The Quest for a Generic Premarin – A Bitter Pill to Swallow

BY JANE ALLIN

The story of the quest for a generic Premarin is an interesting one – one that dates back to the mid 1980’s when the FDA announced that Premarin was effective in combating the bone loss associated with osteoporosis.

To this day an Abbreviated New Drug Application (ANDA) for a generic version has yet to be approved by the FDA – more than 20 years after two companies vying for a piece of the pie lost their bids to market a generic version of Premarin.

The history behind the failure of the FDA to approve any generic version of Premarin is intriguing yet pretentiously motivated based on a so-called “impurity” named delta 8,9-DHES.

Premarin’s patent expired in 1971 and until 1986, when the news of its efficacy in minimizing bone loss associated with osteoporosis was publicized, there was little to no interest from competing drug companies to produce a generic version of the drug.

    “There was not a large market for anyone to do anything about it until Premarin was granted the osteoporosis indication,” says Kenneth Phelps, vice president of clinical operations at Duramed Pharmaceuticals, Inc. (Cincinnati, OH). Duramed had a generic version of Premarin, known simply as conjugated estrogens USP, which it hoped to exploit in this newfound niche. “The market burst open, and Premarin seized the day. [There was talk that] literally every postmenopausal woman should take Premarin for the rest of her life,” Phelps says.” [1]

When Premarin was first introduced in 1942, Wyeth-Ayerst was only required to prove its safety, not its effectiveness and at that point it was unclear exactly what it contained. With time and advancing scientific techniques Premarin was found to be comprised of at least 10 different identifiable and quantifiable estrogens two of which, in 1972, the FDA declared responsible for Premarin’s efficacy – estrone sulfate and equilin sulfate – the rest being ancillary estrogens deemed not to participate in its activity. [2]

This opened the door for competing drug companies to submit Abbreviate New Drug Applications (ANDA) for their generic versions.

In 1991, six years after the announcement about the benefits of Premarin as an osteoporosis preventative, Duramed Pharmaceuticals submitted an ANDA for the approval of Cenestin – a generic version of Premarin.

Around the same time another pharmaceutical company, Barr Laboratories, had also developed a generic version and were eager to compete in the lucrative market offered by this new revelation and the possibility of an untapped target audience.

However the prospect of a generic entering the melee triggered a scientific debate that would persist for many years.

Despite the fact that the generics appeared to be interchangeable with Premarin this was really not the case.

To begin, the FDA discovered that Premarin had a slow-release bioavailability mechanism meaning that generic copies would need to have similar release characteristics to be considered bioequivalent. Testing, however, proved the generics to be immediate release in their action. [3]

This finding further clouded the question of what the actual active ingredients in Premarin were since bioequivalence testing is typically based on the active ingredients, or their metabolites, of the product. This is a function of the complex nature of the CEEs that contain numerous estrogens in smaller quantities in addition to other steroidal compounds that may furnish some level of biological activity in the human body. [4]

Note: CEEs stands for conjugated equine estrogens, made with urine collected from pregnant mares.

Accordingly from a purely scientific perspective they were not the same.

To add fuel to the fire Wyeth-Ayerst also issued dire warnings that this alleged discrepancy of how quickly the estrogen entered the bloodstream could increase the incidence of cancer in users.

Consequently, in 1991, the FDA abruptly withdrew approval of all ANDAs for generic Premarin and swiftly stipulated that in addition to estrone sulfate and equilin sulfate any potential generic must contain three additional estrogens as concomitant components – not considered active ingredients but nonetheless requirements to apply for an ANDA. [5]

Interestingly enough the Canadian version of Premarin was found to be as fast-acting as the generics.

    “Canada’s regulatory agency rejected Wyeth-Ayerst’s objection to a generic Premarin produced by ICN Canada Ltd. and left it on the market. A Canadian drug advisory committee concluded in a 1991 report, “If Wyeth’s position were correct, then Premarin had been producing unsafe plasma levels in Canadian women for years” (J. Carey, 1997, p. 130). This statement apparently went unnoticed by the FDA” [6]

Despite this major setback for Duramed and Barr Laboratories, both companies, eyeing the tidy profits to be made from the potentially burgeoning market for the drug due to its ability to mitigate osteoporosis, forged ahead and developed new generics that would satisfy the estrogen requirements together with demonstration of bioequivalency.

However in the interim Wyeth was already strategizing to protect their control of the HRT and newly-realized osteoporosis market.

As a result of their clinical studies Wyeth-Ayerst filed a citizen’s petition in November 1994 requesting that the FDA designate delta (8,9) dehydroestrone (DHES) a concomitant component of conjugated estrogens citing it as having a critical profile and that the FDA not approve any generic versions lacking this component. [7]

In response the FDA ruled unanimously that delta 8,9 DHES was an impurity and was not a required ingredient of any generic. [8]

This move by the FDA led Duramed and Barr to believe that approval of their generics would be forthcoming and both submitted new ANDAs – Duramed in September 1995 and Barr the following July.

But Wyeth-Ayerst was not ready to give up on its fight to maintain control of the market. What followed was a massive advertising campaign of propaganda, both aggressive and defensive, to uphold the credibility of their product.

This strategy consisted of blatant lies and exaggerations of the benefits of Premarin. In addition to relieving the symptoms of menopause it was touted as aiding sexuality, the brain (cognitive function, memory, Alzheimers), cataracts, teeth, heart, bones, colon, you name it – a miracle drug.

Wyeth-Ayerst also “persuaded” physicians to hand out complimentary videos and brochures about the drug.

Premarin foals.
Premarin foals.
    “The brochure, titled Quality,Commitment, and Caring, stated, ‘No synthetic components have ever been introduced to the unique combination of natural estrogens.’ The brochure not only praises Premarin and its ‘unique’ qualities but also featured color photographs of beautiful horses grazing in fields. The captions with these photographs stated, ‘The mares are highly prized and well cared for’ and ‘Providing for the care and well-being of horses is crucial to the production of Premarin.’ The text stated, ‘No other type of livestock ranching has as many checks and balances for animal care and welfare’ ”. [8]

It did not stop here – this devious marketing ploy became politically motivated when Wyeth-Ayerst recruited Senators to pen letters to the FDA to halt generic Premarin progress.

Moreover women’s groups were enlisted to join the cause.

Needless to say large sums of money passed between hands. This in itself is worthy of a story on its own.

While all of this was happening, the US Food and Drug Administration’s advisory panel for Fertility and Maternal Health Drugs met in 1995 to discuss the composition of conjugated equine estrogens but failed to reach a verdict on whether delta 8,9 DHES (and potentially other components) in Premarin were concomitant entities or critical to its clinical benefits.

At the time delta 8,9 DHES was not included in the generic versions of the drug yet Wyeth was resolved to maintain its importance.

Wyeth’s arguments in making the claim for the clinical significance of the delta 8,9 DHES were multi-fold: (1) ~ 18% of circulating estrogens in women taking Premarin, reflecting a far greater bioavailability than indicated by the amount actually present in the product (about 2%-6%); (2) greater activity than predicted by its estrogen receptor binding affinity since the potency of delta-8.9 DHES was found to be similar to estradiol (a potent estrogen); (3) evidence that delta-8,9 DHES might have 10 times the potency of estrone sulfate, a major component in Premarin; (4) different estrogen components have different effects on different tissues, and that there may be synergy between certain components and; (5) two more estrogen components of Premarin (on top of the ten already described) were identified and a characterization of a third was underway. [9]

The counter-argument from Barr Laboratories, one of the generic hopefuls, argued that delta 8,9 DHES and other components of Premarin should be declared impurities claiming that a receptor binding assay showed that both equilin sulfate and estrone sulfate, thought to be the original active hormones, bound to 60% of the available receptors and delta 8,9 DHES only 0.2%. [10]

This fell flat with one panel member who made the comment that this was not new information but rather a theoretical discussion of what Barr believed was correct. [11]

In the end, the only thing the panel agreed upon was that more trials were required, particularly in terms of efficacy related to dosage and comparative safety – a stalemate so to say.

Finally in 1997, with delta 8,9 DHES as the focus of their defense, Wyeth-Ayerst presented newer laboratory and clinical studies to the FDA. Together with the previous findings this data was meant to demonstrated that this particular component of Premarin was not simply a concomitant entity but rather an active constituent of Premarin. After repeated doses of Premarin, the blood concentration of the active metabolites of delta 8,9 DHES were found to be at the same level as the metabolites of both estrone and equilin.

    “An FDA spokesman said that ‘for something to be generic, it has to be exactly identical and deliver the same active ingredients as the original product,’ and the generics have not been able to do that. The generic companies may have products that legitimately treat a lot of the same symptoms of Premarin, but the agency has to know that it is bioequivalent to approve it, he added. One concern is that a generic without exactly the same ingredients may not confer the same long-term clinical benefit of Premarin, such as protection against osteoporosis and cardiovascular disease.

    ‘Although this finding does not prove that the DHES in Premarin has an important therapeutic effect, it underscores the lack of knowledge of the makeup of Premarin and the relative importance of its components, and therefore the lack of a standard on which to evaluate a generic copy,’ said Dr Woodcock. ‘A lot of information is needed before generic versions can make it to the market,’ she noted, adding that there are many other estrogen replacement products available which are approved for long-term use to prevent osteoporosis.” [12]

So where did that leave the generics?

They had several options, none of which was particularly inviting – they could appeal the decision, reformulate their products with delta 8,9 DHES and repeat the bioequivalence testing, conduct trials with Premarin to determine the active ingredients in it and attempt to replicate that, or perform large scale trials to demonstrate whether the long-term long clinical benefits were equivalent.

Unfortunately all of these possibilities were time-consuming, expensive and not without risk of falling short of expectations.

With the road to the generic competition of Premarin effectively blocked, both Duramed and Barr Laboratories chose to go down different pathways. Duramed decided to submit a New Drug Application (NDA) for Cenestin which precluded it as a generic of Premarin – it is not a conjugated estrogen by compendial standard and is specifically called ”synthetic conjugated estrogens-A”. [13]

Cenestin is a mixture of nine synthetically derived estrogen compounds manufactured from soy and yam sources and contains no delta 8,9 DHES.

Barr Laboratories opted to continue its search for a generic form of Premarin. In 2002 Barr announced that it had signed an agreement with Natural Biologics to develop an “AB” conjugated estrogens product using “equine-based” raw materials feeling confident that this would satisfy the requirements for FDA approval of a generic Premarin. Founded in 1993, Natural Biologics was the first company to produce equine-based bulk conjugated estrogens for use in generic product. [14]

Eventually on June 30, 2003, Barr filed an ANDA with the FDA for their version of a generic Premarin.

However this backfired when the U.S. Court of Appeals for the Eight Circuit upheld a lower court decision that Natural Biologics misappropriated trade secrets related to Wyeth’s chemical process for extracting estrogens used in Premarin. [15]

Subsequently Barr withdrew its application pending at the FDA for a generic version of Wyeth’s Premarin.

    “Under the lower court’s ruling, Natural Biologics and ‘anyone acting in concert with it’ are prohibited from using Natural Biologics’ misappropriated process for extracting bulk natural conjugated estrogens for any hormone replacement therapy drug and from further manufacture or sales of Natural Biologics’ bulk product.

    ‘Natural Biologics also must retrieve and destroy any bulk material produced to date, and can no longer engage in research and development of any natural conjugated estrogens product or transfer that knowledge to a third party,’ Wyeth said.” [16]

But the continuing Premarin generic saga fueled by Wyeth’s insatiable greed (now the equally corrupt Pfizer) doesn’t end here. In 2007 they were still fighting to cement their foothold on the HRT market in the US – and of course they won the battle.

    “A group of pharmaceutical wholesalers has lost an appeal brought against Wyeth-Ayerst Laboratories over claims the drug maker hiked up the price of its hormone medication while keeping its competitor out of the lucrative market.” [17]

The claim from competitor, Duramed and their HRT drug Cenestin that received approval from the FDA in 1999, not as a generic version of Premarin, but rather as alternative, was based on Wyeth’s increase in the cost of Premarin following an aggressive campaign by Wyeth to boost the sales of Premarin at the expense of Duramed – their rival in the market share of estrogen supplements for the relief of menopausal symptoms.

The ruse employed by Wyeth, intended to destroy the HRT market share held by Duramed, was sinister and was instigated 3 years prior to Cenestin’s market entry.

Wyeth lured the wholesalers with incentives of rebates for selectively purchasing Premarin over Cenestin – lucrative rebates that matched the rebate rewards to market share. This was termed the “Premarin Preemptive Plan”.

    “In one reimbursement agreement, Wyeth promised rebates only if Premarin’s share in the estrogen market did not fall below 81%.” [18]

Even more despicable were Wyeth’s blatant threats to these wholesalers.

    “Wyeth’s tactics also included warning wholesalers that while they would save money purchasing the lower-priced Cenestin, they would lose much more in rebates. The company demonstrated the effects using its ‘Cenestin Impact Model,’ instructing one wholesaler that it would save $100,000 buying its rival’s drug, but would lose almost $4 million in rebates if Cenestin’s national market share grew to 4%.” [19]

Despite the Machiavellian nature of these contemptible tactics, the only resolve available to Duramed was to demonstrate that while Wyeth was limiting sales of Cenestin via their questionable strategies, at the same time they were increasing the price of Premarin, hence guilty of monopolizing the market and in violation of antitrust laws under the Sherman Act. [20]

In the end it was not just a defeat for Duramed but also for anyone campaigning for the widespread availability of an effective alternative to equine hormones for the relief of menopausal symptoms.

    “Upholding the judgment, the appeals court said it could find no causal connection between Wyeth’s Premarin Preemptive Plan and an increase in the price of its drug.

    ‘That Wyeth recognized that its superior market position decreased the necessity of adjusting its own price does not demonstrate that its particular efforts against Cenestin prompted a price increase,’ the circuit judges ruled.” [21]

Yet another incident of the FDA, the government as a whole, and the law in bed with Big Pharma – nothing new here.

Brand name drug companies have all sorts of tricks up their sleeve, so to say, when it comes to intervening in national procedures for generic drug approvals as well as preventing entrance of generics to the marketplace when a drug falls off the patent cliff, often for years beyond patent expiration.

For every day the legal system delays approval of a lower-cost generic, a brand name pharmaceutical company collects millions more dollars in unlawful proceeds.

This is far more cost-effective than allowing the entrance of the generic to the market place – the legal fees pale in comparison to the revenue collected from the sales of patent-expired drugs that maintain market exclusivity.

This is nothing new – it has gone on for years.

Why? It’s simple – the U.S. government has failed to enact reforms.

However, in reality, it is not so simple. The FDA is failing at its stated mission – all at the expense of the consumer – from pocketbook to grave.

    “. . . . systematic, quantitative evidence that since the industry started making large contributions to the FDA for reviewing its drugs, as it makes large contributions to Congressmen who have promoted this substitution for publicly funded regulations, the FDA has sped up the review process with the result that drugs approved are significantly more likely to cause serious harm, hospitalizations, and deaths.” [22]

FDA Conflict of Interest Cartoon

The diabolical intentions of the pharmaceutical industry to increase market share and boost profits falls nothing short of criminal.

The failure of the U.S. government, particularly the FDA, to push for reforms continues.

To date, Big Pharma and its lobbyists have been largely successful in being able to maintain business as usual.

After all – it’s all about the bottom line.
____

[1] http://goo.gl/obDhLE
[2] http://goo.gl/4CKIHu
[3] See also at 1.
[4] See also at 2.
[5] See also at 2.
[6] http://www.sagepub.com/jowett5estudy/cases/77821_c2.pdf
[7] http://goo.gl/Shmgr3
[8] See also at 7.
[9] http://goo.gl/1HkRvt
[10] See also at 9.
[11] See also at 9.
[12] http://goo.gl/Q8CPVg
[13] http://goo.gl/oaLnjZ
[14] http://goo.gl/TXX5mx
[15] http://goo.gl/nwqe7G
[16] See also at 15.
[17] http://goo.gl/VFSgYO
[18] See also at 17.
[19] See also at 17.
[20] See also at 17.
[21] See also at 17.
[22] http://goo.gl/8RYyUC

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