Last month I read Tyler Hamilton’s “The Secret Race” and chased it with the USADA Reasoned Decision. There are many references to EPO, the blood boosting hormone that riders inject. So many that it takes on a variety of nicknames, that the method of injection is explained – both subcutaneous or intravenous – and consideration is given to the storage, whether the domestic refrigerator or a thermos flask for portable access. Even the means of hiding it are explained, from making your team mate store the stash to hiding the vials behind the vegetables in the kitchen refrigerator.
But if it was so widely used it’s rarely stated that injecting EPO is bad for your health. From blood clots to cancer the use of this drug comes with risks when administered under normal conditions. When abused by athletes, nobody knows what the risks are and that’s before we get to the mafia and its role distributing this drug.
First a quick explainer. You probably know it but EPO is short for erythropoietin, a hormone that controls red blood cell production. The red blood cells carry oxygen. So in simple terms taking EPO increases red blood cell production and consequently for an aerobic sport like cycling the ability to take more oxygen to your muscles during competition is a big advantage. EPO is produced naturally but Eugene Goldwasser and others eventually managed to synthesise it.
The drug has been a block-bluster for the companies that developed it, doping the sales of Amgen and Johnson & Johnson although in recent years it’s become a liability because of exposed practices of these pharmaceutical firms but also because of the molecule itself.
After being promoted as a wonder drug at first wider use and statistical analysis began to show it came with risks and by 2007 the US Food and Drug Administration, the national pharmaceutical regulator and by extension a worldwide watchdog, put a “black box warning” on the product, an official warning that’s similar to the black and white text found on cigarette packets in many parts of the world. In very simple terms using EPO can increase the chance of cancer by stimulating malignant cells meaning if it’s used by cancer patients to help recover from treatment it needs to be used responsibly.
But medics weren’t always so cautious. In the 1990s EPO became more and more promoted as this TV advert shows, ending with the man saying “I got two speeds, fast and faster“:
A recent feature on cyclingnews by Kathleen Sharp* tells how dosages for the medicine were set by regulators – after obvious lobbying – at maximum of 7,500 units:
…Amgen pushed for a higher dose of 7,500 units, said Dr. Joseph Fratantoni, an FDA official who took part in the discussions. “They won the day,” he added. In time, the drug’s label would list a starting dose of 10,000… …Compare that with the 2-3,000 units used every few days by cyclists in the 1990s
At first glance the comparison sounds OK. Our racing cyclists were taking small doses compared to the approved amounts, right? Only the approved amounts were recommended for people with kidney problems or on chemotherapy or another condition where medicine was needed to recover. In other words 7,500 units was for a sick patient, perhaps somebody with a haematocrit of 30% or less. By contrast the cyclist who had healthy blood and started injecting EPO was taking a leap into the dark. Literally in some cases as early tales said some Dutch and Belgian riders started to use EPO fell asleep and never woke up, suffering a stroke or brain haemorrhage in their sleep but this was never proven.
In time the dangers were learned in cycling. As well as a portable centrifuge to measure their blood count, the typical pro cyclist in 1990s also invested in another vital piece of medical equipment: an alarm clock. Riders had to wake up in the night to start exercising and get the blood flowing in case their ketchup-like blood began to clot and kill them in their sleep. And so it came that riders were going to bed with three or four travel alarm clocks ticking away on the bedside table, two to wake up at night plus a back-up in case the battery went in one during the middle of the night, plus a normal one to get up in the morning. In motels in France and Italy cyclists would rise at 3.00 am to suddenly start doing press-ups or ride their noisy indoor bikes.
These nocturnal habits were not limited to a few sneaky cheats. Sales of EPO soared in Europe. Italy’s Sandro Donati reported:
between 1997 and 2000 the amount of the blood-booster erythropoietin (EPO) sold in Italy doubled even though the number of prescribed kidney patients, for whom the drug was originally developed, remained roughly the same
Donati went on to claim that sales of EPO exceeded clinical needs by a multiple of six. In other words for every vial of EPO going to a sick patient up to six were going to people for doping. Donati’s ratio is an estimation, it’s probably – surely, hopefully – not so high? It’s hard to know the precise multiple. As Kathleen Sharp has shown sales galloped ahead by other means but it is clear that a significant amount of consumption went to healthy athletes and not sick patients.
One reason why it’s hard to track the illicit use has been because the simplicity of buying it. If it was not promoted on TV, EPO has been easy to get. The sale in Italy required a prescription but that’s 20 seconds for a corrupt sports doctor on commission. Besides over the border in Switzerland anyone could walk into a pharmacy and ask for some vials of EPO, pay and leave with the goods. In time people were moving house to stay near ready sources and teams were hiring backroom staff thanks to their ability procure EPO at good prices. It wasn’t just cycling, the Juventus team doctor was prosecuted and other sports were caught too, from athletics to skiing and remember that track and field sprinters were using it, even horses too.
But Donati’s main claim was that much of the sale was being controlled by organised crime. In Italy sales of EPO correlate suspiciously well with the most infamous regions of the country. Normally EPO scored low for sales in most regions, for example 11th in
Lombardy, 30th in Veneto and the 90th best-selling pharmaceutical in Valle d’Aosta. But it was the numero uno product in Campania, second in Basilicata and Sicily, and third in Apulia and Calabria and coincidentally each of the regions is home to a powerful mafia group. But before we get carried away a paper claimed this was due to more legitimate reasons. But both hypotheses are probable.
Crime is no speculation. Police work in Italy did catch several gangs stealing and selling doping products including EPO. Some cases were not solved, for example the raid in 1999 of a pharmaceutical warehouse in Cyprus saw more than 4.5 million vials stolen, an act of very organised crime given the need for careful handling and a refrigerated get-away vehicle, and this just to seize the product, yet alone handle the sales channels. Over in the US authorities were struggling with counterfeit products coming from places like China, Thailand and Russia. EPO isn’t just bad for an athlete or a sport but society too.
All this is before we get to the unreported effects. If the FDA and others were reviewing the health risks for chemo and dialysis patients obviously nobody was looking into the health of pro cyclists. Even team doctors busy administering EPO were unlikely to consider the risks involved. But there’s more here because EPO might have an effect on the brain chemistry too. Anecdotally riders have talked of depression surrounding the (ab)use of EPO and when they stop using it but clinical trials also link to anti-depression too.
If EPO went from experimental to banal in clinical terms, this happened in sport too. When test finally appeared moves to control its abuse in sport implicitly encouraged alternatives. Just as EPO has been a wonder drug it because it helps produce new red blood cells the real jackpot comes in a product to replace human blood or at least red blood cells, or if not then just haemoglobin, the oxygen-carrying protein. Banked supplies don’t last too long as your hospital manager or Riccardo Riccò will tell you. A chemical substitute has been a big goal for many companies.
One company that came close was Biopure with its products Hemopure and Oxyglobin, for human and veterinary use respectively. Only Biopure could never get full international approval and the company was liquidated. But this didn’t stop the product attracting attention, with Hemopure being linked to disgraced Dane Michael Rasmussen and the animal version, Oxyglobin, going to Jesus Manzano.
Similarly other EPO-like products were produced but have been dogged by patent claims, for example Mircera for which the manufacturer Roche co-operated with WADA to help ensure a test was readily available, leading to several cyclists being caught in the 2008 Tour de France.
“Got some Poe I can borrow?” The abuse of this product by cyclists is well known to the point where it took on coded “street” names.
Over time the risks of the drugs have become known, whether from clinical trials or tales of cyclists who never wake up in the morning. These days the product comes with explicit health warnings on the box, something you suspect a dodgy doctor doesn’t tell an athlete.
Sales of EPO flourished thanks to the clinical needs of many patients but also, as Kathleen Sharp has shown, thanks to soft prescriptions and aggressive sales techniques. In time other versions appeared and the patent lawsuits followed. But questionable sales techniques almost look small alongside the claims that the legitimate use of the drugs has been dwarfed by illicit use of the product, namely for doping athletes. It’s hard to quantify as sales channels don’t specify the end use. And when the drug proves hard to source we see the involvement of crime syndicates providing a service that the free-market cannot.
The drive to produce these blockbuster drugs and wonder molecules has provided many patients with health and hope and rewarded investors along the way. These days EPO is proving a liability for its makers too as lawsuits and settlements replace prescriptions and profits but Amgen’s stock price is close to an all-time high and it is produced by others. To this day it is being abused, see David George.
Looking ahead and the hunt for synthetic blood continues in research labs and clinical trials and any advances in science will sadly show up in sport too.
- * I’d been sitting on a draft of this piece but the recent feature on cyclingnews.com was a good motivation to finish it and the information on dosages was useful to this.
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Interesting article. Information of this sort should have been included in the Hamilton/Coyle book.
I think that was more Hamilton’s tale. He recounts how he gets the EPO from team mates or the doctors but it’s not said where they get it from. Presumably from “friendly” pharmacies and writing phoney prescriptions.
Am I alone in thinking how ironic it was that Amgen sponsor the Tour of California?
I’m not sure if it’s ironic. They might have made money out of cycling. But cycling has been used to market EPO before:
No you’re not alone. It seemed downright weird.
Edgar Allen POE..
Another good read. I guess the question is if/when pharma execs knew so much income came from sports doping?
That’s a very good question. Even if we ignored the 1 clinical : 6 doping ratio and said, say, 6% of sales were going to athletes then that’s still significant. But will a company say it knew a proportion of its production was going to unapproved uses? I doubt it.
I’ve spent many years marketing pharmaceutical products in the US and thought I would shed some light on this…
To answer your question, absolutely, companies know how much revenue is coming from unapproved uses. In the US, we call this “off label” use. Though drugs are clinically tested and “indicated” for specific diseases, doctors are allowed the discretion to prescribe drugs for whatever they want (ie. off label use), and this is done very frequently (for example, a lot of anti-depressants are prescribed as a sleep aide, to help sexual libido, with pain management, etc…). The major challenge for pharmaceutical companies however, is that they can’t promote (advertise, recommend, suggest, or even necessarily acknowledge that they know of) off label use because there are harsh penalties from the FDA for companies that are found guilty of this.
It’s an interesting side of the industry. Some drugs derive 50-60% of their revenue from off label use (most for very legitimate reasons), even though, technically, they shouldn’t. Companies can’t promote or condone this, but you can sure bet they like that it’s happening.
Good compilation, seriously nice to read. Especially the 1:6 ratio in Italy is breathtaking.
However I have one objection: I know it from my very own family that anemia is a side effect of chemotherapy / cancer treatment. The Procrit commercial you’ve posted refers exactly to this situation and is surely not a promotion for a new “life-style/feel healthy” drug.
Keep up the good work.
Thanks and on your objection, I didn’t quite mean it was for lifestyle but the ad is directed so people ask their medic for the product, it was more to show how mainstream it had become.
i would imagine that italy, like the US, has “off label” use of EPO. by that, i don’t mean use for sport doping but rather actual clinical use for patients other than “kidney” patients.
not sure from this if the 1:6 includes only “kidney” patients (i.e. approved indications) which would tend to skew the numbers, or if it’s all legitimate clinical use.
the doubling of use from 1997 to 2000 more than likely contains a fair amount of increase due to very effective marketing campaigns by pharma.
would be interesting to tease out those numbers and get a bit more granularity.
Interesting to read about the manufacturer of CERA cooperating with WADA to get those effective tests in place in 2008. I sincerely hope this type of partnership at the cutting edge of doping is something that has been developed in the years since to keep the tests up there in the arms race?
If a company stands to gain plenty in sales will it provide WADA with the means to help reduce these sales? I’d like to hope the answer is yes but if Donati is right (big IF) then the incentives say otherwise, no?
Absolutely, which is why I was so surprised to read about that particular co-operation that lead to the positive CERA tests in 2008. I’m hoping there is more of this partnership work since that time, even though I concede that money will talk (and drown out the morals) in the majority of cases.
It leaves me wondering why the CERA manufacturer co-operated in that instance – any lessons to be learned from that exceotional (?) example that may encourage others to do likewise in working with WADA.
The WADA has their ‘2 fields 1 goal’ program to develop better links between members of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) and anti-doping agencies. And there is a big conference in Paris next week: http://playtrue.wada-ama.org/news/wada-confirms-agenda-for-pharmaceutical-conference/
So we’re likely to see some Press Releases from the WADA next week.
It’s a good step in the right direction but it remains to be seen whether it is a PR exercise on the part of the big pharma companies and if start-up pharma companies (which Amgen was when it developed Epogen) will ever choose to be involved. Amgen are being sued for $780 million for their mis-selling but as Kathleen Sharp says they were making $2billion a year in 1993. The math is simple (sadly).
Thanks for the info, will eagerly anticipate some updates in the near future, hopefully.
BigPharmas should be co-responsible in the process every time a group of athletes are caught using their drugs illegally. Or, in order to safeguard their products, they should work hand in hand with the antidoping agencies as soon as it gets clear that the drug in question has the potential to be used as a performance enhancing drug.
Just a thought. But you guys got here first 🙂
@Inrng theoretically, using warnings and photos of dying people on cigarette packs should reduce sales, nonetheless companies are obliged to do so.
the 6:1 ratio is just a description of the surplus over the legitimate market. Much of that probably expired or was destroyed without finding a buyer. Abuse for performance enhancement is only one explanation of where the extra might have gone. It sounds like manufacturing was cheap (the costs are all in research) and the opportunity cost of a shortage outweighed the over-expenditure of creating a surplus. This may have made it easier for athletes to come by the drug but I have a hard time believing there are enough reckless yet well-funded athletes in Italy to create that kind of demand.
The Cyprus theft caper tells a lot. 4.5 million doses just vanished. What were they doing on the tiny island to start with? No shortage of the drug was reported after this massive theft. The people who make this stuff know damn well a huge portion of it is being used for sports doping, but they don’t care. When it comes to Big Pharma, greed seems to come before pretty much everything else, certainly before clean sport!
I’ve read the Donati Report and I think he made an incredibly stupid error. It looks like he (and other news organizations) confused units of EPO with vials of EPO. Vials of EPO are packaged in vials of 20,000 units each (see the picture above). 4.5 million units of EPO is equivalent to about 225 vials.
Look at the following news article from a US newspaper archive.
That article states that the loss was about 26% of the available stock on Cyprus. There is absolutely no way that Cyprus had 18 million vials of EPO. That’s likely several years of production by Amgen and would be worth billions of dollars.
There was a similar theft in Australia prior to the Sydney Olympics. 1000 vials went missing, worth millions of dollars. This news made a much bigger impact and articles on this theft are easy to find, unlike articles on the Cyprus theft. The likely reason is that the Australian theft was more than four times as large, instead of less than one thousanth.
The unfortunate thing is Donati carried this mistake through his whole report, greatly overestimating the amount of EPO diverted from legitimate medical use to the black market. I am astonished that no one fact-checked or peer-reviewed this report, as is acknowledged on its front page. I agree that doping likely involves organized crime but badly researched reports like this do more to hinder the fight against doping than help it.
Thanks, that explains a lot. Cyprus could be a special distribution point for Europe or even the Middle-East but it would be an odd choice given its lack of transport connections.
Even horses were using EPO! I have never trusted those cheating scumbags.
Interesting article, you could almost write a book on this stuff – it does feel like we are looking in a rearview mirror all the time but I wonder what the latest “EPO” is that we won’t find out about until 2020. Maybe we should just ask the pharma boys what are the hot sellers ! (leaving aside, Mr George who hadn’t read the doping instructions carefully enough and failed the IQ test) .
Thanks for the post. Really fascinating stuff. I remember watching that commercial and having no idea it is the same drug that athletes misuse to dope. Need to read Kathleen Sharp’s book too. This story is so much deeper than the latest cycling scandal.
try looking at the academic publications, Lopez Lopez piece is worth a read and you can find many references in his footnotes
Nice piece, but from my discussions with doctors specializing in treating patients with kidney problems, EPO is a very safe and effective drug when administered properly and actually has very few serious potential side effects. A new form can be taken intramuscular just once a month. Like other forms of prohibitions of drug use, the real danger is use without proper medical assistance and the black market which arises in such circumstances. I would lift the ban and encourage athletes to get good medical help which will at least be safer than the ad hoc use of a great drug which has helped many sick people and which has given our sport some of the greatest performances ever in history. As long as it’s safe and effective, officials (government or otherwise) have no business interfering.
Hi Neil – in your scenario of legalising ‘a great drug’ what happens to those athletes that do not wish to take it? Should they just be resigned to the fact that they will never be able to compete with those that use EPO?
Did your doctors comment on sustained use over a long period, for example, a cycling career? I cannot believe that is good for you?
There’s nothing wrong with the drug – just the people who make it.
Ignorant response – the problem with the drug is the people taking who have not reason to (medically)…. not the “people/industry” that have researched and developed medicines for patients with live threatening diseases.
Read the Kathleen Sharp book and you would change your tune. Amgen didn’t even do the research. Like many of the recent developments it was all funded by the US tax payer and then sold at a discount rate to a commercial enterprise.
The people who’d prefer to be able to compete in sports without having to retain medical doctors and/or become proficient in medical methods, and amateur experts in fields like haematology have a right to form their own associations dedicated to “sport sans medicine”. Guess what, they’re called things like “IOC” and “WADA”, and many other sports bodies are affiliated with them.
The people who are cool with being medical guinea pigs, they can go form their own “dope as much you like” associations. And guess what, they effectively exist. There are body-building, baseball, triathlon, and bicycle competition organisers who don’t do dope testing and hence effectively tacitly allow doping in their sport. T
The dopers are perfectly free to go join those doping-tolerant sports. They are not free to join the “sports sans medicine” sports and expect any mercy or tolerance when caught.
Neil – I have to say that’s an extraordinary comment. “As long as it’s safe and effective, officials (government or otherwise) have no business interfering.”
What about amateur cycling (who won’t have “proper medical assistance”)? Or teams who want to save a few dollars? I’d argue that it could never be wholly “safe”.
What about the fact that not everyone will respond equally to the PED? Or that not every will *want* to take it? That wouldn’t be my idea of “effective”.
@inrng – first comment here, and I’m a new reader of a few months now. Thank you for what you do.
Safe and effective is the standard at the FDA for all drugs. As long as a doctor prescribes it and the athlete is informed of the benefits and risks, I don’t see why anyone has a right to interfere. It should be the athlete’s decision. There are lots of things some people can’t afford to compete on an equal basis, like the fanciest best bikes, nutritionists, doctors, buses, soigneurs, etc. That’s just life and life’s not fair.
Life’s not fair but the sport has agreed rules and every participant signs up to them… or they can go and create their own federation, sport and rules.
Well if the rule is clearly not working, and who could contest that, why not do away with it? Leave it up to the individual athletes.
To reply to your point below, because if you allow athletes to take X units of EPO, in no time someone will be taking 2X and another 3X and before we know it, they’re dead in their sleep.
I’m all for safe and effective drugs for those who are suffering or seriously ill but making the leap, in the next breath, to enhancing sports performance is, for me, wrong on so many levels. I would point you towards an excellent summary of the most pertinent points from a blog on this very site just a few weeks ago https://inrng.com/2012/10/level-playing-field-doping-myth/
The legit pharma companies may not be making vast profits from sporting/cheating use of EPO, I would guess that a lot of the EPO used for that is from even less reputable sources.
that Amgen poster is classic! Great post once again.
I think everyone who thinks athletes were making up such a big % of Amgen’s profits should think about the math. What are we talking about – maybe 1,000 endurance athletes max were using it? But in lower doses and not all the time (no off-seasons, only certain races). Versus probably hundreds of thousands of kidney and cancer patients with anemia who need the drug daily and at higher doses. I’m sure there were more off label uses for EPO other than athletes that would have been a greater impact. Happens with all new drugs because the manufacturers only get approval for the one use, but the drugs often have broader applications.
1,000 max? It’s been used by pros and amateur cyclists alike, so I’d say over 1,000 road cyclists in Italy alone is normal. We had most pros and many top amateur teams were on programmes and it went quite far down into gran fondo riders and local racers. That’s before we do other countries and sports.
But yes, let’s take caution with the 1:6 ratio. Like I say above, even if it was 6% of sales it’s still a significant boost.
And this – boosts the numbers a bit (note the reference to other runners telling him..)
Interesting read. But, just wondering if there were “other” clinical oxygen drugs made only available to someone like Lance as part of trial testing. It seems that Tyler, Landis and others using EPO never really measured up to Lance’s superhuman level. Lance had the connections to the pharmacons (he publicly stated he told the hospitals and doctors to use the most aggressive means to combat his cancer) and so I’m wondering if there is more to the story of Lance doping and why he wants to protect his relationships with these companies.
Maybe not so relevant to the current posting, but some interesting information about rhEPO compared to endogenous EPO. The difference is in the glycosylation pattern of the glycoprotein (the amino acid sequence is identical). The current “direct” EPO test is based on this difference. Worryingly, there is no reason to rule out the existence of a synthetic EPO variant with a glycosylation pattern that will not be differentiable from the natural version.
With traditional biotechnical methods for EPO preparation, this cannot be done yet as far as I know. But recently Danishefsky and coworkers have published an article on chemical synthesis of EPO glycoforms, implying unprecedented tunability. (http://onlinelibrary.wiley.com/doi/10.1002/anie.201206090/abstract)
Right now it is probably to expensive to produce these types of EPO variants, but this might change. From BALCO we know that “designer” pharmaceuticals are used by athletes if it can give them an edge.
Undetectable EPO would be quite interesting in combination with blood manipulation to modulate the biological passport.
Great piece as always, you really do a great job in all of your posts.
I am a sports med physician in the US who has worked on the Pro Conti level, and am also a family physician by training. A few comments on the post.
First – there are “off label” uses for many drugs but EPO really doesn’t have that many so I find it hard to believe that “off label” is a legit reason for its numbers. On the other hand it is not pharma’s legal responsibility to account for all of their medication. It would be good corporate relations though. Think of the alcohol industry, up until recently they put no money into “drink responsibly” campaigns but finally there was enough pressure to start these however you don’t see alcohol producers showing up at college parties, instead data shows binge drinking going up despite the new ads. I am simply saying there are many chemicals with good and bad sides and it’s up to the user to decide.
Second – doctors, they are not always what you think. Most folks picture their regular physician and generally think he/she is a solid individual with good morals (otherwise you probably wouldn’t have them as your doc) Well, many physician are not like that at all, complete with ego driven god complexes that make cyclists look timid. They can be very competitive and downright cut-throat as well in practicing their trade. Make no mistake Ferrari and Fuentes were competitors to see who’s riders did best and therefore could command the greatest fees. These physicians are a disgrace to the practice of medicine and should be strongly prosecuted and banned from the sport for life. In my opinion there is a line that gets crossed. As a team physician I see my role as one to keep riders healthy but should never be to improve the riders performance. If a physician is looking to improve riders performance it is far to easy to consider banned methods. It becomes a power trip that you can provide access to medications that they could not obtain otherwise. I do not see at is my responsibility to make sure riders are “safely doping” nor do I even want to think about that regardless of the safety or dangers of the medications, it’s simple ethics. Fortunately in my 6 years of working with professional cyclists I have never once been asked by a rider about performance enhancing drugs which either means the riders are clean or they know I won’t help them. Either way is good with me
“These physicians are a disgrace to the practice of medicine and should be strongly prosecuted and banned from the sport for life. ” What about their medical license?
Taking their license in the US is not easy (particularly if there is no harm to their health) but banning them from the sport is more manageable.
Very good piece, really. One continues to be, nevertheless, under the impression that authorities and media tend to exaggerate the harmful consequences of EPO on human health. Considerations about dosage should certainly go deeper than this.
It’s also necessary to take a look at the victims there might have been over the years. Apart from those circa-1990 deaths in the Netherlands and Belgium (Johannes Draaijer and the like), the number and cause of which have by the way never really established and have no doubt been exaggerated, it’s difficult to say categorically that Ferrari or Fuentes have harmed their clients’ healths. It makes me remember Anquetil’s words: if a doctor thinks, in his medical responsibility, that it’s ok to prescribe a certain substance, end of story.
To be banned, a certain substance or treatment should:
a) Make a noticeable difference in performance
b) Be detectable in urine and blood controls
c) Have been proven to cause, in itself, or beyond a certain threshold, harm to the health
It’s this last point that should be discussed further, with regard to EPO. Not only should riders be credible about observing the rules, the rules should also be credible about what they are trying to achieve.
Another great and informative piece. Hats off.
Great read. Thanks!