Passport to Clean Competition a “Biological Passport” May Deter Athletes—And the Sports Doctors Who Help Them —From Using Banned Substances

LONDON OLYMPICS

bmj.com/olympics ЖЖ Visit the BMJ Group Olympics portal for all the latest articles, podcasts, and videos about London 2012 podcasts.bmj.com/bjsm ЖЖ Alan Vernec of the World Anti-Doping Agency (WADA) talks to the British Journal of Sports Medicine about blood passports and doping detection Passport to clean competition A “biological passport” may deter athletes—and the sports doctors who help them —from using banned substances,

finds Kirsten Patrick DESIREEMARTIN/AFP/GETTY IMAGES

s the stakes for top level competitive 3 Tested positive: professional cyclist Alberto Haemotological tests in the biological passport athletes become increasingly Contador (main picture). Eufemiano Fuentes • Red blood cells high, so does the pressure to (inset), the Spanish gynaecologist implicated in • Packed cell volume blood doping perform better. The use of banned • Haemoglobin substances is widespread. But • Mean corpuscular haemoglobin catchingA doping cheats is difficult, as highlighted • Mean corpuscular haemoglobin content by the drawn out case that resulted in the • Mean corpuscular volume recent suspension of Alberto Contador from • Absolute number of reticulocytes professional road cycling for two years. Contador • % of reticulocytes tested positive for clenbuterol in a blood sample • OFF-hr score (haemoglobin− 60√% reticulocytes) taken on 21 July 2010, but it was not until February 2012 that the Court of Arbitration example, and many substances have a short win- for Sport ruled on the matter after much legal dow in which their metabolites are excreted and wrangling.1 In the intervening time Contador detectable. Some substances that are banned in won the 2010 Tour de France and the 2011Giro competition, such as corticosteroids, may be used d’Italia. to treat an injured athlete, which, as the World Traditionally, doping tests have focused on Anti-Doping Agency (WADA) acknowledges, can

detecting banned substances in blood or urine hardly be branded as cheating. It has developed MANUMIELNIEZUK/AP/PA samples provided either at the time of competi- guidance that requires athletes to declare the ther- Another problem that grew towards the end tion or at random time points outside competi- apeutic use of banned substances.2 It’s also not of the last century is “blood doping”—that is the tion (as introduced by the International Olympic uncommon for athletes to claim that they have infusion of homologous or autologous red blood Committee in 1994). The drawbacks of direct tested positive for a substance because they have cells before a competition or, more recently, the testing are many. Athletes may dodge tests, for eaten contaminated food. use of recombinant human erythropoietin, which stimulates endogenous red blood cell pro-

duction. Blood doping enhances performance by Actual values of each test Actual values of each test Upper and lower reference values improving an athlete’s oxygen carrying capac- Upper and lower reference values ity, which is particularly desirable in endurance sports. It was made illegal only in 1986—the US cycling team at the 1984 Olympic Games used Haemoglobin concentration Haemoglobin concentration blood transfusions. Use of blood transfusions is

difficult to prove because it is hard to establish that high red cell and packed cell volumes are OFF score OFF score due to blood doping, although tests are now being developed that can tell whether red blood cells have been stored. Recombinant erythropoietin can be detected by a reliable urine test that has been in use for nearly 10 years, but poor Sample No Sample No timing of a test can still miss a user and, just as Fig 1 | Normal haematological profile of an athlete Fig 2 | Profile of an athlete convicted of doping in the recreational drug market, new synthetic

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biological passport (that is, without any positive test results). The Portuguese Athletic Federation declared him ineligible for competition for four years after analysis of blood samples collected between December 2009 and November 2010 as part of the International Association of Ath- letics Federations’ (IAAF) biological passport programme suggested use of banned drugs or blood doping. IAAF president, Lamine Diack, said: “Those who try to cheat within the athlet- ics community should be warned that the athlete biological passport is not merely a concept but rather an efficient method that is now being used by the IAAF anti-doping department to identify, target, and catch those who believe that doping is the . . . route to success.”

How does the biological passport work? The athlete’s passport builds on WADA’s existing strategies to test elite athletes for banned substances. Top level competing athletes who are affiliated with a sporting organisation that subscribes to WADA’s anti-doping requirements must give information on their whereabouts for every day of the year so that they can supply a sample for testing when required. For the biological passport athletes are tested without notice both in and out of competition, with roughly 15-20 tests over two years. Changes in biological and non-biological markers are tracked over time through statistical modelling using the athlete as his or her own reference. This system allows authorities to consider whether competition values fall reasonably within a range that According to UCI’s medical adviser, Mario Zor- could be expected for that individual based on Blood doping enhances performance zoli, the organisation made it compulsory for observed intra-individual variability over time by improving an athlete’s oxygen professional road cyclists to participate in its bio- and natural variability for the marker within a carrying capacity, which is particularly logical passport programme in 2010. The pro- population reference group. For the haemato- desirable in endurance sports. gramme is used both for profiling athletes and logical measurements (box) only haemoglobin as a basis for sanctioning them. Previously a few and the OFF-hr score, which takes into account agents that may not be detected by current tests cyclists had been disqualified or suspended from the relation between haemoglobin and reticu- are constantly being developed. competition because their reticulocyte count locyte concentration, are used in the bayesian during a competition was much higher than in model that is used to define a possible anti- Longitudinal monitoring training periods. The biological passport for- doping rule violation. Since reticulocytes tend to How can sporting authorities hope to stay ahead malises this approach. The top cyclists in other decrease when haemoglobin is artificially high, of the increasingly sophisticated doping game? disciplines, such as track and off-road cycling, the combination of high haemoglobin and low For some banned substances a shift away from are also now subject to regular sample collec- reticulocytes gives a high OFF score. direct detection to indirect detection through tion both in and out of competition, although So far at least eight cyclists have been sus- longitudinal monitoring of biomarkers seems to not necessarily as part of a biological passport. pended on the basis of data from their biological be an appealing answer. A practical application of To date some 19 national and international passport. In some cases the biological passport the athlete’s “blood passport” was first developed sporting organisations have implemented some has led to targeted out-of-competition testing in 2005, and WADA finalised its operating guide- or all aspects of the athlete passport. Recently, for erythropoietin, which was subsequently lines for biological passports in December 2009. Hélder Ornelas, a long distance athlete from Por- detected. The International Cycling Union (UCI) was the tugal, became the first runner to be found guilty Of course, as with any positive test result, first organisation to adopt biological passports. of a doping violation solely on the basis of the the athlete is given the opportunity to explain

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“How can sporting authorities hope to stay ahead of the increasingly BMJ.COM BLOGS Richard Smith sophisticated doping game? For some banned substances a shift away from direct detection to indirect detection through longitudinal monitoring of Why I won’t be retiring biomarkers seems to be an appealing answer” to the seaside

athletes. Fuentes has denied performing illegal Taxi drivers rank alongside hairdressers operations. Athlete passports are also likely to as sources of deep information about discourage doctors from aiding doping. communities, and the one who drove me on Sunday morning from Padstow on the Expansion Cornish coast to Bodmin Parkway confirmed So does this mean that the days of cross sec- for me that it’s a bad idea to move to the seaside when you retire. tional testing for banned substances may be “A lot of my business is driving people to over? The main limitation of the biological and from the hospital. It’s sad. I see it time passport is that it is very costly—administering and time again that people move down here the passport for professional road cyclists alone when they retire and in no time I’m driving costs several million euros a year. Much of this them to and from the hospital. The hospital is met by the cycling teams (about €120 000 Recently suspended German cyclist Jan Ullrich ALESSANDROTROVATI/AP/PA pays for the patient but not for visitors. (£96 000; $153 000) for a team of 25 cyclists a A lot of them are diabetics. They seem to the abnormal findings (for example, by claim- year), although UCI contributes and the major be driven to and from the hospital just for ing a normal physiological condition, medical competition organisers also pay an annual fee. a blood test. One woman has to get her condition, or treatment of a medical condi- Zorzoli says that although the laboratory analy- husband up at 6 in the morning to get him tion) and may contest the allegation of doping. sis of samples is quite cheap, frequent collec- ready. Normally he doesn’t get up at all. However, in the past when the only scientific tion of out-of-competition samples by trained “Then one of them dies. That’s when it tool available to anti-doping organisations individuals all over the world and transport of gets really sad. Often I’m the only person was direct testing, athletes suspected of blood samples to the laboratory within 36 hours in the one left speaks to. And they all talk to doping often had their homes searched for refrigerated conditions, as set out by WADA, themselves. They talk to themselves while blood products, transfusion equipment, and is expensive. In addition, not all banned sub- they’re in the car. Then they apologise. I drugs, and the biological passport may obviate stances are currently covered by the biological don’t like to get too close. I know they’ll be the need for such invasion of privacy. passport, though it is likely to be expanded in dead soon. Furthermore, according to Zorzoli, the intro- the future. WADA is, for example, currently “The families, if they have one, have to duction of the biological passport has had a developing the capacity to include an endocrine travel miles to see them. The families try to measurable deterrent effect on doping. Together module that will allow steroid profiling—an get them to move closer, but they don’t want with his colleague, Francesca Rossi, he examined “individual hormonal blueprint.” to. They don’t want to leave the dead one. 10 years of data from cyclists’ tests and found In future it may be possible to track a wide “Often these people leave their money to that the proportion of extreme values pattern of range of variables for a single athlete over time, the gardener, the cleaner, or the dog walker. reticulocyte percentage—one of the most reliable and the importance of the biological passport I worry that they might leave money to me. I markers of blood doping—has fallen dramati- in detecting cheats may supersede that of tradi- don’t want their money. cally, with almost none detected since 2009, the tional doping tests. Although it is not currently “I think that people should stay where year after the passport wasintroduced. 4 feasible that every athlete competing in the 2012 they’ve lived their lives. And it’s best in Although an athlete’s biological profile is kept Olympic Games should be required to have an towns or cities. Then they can totter to the confidential— only a few people fromregulatory athlete’s passport, the International Olympic shops. See other people. Mind you, it won’t authorities and the athlete have access to the Committee may require it for future games. be good for my business if they do stop password protected data— some athletes have Kirsten Patrick is editorials editor, BMJ retiring to the seaside.” published data from their biological passports to [email protected] Richard Smith was the editor of the BMJ until 2004 encourage clean competition. In 2009 the Brit- Competing interests: None declared. and is director of the United Health Group’s chronic disease initiative ish cyclist Bradley Wiggins began publishing Provenance and peer review: Commissioned; not externally peer reviewed. his haemoglobin and OFF score results online • Read this blog and others at bmj.com/blogs 1 CAS sanction Contador with two year ban in clenbuterol before and during the Tour de France. case. Cycling News 2012 Feb 6. www.cyclingnews.com/ Of course, athletes who practise blood dop- news/cas-sanction-contador-with-two-year-ban-in- clenbuterol-case ing need doctors to help them to do it, as high- 2 World Anti-Doping Agency. Therapeutic use exemptions. lighted by the case of Eufemiano Fuentes, the 2011. www.wada-ama.org/en/Science-Medicine/TUE 3 World Anti-Doping Agency. Athlete biological passport controversial Spanish gynaecologist and sports operating guidelines. www.wada-ama.org/en/Download- physiologist. Fuentes was arrested after a series Centers/SC-Athlete-Passport/Archives/Athlete-Biological- of police raids across five Spanish provinces in Passport-Operating-Guidelines. 4 Zorzoli M, Rossi F. Implementation of the biological 2010, in which blood products, equipment, passport: The experience of the International Cycling hormones, anabolic steroids, and erythropoietin Union. Drug Test Analysis 2010;2:542-7. 5 5 Cossins P. Playing God: Eufemiano Fuentes. Cycling News were seized. He is alleged to have worked with 2011 Apr 20. www.cyclingnews.com/features/playing- a number of high profile road cyclists, includ- god-eufemiano-fuentes. ing the recently suspended German cyclist, Jan Cite this as: BMJ 2012;344:e2077 Ullrich, as well as with footballers and track ЖЖPERSONAL VIEW, p 33

22 BMJ | 26 MAY 2012 | VOLUME 344 DRUG TRIALS

Why the exclusion of older people from clinical research must stop Age bias in clinical research leads to uncertainty about risks and benefits of new treatments for older people. Geoff Watts looks at the barriers to recruitment

xclusion of older people from clinical research, and of under-recruitment to clinical trials, is widespread.1 This problem has stark consequences, according to an expert committee of Ethe European Medicines Agency (EMA). “The drugs we are using in older people have not been properly evaluated.” While the paucity of clinical trials on young children is well documented and frequently discussed, the same cannot be said of a similar shortfall at the upper end of the age spectrum. In fact older people are proportionately under- represented or even absent from most drug trials. This matters because just as children are not physiologically identical to adults, neither are very elderly people equivalent to those decades their junior. Recognising this, and mindful that the older DIGITALVISION/GETTY IMAGES generation (those over 80) are the fastest grow- Why do trialists turn their backs on older people? ing sector of the population, the EMA recently held a workshop at its headquarters in London level of eligibility criteria is still very common,” When PREDICT organised a survey of health to consider what might be done. according to Cherubini. Exclusion of patients professionals and older patients, it found that One group active in this field is PREDICT with comorbidity and cognitive impairment also both groups were conscious of factors that tended (Increasing the Participation of the Elderly in tends to keep older people out of trials. “We’re to militate against inclusion. Health profession- Clinical Trials), a consortium funded by the now working on oncological disease, and the als often felt under no special obligation to recruit European Union to study the participation of situation we’re finding is exactly the same.” elderly people; patients were discouraged by elderly people in clinical trials and propose James Goodwin, head of research at Age UK, a dislike of randomisation, concerns about the ways of boosting recruitment. The group began told the London audience at the EMA work- consent procedure, and practicalities such as by checking that the under-representation is shop: “I regard this as absolutely scandal- transport. real. It reviewed trials completed during the past ous. This kind of age bias leads to uncertainty One delegate at the London meeting also 10 years in six conditions: heart failure, hyper- about risks and benefits in new treatments for blamed research ethics committee rules. “Eth- tension, coronary heart disease, depression, older people, and delays in bringing them new ics committees don’t let us phone patients,” he Alzheimer’s disease, and colorectal cancer.2 treatments.” There was, he added, a general complained. “The only way we can contact them Antonoio Cherubini is a professor of geri- prejudice against the old in our society. He cited is to let GPs write, and no more than twice. Then atrics at Perugia University and a member of a study of activity in one stroke unit in which they get a four or five page information sheet that the EMA’s geriatric expert group. “The PRE- 26% of patients under 75 received magnetic worries them by saying things like ‘There’s a small DICT study confirmed that in every condition resonance imaging compared with only 4% risk of death.’” These things, he suggested, were there was a wide gap between the real clinical above that age.3 barriers to recruitment. “What is really unethical practice population and the patients who were at the moment is that patients are not going into included in clinical trials,” he said. Both age Barriers trials because of the barriers.” and sex were out of kilter. But ageism aside, why does he think that older Cherubini agreed. “We cannot necessarily The group then checked to see if this distor- people find themselves so often excluded from use the same consent form for a 90 year old per- tion is continuing. Using a World Health Organi- clinical trials? Goodwin identified several son as for a 40 year old one,” he said. “We need zation database of current clinical trials in heart reasons, including resistance to change, a per- simplified explanations.” failure the PREDICT consortium identified the ceived absence of models from which to garner This is only one of a stack of ideas put for- same pattern. “Exclusion of older patients at the expertise, and a lack of adequate resources. ward by the PREDICT consortium to boost the

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Do we just have to lift the upper age limit of clinical trials, or do we need specific trials for elderly people?

recruitment of elderly patients. Trial organisers encouraged by their own doctors, appointments Another industry representative, Philippe will need to make all sorts of changes to com- could be scheduled to meet their needs, and Guillet, Sanofi-Aventis’s head of healthcare missioning and ethical arrangements, to the transport costs reimbursed. technologies for ageing, also regretted the recruitment process, and to the conduct of trials, Goodwin put forward what he called some general exclusion of the oldest patients from Cherubini suggested. He advocated simplified “golden principles” for boosting involvement. pre-authorisation clinical trials. “We need to protocols, fewer exclusion criteria, more train- These included the use of older people’s existing include them . . . and to take into account their ing for research staff, more emphasis to patients networks when recruiting and the creation of a specific characteristics,” he said. “We need on the benefits of participation, easier physical more user friendly climate. In an effort to stimu- to shift from the paradigm of product centred access to research institutions, the possibility late interest and encourage clinicians to take innovation to patient centred innovation. We of home visits, more frequent follow-up and the problem seriously, PREDICT has compiled a need to understand the unmet needs of the older contact . . . The list goes on. charter for the rights of older people in clinical population to ensure that whatever we look for Formal studies on improving the participation trials (box).5 in the preclinical animal models is translatable of older people are thin on the ground. Direct con- into relevant measures in clinical studies.” Charter for the rights of older people in tact with patients, involving their general practi- 5 Practical help on some of these issues will soon tioners, and providing more information seem to clinical trials be available in the form of a 30 page document, help, said Cherubini. “But while a lot of opinions • Older people have the right to access evidence Geriatric Research Guidelines, to be published based treatments have been expressed about strategies, we don’t by the Brussels based European Forum for Good • Inclusion of older people in clinical trials should be have a formal evaluation of which interventions Clinical Practice. A draft version6 is already avail- promoted and discrimination prevented are most effective.” • Clinical trials should be made as practicable as able on the web and will be finalised at an open The European Organisation for Research and possible for older people meeting to be held on 11 June at University Col- Treatment of Cancer (EORTC) is another body • Older people should be safe in clinical trials lege London. that has taken a close and critical look at clini- • Outcome measures should be relevant to older According to one of its authors, Florian von cal trials in older people.4 The obstacles it identi- people Raison, “The document provides recommenda- fied include aspects of trial methodology such as • The values of older people participating in clinical tions on various ethical aspects of clinical trials upper age limits and the definition of appropri- trials should be respected performed in older people, and who may belong ate endpoints, and inadequacies of the regulatory to a vulnerable patient population. This will con- framework. It perceived only a limited interest in Role of manufacturers tribute to the protection of all older patients in change on the part of the drug industry. Given that drug manufacturers hold the purse clinical trials, and to a better inclusion rate.” strings for many trials, their interest in the mat- In the end it was Cherubini who issued a call to Different perspectives ter—or lack of it—is a key consideration. In spite action on bringing more old people into clinical So what to do? “Do we just have to lift the upper of some appearances to the contrary, there are trials. “It’s time to move from research to imple- age limit of clinical trials, or do we need specific people in the industry who favour change. The mentation,” he declared. The geriatric commu- trials for elderly people?” wondered Ulrich Wed- European Federation of Pharmaceutical Indus- nity will need little persuading of this; whether ding of the University of Jena in Germany and a tries and Associations has surveyed 15 of its the rest will be quite so eager to follow their lead member of EORTC’s cancer in the elderly task members. To judge by what Brigitte Stemper of is more questionable. force. “And what are the appropriate endpoints Bayer told the meeting about the key findings, Geoff Watts freelance journalist, London, UK for elderly cancer patients?” Classic endpoints, the industry’s position might be described as [email protected] he said, are often inadequate. There’s a need for cautiously sympathetic. Competing interests: None declared. more emphasis on quality of life measures and In most circumstances manufacturers claim Provenance and peer review: Commissioned; not externally the preservation of functional capacity. “If you that they would favour including a representa- peer reviewed. ask older cancer patients themselves what is tive group of older people in large trials. But she 1 McMurdo ME, Roberts H, Parker S. Improving recruitment of older people to research through good practice. Age most important they will often say it is to main- added: “In certain conditions it might make Ageing 2011;40:659-65. tain their independence. We haven’t addressed sense to have a completely separate trial, though 2 PREDICT. Increasing the participation of the elderly in clinical trials. Literature review. 2008. www.predicteu.org/ this endpoint so far in clinical trials.” that is a secondary option.” Registry data are Reports/PREDICT_WP1_Report.pdf. PREDICT asked more than 500 health profes- also useful, she said, but this too is a secondary 3 Kee Y-YK, Brooks W, Bhalla A. Do older patients receive sionals how to increase the recruitment of older option. Data from randomised controlled trials adequate stroke care? An experience of a neurovascular clinic. Postgrad Med J 2009;85:115-8. patients. Among their suggestions were a specific remain the preferred alternative. 4 Pallis AG, Ring A, Fortpied C, Penninckx B, Van Nes requirement to undertake such recruitment and, Many of the manufacturers’ thoughts seem MC, Wedding U, et al. EORTC workshop on clinical trial equally realistically, that any financial reward to echo those of the academics at the meet- methodology in older individuals with a diagnosis of solid tumors. Ann Oncol 2011;22:1922-6. they were receiving should be adjusted to recog- ing. The choice of appropriate endpoints, for 5 PREDICT. Charter for the rights of older people in clinical nise the extra work involved. example. Are standard endpoints always rel- trials. www.predicteu.org/PREDICT_Charter/predict_ charter.html. Questioning the patients themselves revealed evant in older patients? “One thing emerging 6 European Forum for Good Clinical Practice. Geriatric that their willingness to take part would be more and more,” said Stemper, “is the need to research guidelines. www.efgcp.eu/WorkingParties. boosted if, among other things, follow-up evalu- focus on quality of life measures and on activi- asp?what=6&L1=5&L2=5. ations were done at home, participation was ties of daily living.” Cite this as: BMJ 2012;344:e3445

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