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Because it can take time to obtain independent EC or review board approval, the temptation to start a study without it can become strong.
Speaking on clinical research fraud at the ACT Summit in Brussels last year, we were asked by someone why we were worried about it. "After all" he said, "surely it's a victimless crime?"
Much has been written about research fraud and there have been many high-profile cases. But there has been little—if anything—written about its impact on the victims. There are obvious victims: sponsoring pharmaceutical companies. But of great concern to us are the direct victims of the fraud: patients given inappropriate treatment or denied full safety assessment while taking an experimental drug. Then there are the invisible victims, patients of a doctor removed from practice having been found guilty of research fraud. We'd like to share the stories of some of these victims.
Many protocols require patients to be treatment-naïve or uncontrolled on present medication. When we interviewed patients in a depression study, we saw patient notes altered to make it appear that the patient fitted the inclusion criteria. The records showed that a husband and wife participated in the same study. Both agreed that they had been asked to take part in the study, both discussed participation, and both had signed consent forms. So what, the husband was asked, was his history of depression? "I've never been depressed in my life!," he responded. The doctor had explained that it would help his wife if he went into the study with her. "I did it all for her." On the face of it this seems almost comical, but he had had a miserable 12 weeks with every known side effect. His wife, however, complained that she had received no benefit whatsoever from being in the study. He had received the active medication, and she—who needed the drug—had received placebo. Both of them suffered; she was denied medication and he was treated for a condition he did not have. Furthermore, his notes now show that he suffered from depression, which may influence future choices of treatment, employment, and insurance.
Sometimes, the impact on patients can be financial as well as a loss of trust. One elderly woman on income support was phoned by her general practitioner (GP) late one afternoon. The GP needed her to come to surgery to have blood taken for tests. He persisted, and she took a taxi at a cost equivalent to two days food. We later discovered that she was in three studies at the same time, and that the blood samples were needed to fulfill the needs of the protocols. She had no knowledge of any of the studies, and was so distressed and appalled by the abuse of the doctor–patient relationship that she travelled to London (several hundred miles) to give evidence from a wheelchair at his court hearing. She died less than two weeks later.
She was not the only patient in that practice who adored her doctor. Many protested when he was charged with research fraud, and held a collection to fund his appeal when he was found guilty.1 When he failed to launch that appeal, the realization dawned that the charges were true. Thousands of patients were deprived of their doctor; despite his fraud, he was widely held in great respect and affection, and his patients found it hard to understand.
New drug development revolves around the need to show efficacy, safety, and quality. Unless all three are measured accurately, any conclusions will be false. A clinical research associate once returned from a monitoring visit worried, but unable to pinpoint what it was that made her uneasy. Her manager, a scientist with many years' monitoring experience, performed the next visit. He asked the study nurse how she measured and recorded heart rate, and was told that she counted the radial pulse for 15 seconds and multiplied by four. Yet very few of her patients' heart rates could be divided by four. At this point she broke down in angry tears. The unit had many studies with insufficient research staff and she couldn't do all the tests laid down in the various protocols on all the patients. So she made up some of the data. Her justification was that she "never made up important data. That's all real." This was a drug just starting its course through Phase III, with much still unknown about its safety and efficacy. She had no reason to believe that the heart rate would be an unimportant measurement.
One might expect investigators working with drugs known to affect heart rate to be more careful about recording cardiac function. But sometimes fraudulent doctors seem to get careless. Years ago, electrocardiograph (ECG) recordings were done on long strips of heat-sensitive paper, which were cut up and mounted on a sheet of paper. Part of the safety assessment in one study comparing a calcium channel blocker with a beta-blocker was an ECG taken before and after 12 weeks of treatment. One would expect that patients on the calcium channel blocker would show a faster heart rate on treatment, and those on the beta-blocker a slower one. Amazingly, in this study no patient showed any change whatsoever. Looking closely at the ECG tracings we realized the benefit of long strip recordings. The paper manufacturer's name was repeated all along the lower edge. When the section for each lead's recording (I, II, III, etc.) was cut up for mounting, the cut inevitably passed through words. It was easy to match the cut-up words and see beyond doubt that the investigator had done one double-length recording at visit one, then cut each lead into two parts before mounting onto two separate sheets. He hadn't noticed that lead I on the pretreatment trace had "Cambridge scienti" written along the bottom, while on the same lead on the alleged 12-week trace was "fic papers." This breach of safety assessment was quite clearly crucial to the safety of patients.
Not all fraud is so evident. Ethical review of clinical research is vital to protect the rights of patients. But because it can take time to obtain independent ethics committee (EC) or review board approval, the temptation to start a study without it can become very strong. When investigating cases of alleged research fraud, we approach ECs to ask for details of other studies they have approved for the investigator under suspicion. We have seen several studies where EC approval has never been sought, although sponsoring companies have been told the contrary. With scanners and modern copying equipment, it is relatively easy to produce a letter seeming to give EC approval that would pass casual inspection. But the EC chairman only has to compare it with the minutes of relevant EC meetings for that fraud to become glaringly obvious. If that check is not made, a whole study's worth of patients at that site have been denied the most basic level of protection, that of impartial protocol review.
Another real root of ethical research is informed consent. Yet one of the most common responses we hear from patients in a study where we suspect fraud has taken place is "Study? What study?" Some of these cases have involved patient safety, some "just" an abuse of their rights. But all of these patients are victims.
One young man is lucky to be alive. He presented to his GP with suicidal thoughts. His GP told him he had some new treatment that would help him enormously, but that as it was not on the market in this country he must sign a receipt for it. This the young man did, but his failure to respond so concerned his parents that they took him to hospital and got him effective treatment. It was only when we were asked to investigate possible research fraud that the truth became known. What he had signed was actually a consent form, yet he had been given no information that he was a research subject taking unlicensed medication. The fact that his allocation was to the placebo group merely made matters worse.
The drug in the desk drawer is a familiar story. We were asked to look into a hormone replacement therapy (HRT) study. Although informed consent forms had been signed, the signatures all looked very similar to each other and to the handwriting of one of the study staff. The study involved the women taking HRT over several months, with a biopsy of their uterine lining being done before and after treatment. All had been supplied with the drug "as a personal favor" by their GP. Many had been with their GP for years and had trusted him with their family's care. To find that he had used them for personal gain and had performed invasive biopsies not for their good but to fulfill the terms of the protocol was devastating to all of them, and when last heard at least one was considering civil action for assault over the biopsy.
Recourse to the civil courts is also technically open to pharmaceutical companies, though we have not heard of this being exercised. Yet research fraud is an expensive matter for the pharmaceutical industry. It is not often that an entire study must be scrapped because of fraud, but we have recently confirmed as fraudulent the seventh investigator in an 11-center study. Clearly the results of that research will never be used.
Withdrawal of a drug is much more expensive. When done because of the results of fraudulent research, the price is too high. William McBride, an Australian obstetrician, was one of the first to highlight the dangers of thalidomide for pregnant women, suggesting that the drug caused limb deformities in babies.
Twenty years later he published research on Debendox, a drug for morning sickness, claiming it caused birth defects in rabbits.
The manufacturers took the drug off the market and lawsuits followed. Only when nobody could reproduce his work did it transpire that McBride had altered research data: in fact, Debendox had no ill effects. Ten years later he was found guilty of scientific fraud by a medical tribunal and removed from the Medical Register.
The obvious victim was the drug company, but what of the pregnant women who had already taken Debendox during early pregnancy? There must have been many thousands who continued their pregnancies in fear and dread.
Another victim of this case was Phil Vardy, a scientist working with McBride who blew the whistle on him. When he confronted McBride he was sacked, and found it impossible to get another job until he moved away. He lost his marriage in the process.
It is hard to feel sorry for fraudulent doctors who lose their license to practice medicine, as the choice to perpetrate fraud was their decision. But it is callous not to feel sympathy for their spouses and families, suffering a drop in standard of living and public shame and dishonor. At least two doctors have taken their own lives when sponsoring pharmaceutical companies were getting close to unravelling their long-term research fraud. Both were family men, so two women were widowed and several children grew up without their fathers. In both cases they were popular GPs, so many thousands of people were affected by their deaths.
Like these two, in most cases of fraud we have investigated deceit has been practiced for many years—on average five to 10 years. In many cases, one or several pharmaceutical companies have been using the site on an almost continuous basis. Quite often, therefore, one CRA or monitor has been visiting the investigator for a significant length of time. Pharmaceutical company staff understandably get possessive of their sites and fond of the staff, and it is easy for them to be flattered when an eminent researcher seems to welcome visits and calls them by their first name. But we have seen the human response to finding out that a respected investigator is a fraud: the CRAs are devastated. It is infidelity of a sort, and the fact that it is professional rather than personal doesn't make it any less painful. The CRA has to face the fact that he or she has been duped by someone they respected, someone they thought valued them.
Research fraud can never be "a victimless crime." There are victims on many levels, obvious and hidden, financial and personal. Money is money, but we can't replace the lost trust in the patient's doctor, and we can't make them feel less used and abused. Nobody can retrospectively run safety assessments on patients who have been studied without the right tests at the right time. Nobody can make it right to carry out research without informed consent, to give these patients back their most basic human rights. Nobody can give widows and orphans what they want most in the world.
At the 2003 ACT Summit, we asked a large group of delegates whether they had ever seen what they believed to be evidence of clinical research fraud. About 75% of them raised their hands. In Munich in 2004 we posed the same question to another group and saw a similar response. This is particularly worrying, as most of the delegates were at the front line of research. How many prosecutions have ensued? We know of very few outside the United Kingdom, but one pharmaceutical company with a multinational Phase III study has closed seven centers in one European country for fraud. It is time the proactive UK approach to the problem extended into Europe—there is no acceptable reason to ignore and condone such outrageous behavior.
The true victims of research fraud are very real. They are just like us, and members of our family. And while research fraud is allowed to continue, they will continue to suffer.
1 D. Edwards,
Whistleblower. In Fraud and Misconduct in Biomedical Research
, 3rd ed., S. Lock, F. Wells, and M. Farthing, Eds. (London: BMJ Books, 2001).
2 W.G. McBride, "Thalidomide and Congenital Abnormalities," Lancet, 1 2, 1358 (1961).
3 W.G. McBride, P.H. Vardy, J. French, "Effects of Scopolamine Hydrobromide on the Development of the Chick and Rabbit Embryo," Aust J Biol Sci., 35 (2) 173-178 (1982).
4 G.F. Humphrey, "Scientific Fraud: The McBride Case—Judgment," Med Sci Law, 34 (4) 299-306 (October 1994).
Jane Barrett,* MBBS, is medical adviser and director, and Peter Jay is co-founder and chief executive of MedicoLegal Investigations Ltd., Nup End Business Centre, Nup End Green, Knebworth, Herts, UK SG3 6QJ, telephone and fax +44 (0) 1438 820000, email: email@example.com, www.medicolegal-investigations.com.
*To whom all correspondence should be addressed.