (how much total drug enters the blood) of absorption as the listed drug product, Wyeth-Ayerst pounced on this discrepancy and began a campaign to take the generics off the market.

The company argued that even small differences in the absorption rate could lead to increased chances for endometrial or breast cancer and that a lower rate of absorption could leave women unprotected from osteoporosis. It argued that new research revealed that conjugated estrogens had a complex biochemistry which, if not exactly replicated, could make the drug toxic or ineffective.

While Wyeth was arguing that the faster-acting version of Premarin posed unacceptable health risks to women, the Canadian Health Protection Board (HPB) found that the company was actually selling its own fast-acting version in Canada. In fact, Wyeth had used the fast-acting Canadian version in its studies to demonstrate the salubrious relationship between Premarin and reduced osteoporosis. The HPB noted that the "argument used in the U.S. concerning the virtue of Premarin having modified release characteristics is flawed." Wyeth-Ayerst tried to explain the different estrogen release rates as being due to minor formulation changes. But the HPB coldly rejected this excuse, concluding: "The Committee is most skeptical of this explanation and considers that the formulation change is a major one and was most likely undertaken to allow Canadian Premarin tablets to meet the proposed U.S. drug release specifications."

Though its strategy in Canada was exposed, Wyeth continued to whip up hysteria about the absorption rate in the United States, while continuing to sell its own fast-release product abroad. Indeed, Wyeth's double-talk worked effectively at the FDA, which was aware of the shaky absorption argument, but chose not to re-examine the issue. Noting that it was hard to measure rates of absorption, the FDA banned all generic versions of Premarin from the market until the manufacturers could show the same rate as the delayed-release Premarin.

Duramed decided to stick it out and solved the so-called absorption problem.

The Delta 8,9 Deception
But at the same time that Wyeth was using the absorption issue to remove generics from the marketplace, it was busy analyzing Premarin to determine what additional estrogens, if any, existed and whether they affect individual health. The goal was clear: if one or more new components were found to provide a medical benefit, Wyeth would be able to petition the FDA to prevent a generic competitor from reaching the market until it contained that ingredient. The problem with that approach was the absence of any new active estrogens.

In 1970, Premarin's composition had been validated by a non-governmental panel called the United States Pharmacopoeia Convention (USPC). The USPC is the keeper of a chemical compendium that lists all the components of a drug, both active ingredients and impurities. Since the FDA clearly did not require generic companies to include impurities in its products, it made sense to tell the USPC only about newly-discovered active ingredients. And if Wyeth wanted to get the FDA to require a generic company to add any newly-discovered estrogen, it would have to convince the USPC that it indeed performed as promised.

In 1991, Wyeth informed the USPC that it had found such a new component in Premarin, an estrogen called delta 8,9 (because the new molecule had a delta shape). But it did not immediately petition the USPC to list delta 8,9 as an active ingredient. Wyeth lacked any evidence that delta 8,9 provided any clinical benefit. Instead, it argued that because delta 8,9 made up a larger percentage of a typical Premarin tablet than even clinically active estrogens, and because the requisite scientific evidence of its role in Premarin had yet to be determined, the USPC should create a new category of components called concomitants.

According to Wyeth, concomitants were to be defined by what they were NOT. They were NOT active ingredients and they were NOT impurities. Any new generic should now be required to add it, Wyeth argued.

Since Wyeth advanced no clinical claims for the delta 8,9, what did it expect to gain by a new USPC listing? In isolating delta 8,9, Wyeth had developed a process of actually manufacturing the component, a process that, unlike Premarin itself, had a patent. If it could get the USPC to accept delta 8,9 as an active ingredient and it held the patent, Wyeth could indefinitely stymie its competitors from adding delta 8,9. But the USPC found no scientific evidence that delta 8,9 was active. However, under pressure from Wyeth and in a highly dubious regulatory step, the USPC and FDA agreed to create a category of concomitants, though both continued to categorize delta 8,9 as an impurity.

Since the USPC and the FDA declined to recategorize delta 8,9 as an active ingredient, Duramed and another generic manufacturer, Barr Laboratories, logically interpreted the ruling as a green light to go on developing the generic without. Indeed, in June 1994, when Wyeth tried to get the FDA's Office of Generic Drugs to require Duramed to add delta 8,9 in order to get FDA approval, Roger Williams, the Associate Director for Science and Medical Affairs for the Center for Drug Evaluation and Research at the FDA, spoke for the agency in a 1994 letter to Wyeth when he noted: "Delta 8,9 is currently classified as an ordinary impurity....The Office of Generic Drugs sees no scientific justification to change any of the categorizations recommended by the Generic Drug Advisory Committee in February 1991, barring some special safety or efficacy documentation with regard to any of the constituents."

But Wyeth-Ayerst was not prepared to give up simply because the science was not in its favor. In November 1994, it filed a citizen's petition (essentially an injunction to block approval), asking the FDA to require generic drug companies to include delta 8,9 in copies of Premarin.

The citizen's petition claims that, by approving a generic product which was not identical to Premarin in every possible way, the FDA could cause "long term damage to millions of women."

The Politics of Premarin
At the same time it filed the citizen's petition, Wyeth began to organize political pressure on the FDA. First, it moved to recruit women's groups. Next, it rounded up the support of members of Congress. Letters from members serve notice to the FDA that its administrative actions carry both public and political implications. In particular, the FDA has shown itself to be open to such congressional involvement in three areas: when a drug is alleged to be unsafe; when a product's approval affects well-organized interests, such as AIDS activists and women's groups; and when an FDA ruling that curries favor comes at the expense of companies or individuals who lack the political clout to fight back.

Not surprisingly, Wyeth framed the delta 8,9 issue as all three. Letters from key legislators and women's groups poured in expressing concern that allowing a generic drug on the market that did not contain delta 8,9 would threaten the health and safety of millions of women, particularly poor women. All the letters share one statement that is scientifically misleading: that the generic version of Premarin lacks the "same" active ingredients as Premarin.

Given the lockstep fashion in which this argument was framed, it would appear that, at the very least, Wyeth led legislators and organizations to believe that delta 8,9 was an active ingredient essential to the therapeutic value of Premarin.

The company may have misrepresented the delta 8,9 issue to lobbyists and political types just enough to get them to believe that, in taking up Wyeth's cause, they would also be protecting millions of women from long-term health damage. In short, delta 8,9 was no longer a simple scientific concern. It was now a woman's health issue. Indeed, letters from Sens. Barbara Boxer (D-Calif.), Bill Bradley (D-N.J.), Barbara Mikulski (D-Md.), Patty Murray (D-Wash.), and Olympia Snowe (R-Maine) all included the imprecise and scientifically insupportable claim that delta 8,9 was an active ingredient without which a generic version would endanger women's health.

No matter that the FDA had decided twice before that Premarin had only two active ingredients, both of which were already contained in Duramed's and Barr's generic product. In order to protect itself from further pressure, the FDA shifted course. It proposed to hold an advisory committee meeting made up of experts on estrogens and osteoporosis to review new information and invited Wyeth to provide data to substantiate its claims. These experts were to consider whether the USPC guidelines for conjugated estrogens needed revision based on new data and whether to upgrade delta 8,9 from an impurity to an active ingredient. Regardless of the outcome, Wyeth would get at least another 12-18 months with no generic competition.

The advisory committee heard testimony in July of 1995. For the hearing, Wyeth-Ayerst solicited and received support for its anti-generic campaign from a number of interest and advocacy groups including, the Women's Legal Defense Fund, the American Medical Women's Association, Business and Professional Women/USA, Association of Women's Health, Obstetric and Neonatal Nurses, National Consumers League, American Pharmaceutical Association, American College of Clinical Pharmacy, and the American College of Obstetrics and Gynecologists.

Of those testifying, all but two - National Consumers League and the Women's Legal Defense Fund – admitted to having received financial support from Wyeth-Ayerst in the past. In a subsequent conversation with Washington Post columnist Judy Mann, an official of the Business and Professional Women/USA confirmed that her group alone received $65,000 from Wyeth. Prior to this, not one of these groups had opposed a generic version of Premarin or been involved in the issue until it was brought to their attention by Wyeth.

The committee concluded that there was "still insufficient data to demonstrate that delta 8,9 should be a required component of generic conjugated estrogens."

Duramed was told once again by the FDA that, since the scientific issues were resolved, it would issue its decision soon. Again, Wyeth asked the FDA for more time to submit additional data showing delta 8,9's clinical effect. But since the FDA generally accepts the recommendations of its scientific advisory committee, it seemed that the company's string had run out. Most observers expected the agency to approve Duramed's and Barr Labs' application within months after the advisory committee meeting. It seemed that science, not politics, would ultimately prevail.

The White House Coffee Connection
Wyeth's hope for another crack at delaying the generic was unexpectedly realized. In November 1995, American Home Products CEO John Stafford attended one of the now infamous White House coffees with President Clinton. Shortly thereafter, the company bestowed $50,000 on the Democratic National Committee, the only AHP soft money contribution to the Democratic National Committee on record at the Federal Election Commission. Moreover, this meeting also included White House Chief of Staff Erskine Bowles, who owns between $200,000 and $500,000 in American Home Products stock, Wyeth's parent company. Though the details of that meeting are not documented, subsequently, the FDA's pledge that it would make a decision "soon" was forgotten in a steady call for more studies intended to show that delta 8,9 was essential to treat osteoporosis.

Internally, the FDA also made some questionable personnel changes. When it came time to review the data submitted to the advisory committee and to the FDA, Roger Williams, the individual who had quarterbacked the earlier review of delta 8,9 (already rejected once in 1994) was replaced. In his stead, the FDA appointed a former Wyeth employee, Wallace Adams. (At the same time, the agency was asking a medical officer involved with the Premarin issue to recuse herself from further involvement because her brother worked for Barr Labs). When the FDA convened an ad hoc committee to evaluate the data, it excluded Williams, while including Adams.

The Science this Time?
After the November 1996, elections, the FDA announced that it would make the entire docket of information it had received on the delta 8,9 issue public and invited comments and other data which might have some bearing on the agency's decision. The contents of that docket revealed that there was no scientific evidence to support the contention that delta 8,9 is an active ingredient needed to provide health benefits to women. Indeed, an analysis conducted by the FDA's Office of Clinical Pharmacology and Biopharmaceuticals (OCPB) found that "none of the pharmokinetic data presented by the firm can be interpreted as demonstrating that delta 8,9 or its metabolite 17-B is essential to the estrogenic activity of Premarin." They also charged that the data submitted by Wyeth was either incomplete or conflicting.

In fact, the studies which do exist contradict Wyeth's claims. In May 1996, for example, the FDA received data comparing Premarin with a generic conjugated estrogen used in Canada which revealed that both drugs provided the same amount of estrogen needed to protect women against post-menopausal symptoms and osteoporosis. The Canadian generic version does not contain delta 8,9.

Another three-year study begun in 1992, often referred to as the estratab study, demonstrated that administering varying doses of estratab, a drug which contained only the two active ingredients, equilin and estrone, delivered the requisite estrogens levels needed to treat post-menopausal symptoms and osteoporosis.

Indeed, Wyeth's own research shows that, in a significant number of women taking Premarin, delta 8,9 doesn't even appear in the bloodstream. Yet these women had the same levels of equilin and estrone and showed the same effect on bone density.

In fact, no definitive tests comparing conjugated estrogens containing delta 8,9 with conjugated estrogens without delta 8,9 have ever been conducted, either in women or in appropriate animal models.

In early 1997 articles began to appear in Business Week, The Wall Street Journal, and Investor's Business Daily recounting how Wyeth mobilized to delay the FDA. In the wake of these articles, a new wave of congressional letters, this time questioning the FDA's fealty to the Waxman-Hatch Act, were sent to the agency.

On March 19, 1997 before the Senate Labor and Human Resources Committee, FDA Director of the Center for Drug Evaluation and Research Dr. Janet Woodcock was questioned by Sen. Mike DeWine (R-Ohio) about the foot-dragging surrounding approval of the generic. Dr. Woodcock stated repeatedly that the scientific issue had been resolved. But for millions of consumers who were deprived of a less expensive and equally effective treatment for osteoporosis, the decision would come too soon, and the "science" backing it up would be questionable, at best.

On May 5, 1997 the FDA released a statement denying the Duramed and Barr Labs applications. The FDA stated that the active ingredients of Premarin have not yet been defined and it therefore could not approve a generic which did not contain delta 8,9.

Yet, an internal FDA document from the Office of Pharmaceutical Science dated May 3, 1997, two days before the press release, laid waste to Wyeth's scientific claims about delta 8,9 and questioned why the company had suddenly discovered the therapeutic properties of delta 8,9 when there are at least 25 other inactive impurities present in Premarin. The memo raised serious questions about the inviolability of the FDA's drug approval process when it reverses itself on its bioequivalence standards at such a late stage in the process. It also observed that the agency's decisions on these matters could have the effect of not only "impeding generic substitution, but also of reducing or eliminating the incentive to develop the necessary public health information."

The story doesn't end there. On May 16, the Inspector General (IG) of the Department of Health and Human Services also weighed in with a report obtained by Citizens Against Government Waste (CAGW) which provokes even more questions about the FDA's handling of the Premarin issue.

The IG was asked to look at whether or not Wyeth conducted any "unapproved" reformulations on the shellac coating of Premarin tablets in the late 80's. The thickness of the shellac relates directly to the drug's rate of absorption. In attempting to answer that question, however, the IG relied upon the FDA to certify that the reformulations were appropriate, rather than conducting an on-site investigation of its own. Pointedly, the report verifies that the FDA provided the IG with absolutely no documentation to back up its claim that Wyeth's reformulations were sanctioned. When asked for the documentation, FDA staff simply told the IG that "other work precluded their preparing an inspection report."

The IG report also contains a quote from an FDA official who stated in 1993 that "the same bioequivalence standards first raised by Wyeth-Ayerst now cast doubt upon the safety and efficacy of Premarin. It would be neither consistent nor ethical, however, for FDA to apply a more lenient standard to the innovator firm now than was applied to the generic sponsors in 1990-91, when bioequivalence issues were identical."

The IG report also expressed concerns about the FDA's handling of Wyeth's citizen's petition, which it said had been allowed to extend for an "unacceptably long period of time."

On June 5, 1997 Duramed announced that it would appeal the FDA's decision and on July 29, 1997 the company filed its own citizen's petition. Duramed's petition asks the FDA to declare Premarin's labeling "deficient," and to withhold any new indications for Premarin (Wyeth is seeking a new heart disease indication for the drug) until all its active ingredients are fully identified. Duramed Chairman and CEO Thomas Arington states that "the double standard demonstrated by the FDA in this case is unacceptable."

Conclusion: Politics and the Public Health
The politics of Premarin cast a long shadow over Washington. Political considerations are apparently now front and center in the daily determinations of the FDA. A generic version of Premarin would save American women, many of whom are on fixed incomes and must take Premarin for life, hundreds of millions of dollars a year. Similarly, Medicaid and Medicare could save money in two ways. First, a generic version of Premarin would be less expensive. Second, lower prescription costs would allow more women to stay on the medication, thus avoiding the hip fractures and infirmities that cost millions more to treat.

The financial cost of the FDA's delay is also considerable. Wyeth's success in getting the FDA to bow to political pressure regardless of the science may tempt other companies to manipulate the system in a similar way to avoid generic competition. An FDA requirement to include delta 8,9 could open up a Pandora's box of additional Premarin components. The nightmare scenario for generic manufacturers would be that they spend many more millions to comply with the new FDA requirements and resubmit the application only to have Wyeth suddenly identify some other new "active" ingredient. The delays would be endless and Premarin's monopoly would be virtually guaranteed. So, too, would the drugs of many other companies bound to follow in Wyeth's footsteps.

Indeed, even if the FDA approves Duramed's or Barr's product, a dangerous precedent has been set. Wyeth has been able to delay a decision for six years and extend its monopoly for a fraction of the cost of developing a new drug. A victory for the company sets an undesirable precedent which could destroy the generic drug industry and gut Waxman-Hatch, a law which was designed to promote generic competition and allow more Americans to enjoy the blessings of America's medical research enterprise. Changes must be made to equalize the burden of proof so that companies which claim new clinical benefits must present the science to back up those claims in a timely and open manner. Without this change, companies willing to spend a few thousand dollars and push the "right" political buttons in Washington will be able to buy delay and cost consumers billions. With each day of delay, the FDA sends a signal that for the right amount of money, put into the right hands, the public health can be bought and sold.

Recommendations
Congressional hearings into the chain of events surrounding Premarin and the rejection of the generic are surely warranted. The FDA's own internal documents reveal deep divisions within the agency over the science and document how scientific data supporting approval of a generic was systematically ignored. In addition, the May 16, 1997 IG report contains revelations about foot-dragging and shoddy management of the citizen petition process, as well as questions about Wyeth's reformulations of Premarin itself. There is ample evidence of inappropriate political pressure being brought to bear on the FDA, as well as conflicts of interest, to justify a more in-depth review.

Congress has the authority and the obligation to explore, in a public forum, what these decisions portend for the development of future generic drugs and to illuminate and correct weaknesses in the FDA's internal decision-making processes.

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