Some of the frauds at the heart of EPO's rise to becoming America's most popular drug
Title: Blood Medicine - Blowing The Whistle On One Of The Deadliest Prescription Drugs Ever
Author: Kathleen Sharp
Publisher: Plume (originally published by Dutton as Blood Feud)
Year: 2011
Pages: 440
Order: Penguin
What it is: A story about some of the frauds at the heart of EPO's rise to becoming America's most popular prescription drug
Strengths: Sharp takes a complex story and explains it clearly,focusing the story on one of those who blew the whistle on EPO
Weaknesses: Personalising it - making it about the whistle-blower as much as the crimes he blew the whistle on - is a gamble
Puerto and Freiburg shed no light on the matter. USADA and CIRC, they didn't tell us. We simply don't know. We know it happened. We just don't know the how and the when and the who was involved. Maybe we will never know - or not know for many years to come yet - for to discuss it would require discussion of what came before and there are too many invested in the myths of that generation to allow a light to be shone in it. The arrival of EPO in the professional peloton, it remains cycling's great terra incognita.
Even the things we think we know about EPO's arrival, we don't really know. Take the bodies that piled up on mortuary slabs, the young of Gen-EPO sacrificed so that the rest could have a better understanding of how to use the drug. In The Invention of a ‘Drug of Mass Destruction': Deconstructing the EPO Myth Bernard López correctly points to the many inconsistencies in this story, likening the much-repeated claim that 18 (or more) Dutch and Belgian (and other) cyclists died from EPO to the way the deaths of Arthur Linton and Knud Enemark Jensen were hijacked by the anti-doping community in order to further their argument, with scant regard to the truth.
We will never know if EPO killed any of the cyclists whose deaths have been attributed to it, men like Bert Oosterbosch (retired, TVM his last team), Joachim Halupczok (Del Tongo), Patrice Bar (IOC-Tulip), Johannes Draaijer (PDM). We know that these people died, we don't know that they died because of EPO. We can't know. We can only believe or not believe. Some - Michele Ferrari among them - have made the argument that EPO is not dangerous, it is no more likely to kill you than a glass of orange juice will, and so we should not believe.
But we can say that EPO killed, that EPO is a dangerous drug. Kathleen Sharp's Blood Medicine explains just how dangerous, and how - even in its regulated use - it has been linked to countless deaths among those for whom it was prescribed.
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Blood Medicine is not a sports doping book, sport in general and cycling in particular feature only in passing. What it is is a big pharma book, a David and Goliath story of a whistle-blower standing up to a corporate giant. Think films like Michael Mann's The Insider or Steven Soderbergh's The Informant and you'd be in the right ballpark. It's a corporate drama, not a sporting one.
At the heart of Blood Medicine there are two stories. The first is one of corporate rivalry, the second deals with the regulatory world in which EPO exists. They both begin with the creation of Applied Molecular Genetics in 1980 with $200,000 seed capital. Amgen had among its list of goals the creation of synthetic EPO (this at a time when insulin was the only other genetically engineered drug on the market). In 1981 Amgen raised $19.4 million in venture capital and hired staff to work on the EPO project, and others. In 1983, the company made a bit of a breakthrough in its quest to synthesize EPO and off the back of that was able to raise another $42 million, through an IPO in June of that year. In late 1984, Amgen filed a patent for the production of recombinant EPO (which was granted in 1987). But the company was still a long - and expensive - way away from getting the drug to market, ahead lay the FDA's complicated drug approval process.
With most of the IPO money spent, Amgen needed to raise cash, and quickly. The Japanese and Chinese rights to EPO were sold to the Kirin Brewery for $24 million in 1984. That didn't take long to spend, most of it being invested in a production facility (production commenced in 1987). So the following year Amgen hawked some more of the family silver: the European rights to EPO were sold to Johnson & Johnson, along with the US rights for the treatment of non-dialysis anaemia (leaving Amgen the dialysis market). Finally, in June 1989, FDA approval for Amgen's Epogen was granted, trials of the drug having commenced in 1985 (Japan and Seattle) and 1986 (London), with other trials following. Sales commenced immediately regulatory approval was granted. Eighteen months later the FDA approved Johnson & Johnson's version of EPO, Procrit, for use with HIV patients suffering from anaemia (Johnson & Johnson sold EPO in Europe under the brand name Eprex).
"Like a lot of couplings, the one between Amgen and J&J had seemed like a good idea at the time in September 1985, the PLA [product licence agreement] joined the cutting-edge bioscience of a West Coast boutique to the marketing brawn of a venerable East Coast pharmaceutical. Similar deals between biotech firms and drug companies would follow, but none quite like this one, occurring at the dawn of the biotech era when everything was untainted by cautionary precedents. Many a petri dish had been wasted searching for low-hanging fruit, and EPO was one of the few proteins that had a clear therapeutic use. The PLA had been so exceptional that analysts had called it 'the deal of the century'. But its most extraordinary element was that J&J had paid some $6 million for the rights to sell the drug everywhere in the world - except Japan and China - for all indications other than dialysis. That was a steal, and for a ridiculously low price plus royalties, J&J received access to all of the non-dialysis markets in the United States that it could develop. This would prove to be an important distinction. As for Amgen, it got a quick cash infusion, allowing it to report $548,000 in fiscal 1985, its first annual profit."
Amgen's top brass, they thought they had the better end of the deal: they figured the dialysis market - two to three hundred thousand patients - was worth $100 million dollars a year in sales. Then they valued it at $350 million dollars a year in sales. Then they began to realise what it was they'd actually given away to J&J. EPO could be used to treat "AIDS, haemophilia, cancer, maybe even depression." Amgen quickly turned on J&J, first by delaying the FDA approval process for J&J's version of Epogen, Procrit (hence the eighteen month gap between approval of Epogen and approval of Procrit). Then, with Epogen on the market first, Amgen began to lock up potential Procrit clients, signing them to long-term contracts for Epogen. The product licence agreement was supposed to have a mechanism for dealing with this - a certain amount of 'spillover sales' was anticipated from the get go - but in practice that never worked . So J&J struck back: they started to sign up clients who technically belonged to Amgen.
A fight between two big pharma companies, it's the sort of thing you sit on the sidelines watching hoping both will lose. But that is just one part of the EPO story, perhaps even the most innocent part. There was a lot, lot worse going on. Such as the financial incentives offered to doctors, from free product through research grants, the rules for which were routinely ignored. Bigger than that, though, was the insurance fraud.
Typically, the tab for a patient's EPO use is picked up by their insurance provider. A doctor bills the provider, the provider pays. Things get fun when it comes to the amount the insurer pays. The drug companies set prices for their drugs which the insurance companies accept. This is the AWP figure, the average wholesale price. Also known as ain't what's paid. Almost anyone buying the drug would get a discount, pay less than the AWP. A $250,000 order might earn an eight percent discount, $500,000 nine percent. $1.4 million could get fourteen percent. Imagine the scenario. The drug company tells the insurer that the product costs $1,000. The medics buy it at a twenty percent discount, paying $800. But they bill the insurance company for $1,000. That's a $200 profit: doctors were actually making money using these drugs, and the more of them they used, the more money they made.
Ripping off an insurance company, there's a lot of people think that's fair. That it only drives up the premium they pay gets lost. Also lost is the fact that when the insurer is the state - Medicare - that money is coming out of their own pockets, in taxes. But there was an even bigger problem with the way in which EPO was being sold. And that was the the off-label use of the drug. "Under the law, a doctor can prescribe a drug for nearly anything," Sharp writes, "but a company can promote products only for FDA-approved uses." So, for instance, a doctor, using his own initiative, could decide to use Procrit to treat a cancer patient, but J&J could not encourage that doctor to do so. Except, of course, that's exactly what they did.
All of that, though, is nothing compared to the pachyderm in the pantry here: the safety of EPO. The dangers of EPO were not something that initially concerned the FDA when they approved the use of Epogen and Procrit.
"Amgen and J&J were supposed to answer those questions in large, post-approval safety trials, according to Dr Patricia Keegan, MD, then a member at the FDA's biologic division. Manufacturers with products that purport to cure a disease usually submit safety trials before a drug is approved. But EPO was a palliative drug that didn't actually cure a disease; it simply treated the symptoms of a disease. Since FDA approval standards for palliative drugs were more relaxed than for curative drugs, regulators weren't as strict about EPO's trials. 'They [the firms] didn't come in with safety studies at the time of their [drugs'] approval,' said Keegan. 'But they were asked to conduct those studies,' first in 1989, when Epogen was approved, and again in 1991, when Procrit arrived. By late 1992, those studies were still under way."
A decade later, those studies were still underway and the FDA could do very little about it. The regulatory market had changed and - as in the banking industry - there was a soft hand on the tiller. A tougher hand might have done something, especially as the evidence of EPO's danger mounted.
"An independent study published in the October 2003 issue of the British medical journal the Lancet had tested European patients in a well-defined scientific trial. The ENHANCE Study had all the right components and was a randomized, double-blind, placebo-controlled trial of 351 head and neck cancer patients receiving radiation therapy. The researchers had expected that patients who had received the drug before radiation treatments would fare better than the control group who skipped injections. Some oncologists hoped EPO might even help study patients live longer, which would have been a boon for patients and drug-makers alike. But to everyone's shock, the EPO group fared much worse; they were 69 percent more likely to die."
And that was just one study. Others were also pointing to the dangers of EPO. A 2006 study published in The New England Journal of Medicine showed that patients given more than the recommended FDA dose had a 34 percent greater incidence of deaths and heart attacks.
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All of this - the feud with Amgen, the insurance fraud, the off-label sales, the drug's dangers - is revealed in Blood Medicine through the story of Mark Duxbury, a Procrit salesman who got canned by Johnson & Johnson and then went on to launch a qui tam case. Sharp's telling of Duxbury's story is thorough, based on interviews and backed up by detailed research. It gives Blood Medicine a heart and a soul, humanises the story. It's not just about big pharma and big government, it's about the little guy too, and it's the little guy who ultimately paid the price for EPO.
Grounding Blood Medicine in Duxbury's story does, though, make it personal and he himself is not necessarily the most sympathetic character in the book. It also leaves Blood Medicine with an unsatisfying ending, Duxbury's qui tam case unresolved by the time the book ends. Despite these complaints, Blood Medicine is a highly readable take-down of the pharmaceutical industry.
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For all that Blood Medicine tells us about the way in which Amgen and Johnson & Johnson marketed and sold their EPO products, for cycling fans in particular - you, reading this - the real story is in the race to produce synthetic EPO, for somewhere during that time it was realised that this wonder drug would have sporting applications. By the time the Calgary Winter Olympics came around in 1988 EPO was already being talked about as being capable of doing all that blood transfusions could do, and more. Those few years before and after Calgary, when EPO went from something being searched for to something being widely used in the sporting world, for us, that is the real story. And that story remains untold.