The alleged duel-acting horse pee/bazedoxifene drug DUAVIVE—also known as DUAVEE in North America—has now made its way to the EU.
Its foundation drug Premarin, which alone and in combination, has been responsible for countless cancer deaths, has now crossed international boundaries.
How did this happen? Follow the trail.
Wyeth—gobbled up by, and now a Division of, pharmaceutical giant Pfizer—started working on Aprela in 1999 as a sister, or follow-up drug, to Premarin and its family of drugs that include Prempro and Premphase.
These drugs are produced with the estrogen rich urine of pregnant horses to treat the effects of menopause. The drugs also have osteoporosis treatment properties.
What’s the difference between Premarin and Aprela? A subtle one.
Pfizer began working with Ligand in 1991 as a research and development collaboration to develop better therapies for osteoporosis which eventually yielding the formulation of the drug Aprela.
Aprela is a single-pill formulation of conjugated [equine] estrogen and selective estrogen receptor modulator bazedoxifene.
Bazedoxifene is used instead of a progestin to help protect the uterine lining against hyperplasia that may result from estrogen alone treatment.
Wyeth had originally planned to file for FDA approval of Aprela in 2007, but the submission was repeatedly delayed. After the merger Pfizer eventually submitted Aprela on behalf of themselves and its partner Ligand to the FDA in 2012.
Aprela was finally approved under the name DUAVEE during the last U.S. federal government “shutdown”.
DUAVEE (conjugated [equine] estrogens/bazedoxifene), formerly known as APRELA, is a progesterone-free treatment for moderate-to-severe vasomotor symptoms (hot flashes) associated menopausal and the prevention of postmenopausal osteoporosis.
DUAVEE combines the selective estrogen receptor modulator (SERM) bazedoxifene with PREMARIN®.
In October, 2013, DUAVEE was approved by the U.S. FDA.
Additionally, in July 2012, Pfizer announced that the European Medicines Agency (EMA) accepted for review the Marketing Authorization Application (MAA) for bazedoxifene/conjugated estrogens. (see http://www.ligand.com/pfizer)
If you think DUAVEE is not as dangerous to patients as the Premarin family of drugs, look at this:
In the United States, Duavee is marketed with a black box warning. The warning points out that women taking Duavee should not take additional estrogens. The warning also notes that Duavee brings with it an increased risk for endometrial cancer in women with a uterus who use unopposed estrogens.
Also included in the black box warning is a reminder that estrogen therapy should not be used to prevent cardiovascular disease or dementia. In addition, the prescription insert warns that the Women’s Health Initiative estrogen-alone study reported an increased risk for stroke as well as an increased risk for deep vein thrombosis.
DUAVIVE is the European marketing name for DUAVEE.
Ligand issued a News Release that states:
Pfizer received EU marketing authorization for DUAVIVE® (conjugated estrogens/bazedoxifene (BZA/CE)) from the European Commission.
In the EU, DUAVIVE™ is indicated for the treatment of estrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate.
Ligand will be entitled to a milestone payment following Pfizer obtaining pricing of DUAVIVE® in a major European market.
The Ligand News Release also states in its Forward Looking Statements section:
This news release contains forward looking statements by Ligand that involve risks and uncertainties and reflect Ligand’s judgment as of the date of this release. Actual events or results may differ from Ligand’s expectations. For example, there can be no assurance that conjugated estrogens/bazedoxifene or any product in the Ligand pipelines will be successfully developed, that any of the milestone triggers will be achieved, that regulatory approvals will be granted, that acceptable pricing will be achieved in a timely manner, that patient and physician acceptance of these products will be achieved, that final results of human clinical trials will be consistent with any interim results, that final results will be supportive of regulatory approvals required to market products or that any revenue will be achieved from this partnered program. (see link above)
Jane Allin, Research Analyst for The Horse Fund, who has unparalleled specialist knowledge on this issue states:
In other words, take at your own risk. The Pfizer Ph-amily of carcinogens rules.
Don’t believe the FDA approval process or the EU’s. Don’t believe that this drug is safe and most of all, these are simply conjugated estrogens.
And what happened to the “equine” part of them? That they are made with pregnant mare’s urine?
In our opinion this clearly indicates that even more women are at risk to suffer and die. We know for certain from the decades long history of these drugs that the horses used to make them certainly will, and by numbers and in locations that will be close to impossible to discover.
Will the slick deceptive marketing ploy convince countries outside of the US to accept this as the panacea to age-related menopausal symptoms and osteoporosis?
Until now, 92% of the sales of the Pfizer/Wyeth Premarin family of drugs has been apportioned to the United States.
How convenient to market the synergistic effects of a known carcinogen and a risky SERM in a pretty little propaganda package that combats the woes of being female—both here and abroad.
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.” 
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. 
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. 
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. 
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. 
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” 
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. 
In response the FDA ruled unanimously that delta 8,9 DHES was an impurity and was not a required ingredient of any generic. 
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.
“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’ ”. 
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. 
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%. 
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. 
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.” 
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”. 
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. 
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. 
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.” 
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.” 
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%.” 
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%.” 
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. 
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.” 
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.” 
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.
And keep in mind not just a billion dollars, but a billion dollars or more year after year – this has been the profit margin of the Premarin® family of drugs since Pfizer‘s $68 billion acquisition of rival drug maker Wyeth in October 2009.
This collection of contemptible drugs was equally rewarding to Wyeth, one of the very reasons Pfizer lobbied for the takeover despite speculation — a takeover that was to be the biggest merger since AT&T and Bell South combined in a $70 billion deal in March 2006. 
Such a merger typically stifles competition and in this case furthers the power over the FDA and similar regulatory bodies. It is no secret that when it comes to NDAs (new drug approvals) and continued support of questionable medications that the FDA is intimidated by Big Pharma and bows to its demands due to financial incentives -– one need only look at the new combination osteo-menopausal therapy DUAVEE®.
More on that later.
Appalling? Certainly, but this is Big Pharma clout which, by nature, instructs the actions of FDA management and their minions.
“FDA’s own scientists report pattern of intimidation, censorship and scientific fraud that undermines public safety.
In a truly astonishing survey just released by the Union of Concerned Scientists, the Food and Drug Administration’s own scientists describe the agency as an environment of intimidation, censorship and scientific fraud. A survey of 997 FDA scientists revealed that forty percent feared “retaliation” for voicing safety concerns over prescription drugs in public. Over one-third of the scientists didn’t even feel safe expressing safety concerns inside the agency, behind closed doors!
Intimidation and censorship have been well documented at the FDA, and this survey adds further weight to the evidence that the FDA has been utterly co-opted by the pharmaceutical industry and now serves Big Pharma’s commercial interests rather than anything resembling a commitment to honest science or public safety.” 
If this isn’t sobering enough think about the enormity of its effect on our day-to-day lives and the pill-pushing nation we live in.
Not only is it astounding that year after year Pfizer continues to successfully market and sell these HRT drugs despite their carcinogenic toxicity but even more so the fact that over 90% of the sales take place in the United States.
It is disheartening to think of how many women with access to proven evidence of the damage these drugs are capable of still buying into the propaganda doled out by their physician’s undying loyalty to Big Pharma.
Even more daunting is the realization that there exists an untapped market on the international level ready to be infiltrated by this drug Behemoth’s drive to peddle its deadly wares using deceitful marketing strategies and bribery.
And that untapped market is huge. According to a Bloomberg article “Drug Sales in Emerging Markets to Match US by 2016:
“China, India, Brazil, Russia are among 16 emerging markets that will make up almost one-third of global drug spending within four years, as newly wealthy people and nations spend more on health care, a report shows . . . .China is leading the growth in these markets.” 
No doubt this will have an impact on sales of the Premarin® family of drugs.
But I digress.
Getting back to the reason for this particular report, just how many mares are out there on the pee lines?
The gradual downsizing of the PMU ranches began shortly after the WHI results were released and now stand at approximately 22 farms after the shuttering of a farm in North Dakota in early 2012.
NAERIC (North American Equine Ranching Information Council), the non-profit association of equine ranchers engaged in horse production and management of pregnant mares here in North America claims there are approximately 2,000 broodmares involved in the equine ranching industry.  A far cry from 2002 and 2003 where there were as many as 300 PMU farms housing upwards of 50,000 or more mares churning out gallon upon gallon of estrogen-rich urine. 
While it is true that immediately following the release of the WHI study, citing the horrors associated with CEE-derived HRT, there was a precipitous drop in sales of Premarin® and Prempro®, much of that market was reclaimed in time via reduced dosage recommendations, aggressive marketing strategies, price increases and the wide availability of these drugs without prescriptions through Internet sales. This is clearly reflected in the continuing profits awarded Pfizer year after year.
Moreover it is common knowledge these days that there is a thriving PMU industry in China and possibly other foreign countries of the world.
This was revealed by The Horse Fund (working as the Int’l Fund for Horses) in March of 2012 wherein according to information procured from an inside source from a company manufacturing conjugated equine estrogens PMU farms had been in operation in Northern China for the last 8 years, now approximately 10 years.
The following May of 2012 a video entitled “Horse urine a profitable industry” aired on BONTVchina which made its way to North America late last year confirming their existence. 
While we are aware of the roughly 2,000 mares here in North America it would be interesting to have an indication of the total number of mares required to provide the amount of conjugated equine estrogens (CEEs) for the manufacture of this vile family of carcinogens.
There are several variables required to calculate this number:
Concentration of CEEs in pregnant mares urine
Change in concentration of CEEs over the collection period
Average daily urine output
Profits made per annum from the Premarin family of drugs
Average cost of a dose of CEEs
Average dose of CEEs in the HRT products
There is little transparency in the pharmaceutical industry and facts are hard to come by. Accordingly this assessment was a labor of desire in pursuit of answers which are not forthcoming from the PMU or pharmaceutical industry. Answers which are tenuous and may never be confirmed or denied given the tenacity of Big Pharma and its deceptive character.
Of the list of required information perhaps the most difficult to locate was the concentration of CEEs in pregnant mare’s urine. As much as the Internet provides a wealth of data on many subjects there was little in the way of isolating these concentrations in easy to interpret format. In many cases, specifically those from non-scientific articles and websites, the numbers were ridiculously impractical. Therefore why not go to the source?