"On the science and ethics of Ebola treatments", by Joanna Monti-Masel:
> ...The first two patients to be treated were Americans. Prior to this came the old (and historically justified) fear of testing potentially dangerous new treatments on vulnerable populations in developing countries rather than on privileged first world patients. The first ever treatment was not given to an African doctor because of this concern [[1] "Opting Against Ebola Drug for Ill African Doctor" http://www.nytimes.com/2014/08/13/world/africa/ebola.html?_r=1 , by Andrew Pollack, The New York Times, 12 August 2014.]. After Westerners were treated, complaints rose about giving infected Westerners access to a new drug while infected Africans went without. These two concerns are obviously mutually exclusive. People are concerned, they are just not sure about what, sometimes even voicing both concerns in the same article [[2] "Ebola, research ethics, and the ZMapp serum" http://www.washingtonpost.com/blogs/monkey-cage/wp/2014/08/06/ebola-research-ethics-and-the-zmapp-serum/ , by Laura Seay, Washington Post, 6 August 2014.].
>
> An important worry for any drug is that it might have damaging side effects. But if there were ever a disease for which this is not a big deal, it is Ebola
>
> ...To learn about effectiveness, we need to test these treatments on Africans, in the midst of a terrifying epidemic.
>
> ...The WHO has given an ethical green light [[3] "Ethical considerations for use of unregistered interventions for Ebola virus disease (EVD)" http://www.who.int/mediacentre/news/statements/2014/ebola-ethical-review-summary/en/ , World Health Organization, 12 August 2014.] to the use of these experimental therapies, with the caveat that “there is a moral obligation to collect and share all data generated, including from treatments provided for ‘compassionate use’ (access to an unapproved drug outside of a clinical trial).” They mention a number of ethical issues, but leave out the one that troubles me. The unethical behavior here, which was just given a green light by the WHO, is not doing an experiment, but doing an experiment without using a control group. There should be no compassionate use exceptions. Everybody who wants these treatments should have to enter a randomized trial to have a chance of getting them.
>
> Five patients have received the ZMapp serum so far. Two US missionaries recovered, a Spanish priest died, and reports are not yet in for two Liberian doctors. Unfortunately, the supply is now exhausted, and we must wait until more is manufactured. Another experimental treatment, TKM-Ebola, also now has a green light for use in patients [[4] "FDA eases restrictions on experimental Ebola drug as CDC warns of ‘inevitable’ spread to US" http://rt.com/usa/179100-ebola-fda-drug-cdc-spread/ , RT.com, 8 August 2014.]. I don’t know how many people we can treat with the quantity of TKM-Ebola available today. I hope it is many more than the five we could treat with ZMapp.
>
> At least five patients have received a potentially effective treatment, but nobody has yet been assigned to a control group. This is the ethical travesty, and it needs to stop.
>
> With 1013/1848 = 55% of reported Ebola patients dying during this outbreak, you may think that we don’t need a control group. Surely we will notice if the death rate goes down from there [[5] "Ebola prizes revisited" http://offsettingbehaviour.blogspot.com/2014/08/ebola-prizes-revisited.html , by Eric Crampton, Offsetting Behavior, 5 August 2014.]. But this is not as easy as you might think. Some of those infected patients haven’t died yet, but will die later, so the true death rate is likely a little higher than 55%. And neither the typically more privileged patients who receive the therapies, nor the care they receive during their treatment are likely to be representative of the average Ebola patient suffering and perhaps dying at home in their village.
>
> A control group is not only essential for good science backed by rigorous statistics, but it is also ethically sound. Many people are understandably concerned about deliberately withholding potentially life-saving treatment and giving a placebo instead. But this is a moot point; we have no choice about withholding treatment. There isn’t enough of it to go around. The fairest way to distribute it is by lottery. This fairest plan also happens to be the best scientific plan. The question is whether we capitalize on our inability in the service of science by implementing a well-designed lottery, or whether we squander it instead with a less systematic lottery of who gets treated and who misses out.
>
> This situation has an important and telling precedent. The very first randomized clinical trial ever published [[6] "Streptomycin Treatment of Pulmonary Tuberculosis" https://pdf.yt/d/BQ9v5fvb7gUmcrnW / https://dl.dropboxusercontent.com/u/182368464/1948-streptomycincommittee.pdf , British Medical Journal, 30 October 1948.] in 1948 investigated whether antibiotics are effective against tuberculosis with Ebola-like death rates. Just like today, there was a shortage of a new drug, streptomycin. In the aftermath of World War II, Britain received only a very limited supply from American manufacturers. The Medical Research Council controlled this shipment, and seized the opportunity to dictate to doctors that if they wanted access to the drug for their patients, the only way to get it was by taking their chances within a randomized trial. Thus began a golden era of effective medical science [[7] "Controlled trials: the 1948 watershed" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1114161/ , British Medical Journal, 31 October 1998.], led by a strikingly novel and extraordinarily effective gold standard. What is more, to everyone’s surprise, the streptomycin treatment had limited effectiveness against tuberculosis. Patients improved initially, but then the bacteria evolved resistance to the drug and patients deteriorated again. This phenomenon of drug resistance had never been seen before. The randomized trial allowed this failure to be quickly recognized, leading to the improved and effective treatment protocols we have today.
>
> We have so few doses available, and it is unethical to waste them in unsystematic tests that lack a control group. The US should have led the way by tossing a coin to see which of the two American patients got ZMapp and which got a placebo. And then it should have given its second dose to Africa on the condition that it be randomly distributed to one out of two preselected patients in the same manner. This would have been the ethical thing to do.
>
> If ten patients had been rigorously randomized such that only five of them received the scarce ZMapp treatments and the other five got a placebo, and if ZMapp really were a miracle drug reducing the death rate from 60% to 0%, then there is a 69% probability that we would have been able to conclude in a “statistically significant” fashion, from that tiny but well designed trial, that the drug works. We think of randomized trials as huge affairs. And it is true that to detect subtle differences, we do need huge trials. But when the improvements are not subtle, trials can be quite small. Sixteen patients (eight per group) would be enough to have a 95% chance of detecting the effectiveness of a miracle drug. Even if the drug were slightly less miraculous, dropping the death rate from 60% to 30%, the 10-patient trial that we could and should have done with existing resources would have had a 42% chance of detecting the drug’s effectiveness. Our unsystematic trial of five patients will tell us much less, squandering this opportunity to make best use of the limited supply of ZMapp that we had.
>
> ...What we should learn from the history of randomized trials is that the biggest danger with randomization comes from the urge to cheat. It is only natural for doctors to have special sympathy for particular patients, and to rig the game so that their favorite patients end up in the treatment group rather than the placebo. This is the real historical reason that trials were made “double blind” so that neither patient nor doctor knows who gets what. There is a lot of talk about the power of the placebo effect, and it is important for some conditions such as pain, but for most diseases the placebo effect is overrated. A placebo won’t stop you dying of Ebola just because you believe in it. But a double blind design is still an important precaution to make it impossible for well-meaning doctors to rig the allocations.
http://www.cnn.com/2014/08/17/world/africa/ebola-liberia-attack/index.html?hpt=hp_t2 caption, slideshow photo #6:
> Liberian police depart after firing shots in the air while trying to protect an Ebola burial team in the West Point slum of Monrovia on August 16, 2014. A crowd of several hundred local residents reportedly drove away the burial team and their police escort. The mob then forced open an Ebola isolation ward and took the patients out, many saying that the Ebola epidemic is a hoax.
"Controlled trials: the 1948 watershed" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1114161/ Doll 1998
> When I qualified in medicine in 1937, new treatments were almost always introduced on the grounds that in the hands of professor A or in the hands of a consultant at one of the leading teaching hospitals, the results in a small series of patients (seldom more than 50) had been superior to those recorded by professor B (or some other consultant) or by the same investigator previously. Under these conditions variability of outcome, chance, and the unconscious (leave alone the conscious) in the selection of patients brought about apparently important differences in the results obtained; consequently, there were many competing new treatments. The treatment of peptic ulcer was, perhaps, more susceptible to claims of benefit than most other chronic diseases; so that in 1948, when I began to investigate it, I was soon able to prepare a list of treatments beginning with each letter of the alphabet. Standard treatments, for their part, tended to be passed from one textbook to another without ever being adequately evaluated.
>
> ...One way of avoiding such biases would be to divide the patients into two similar groups before it was known which group would get which treatment and then, at the last minute, allocate one whole group to one treatment and the other to another by tossing a coin. This method was proposed by van Helmont, a medicinal chemist, in 1662 when he challenged the academics of the day to compare their treatments based on theory with his based on experience. “Let us take out of the hospitals, out of the Camps, or from elsewhere, 200, or 500 poor People, that have Fevers, Pleurisies, etc. Let us divide them into half, let us cast lots, that one half of them may fall to my share, and the other to yours ... We shall see how many funerals both of us shall have. But let the reward of the contention or wager, be 300 florens, deposited on both sides.”5 Sadly, the challenge was not accepted. The technique was, however, actually put into practice by Amberson et al 260 years later to assess the value of sodium gold thiosulphate in the treatment of pulmonary tuberculosis.6 Amberson et al divided 24 patients into two groups of 12, the members of each group being “individually matched” in pairs. They then tossed a coin to decide which treatment each group should get. This technique suffers, as Armitage has pointed out,5 not only from the virtual impossibility of truly being able to match cases, but also because it provides no means of measuring the relevant random error. Both difficulties are overcome within quantifiable limits by the randomisation of individuals.
>
> ...He [Bradford Hill] did not recommend the randomisation of individuals then, preferring that the two treatments for comparison be allocated to alternate patients because, as he wrote in 1990, by referring to the randomisation of treatments he might have scared doctors off any use of concurrent controls.9 In 1946, when he judged the time was right, he recommended the randomisation of individual patients and this rapidly gained acceptance among medical scientists.10,11 He advocated it not so much because it provided a proper estimate of random error, which was the principal reason it was advocated by Fisher, but on the practical grounds that it eliminated bias in selection.
>
> ...In the trial of streptomycin, the first issue that had to be faced was whether it was ethical to withhold from any patient a drug that had been effective in animal experiments and had had encouraging clinical results in the few published reports. There was, however, only a small amount of the drug in Britain and it was not possible to buy more from abroad. It was agreed to use the limited supplies to treat patients with two conditions that had previously been invariably fatal: miliary tuberculosis and tuberculous meningitis. The amount of streptomycin left over was insufficient to treat more than a tiny proportion of the people desperately ill with other types of tuberculosis. The Medical Research Council’s Streptomycin in Tuberculosis Trials Committee agreed that “it would have been unethical not to have seized the opportunity to design a strictly controlled trial which could speedily and effectively reveal the value of the treatment.”12 The question of whether it was ethically justifiable to withhold the drug from any patient was, therefore, answered with an unhesitating “Yes.”
>
> ...The spread of randomisation, until it became an essential element of trials submitted to licensing authorities for the approval of new drugs, was initially slow and not without opposition. This was most commonly expressed along the lines of Lewis’s criticism of what he called “the statistical method of testing treatment.”14 Lewis was the doctor in charge of the department of clinical research at University College Hospital, London, and the doyen of clinical research in the United Kingdom in the 1930s. He died in 1945 before randomised trials were introduced but I can imagine what his reaction would have been. Lewis thought that when testing treatments for acute diseases two groups of patients that were as similar as possible should be treated in exactly the same way and concurrently, except that one group should receive the remedy and the other should not. However, he added that “it is to be recognised that the statistical method of testing treatment is never more than a temporary expedient, and that but little progress can come of it directly: for in investigating cases collectively, it does not discriminate between cases that benefit and those that do not, and so fails to determine criteria by which we may know beforehand in any given case that treatment will be successful.”14 Lewis’s objection was repeated many times in the first few years after randomisation was introduced. Bradford Hill would reply: “Tell me the criteria to distinguish patients who will respond from those who don’t and we will build this into the trial”(A Bradford Hill, personal communication). There was never any serious response to Bradford Hill’s challenge
>
> ...Early randomised trials can properly be criticised on the grounds that they were often too small to have any chance of detecting moderate effects...For example, many early trials of the treatment of myocardial infarction, stroke, and cancer, which were not large by modern standards, consequently led to the misleading conclusion that there was no benefit. Bradford Hill and his students, such as myself, were primarily concerned with getting the principle adopted, and to have pressed for trials on thousands of patients would have been self defeating. There were too few physicians, leave alone surgeons, who were willing to expose their theories to cold scientific investigation...It was many years before randomisation was accepted as such a normal procedure. Only then did it become possible to organise the groundbreaking international study of infarct survival (ISIS) trials for the treatment of myocardial infarction, which involved hundreds of centres and randomly allocated tens of thousands of patients, and thereby showed the value of moderate improvements in the treatment of common diseases.17
> ...The first two patients to be treated were Americans. Prior to this came the old (and historically justified) fear of testing potentially dangerous new treatments on vulnerable populations in developing countries rather than on privileged first world patients. The first ever treatment was not given to an African doctor because of this concern [[1] "Opting Against Ebola Drug for Ill African Doctor" http://www.nytimes.com/2014/08/13/world/africa/ebola.html?_r=1 , by Andrew Pollack, The New York Times, 12 August 2014.]. After Westerners were treated, complaints rose about giving infected Westerners access to a new drug while infected Africans went without. These two concerns are obviously mutually exclusive. People are concerned, they are just not sure about what, sometimes even voicing both concerns in the same article [[2] "Ebola, research ethics, and the ZMapp serum" http://www.washingtonpost.com/blogs/monkey-cage/wp/2014/08/06/ebola-research-ethics-and-the-zmapp-serum/ , by Laura Seay, Washington Post, 6 August 2014.].
>
> An important worry for any drug is that it might have damaging side effects. But if there were ever a disease for which this is not a big deal, it is Ebola
>
> ...To learn about effectiveness, we need to test these treatments on Africans, in the midst of a terrifying epidemic.
>
> ...The WHO has given an ethical green light [[3] "Ethical considerations for use of unregistered interventions for Ebola virus disease (EVD)" http://www.who.int/mediacentre/news/statements/2014/ebola-ethical-review-summary/en/ , World Health Organization, 12 August 2014.] to the use of these experimental therapies, with the caveat that “there is a moral obligation to collect and share all data generated, including from treatments provided for ‘compassionate use’ (access to an unapproved drug outside of a clinical trial).” They mention a number of ethical issues, but leave out the one that troubles me. The unethical behavior here, which was just given a green light by the WHO, is not doing an experiment, but doing an experiment without using a control group. There should be no compassionate use exceptions. Everybody who wants these treatments should have to enter a randomized trial to have a chance of getting them.
>
> Five patients have received the ZMapp serum so far. Two US missionaries recovered, a Spanish priest died, and reports are not yet in for two Liberian doctors. Unfortunately, the supply is now exhausted, and we must wait until more is manufactured. Another experimental treatment, TKM-Ebola, also now has a green light for use in patients [[4] "FDA eases restrictions on experimental Ebola drug as CDC warns of ‘inevitable’ spread to US" http://rt.com/usa/179100-ebola-fda-drug-cdc-spread/ , RT.com, 8 August 2014.]. I don’t know how many people we can treat with the quantity of TKM-Ebola available today. I hope it is many more than the five we could treat with ZMapp.
>
> At least five patients have received a potentially effective treatment, but nobody has yet been assigned to a control group. This is the ethical travesty, and it needs to stop.
>
> With 1013/1848 = 55% of reported Ebola patients dying during this outbreak, you may think that we don’t need a control group. Surely we will notice if the death rate goes down from there [[5] "Ebola prizes revisited" http://offsettingbehaviour.blogspot.com/2014/08/ebola-prizes-revisited.html , by Eric Crampton, Offsetting Behavior, 5 August 2014.]. But this is not as easy as you might think. Some of those infected patients haven’t died yet, but will die later, so the true death rate is likely a little higher than 55%. And neither the typically more privileged patients who receive the therapies, nor the care they receive during their treatment are likely to be representative of the average Ebola patient suffering and perhaps dying at home in their village.
>
> A control group is not only essential for good science backed by rigorous statistics, but it is also ethically sound. Many people are understandably concerned about deliberately withholding potentially life-saving treatment and giving a placebo instead. But this is a moot point; we have no choice about withholding treatment. There isn’t enough of it to go around. The fairest way to distribute it is by lottery. This fairest plan also happens to be the best scientific plan. The question is whether we capitalize on our inability in the service of science by implementing a well-designed lottery, or whether we squander it instead with a less systematic lottery of who gets treated and who misses out.
>
> This situation has an important and telling precedent. The very first randomized clinical trial ever published [[6] "Streptomycin Treatment of Pulmonary Tuberculosis" https://pdf.yt/d/BQ9v5fvb7gUmcrnW / https://dl.dropboxusercontent.com/u/182368464/1948-streptomycincommittee.pdf , British Medical Journal, 30 October 1948.] in 1948 investigated whether antibiotics are effective against tuberculosis with Ebola-like death rates. Just like today, there was a shortage of a new drug, streptomycin. In the aftermath of World War II, Britain received only a very limited supply from American manufacturers. The Medical Research Council controlled this shipment, and seized the opportunity to dictate to doctors that if they wanted access to the drug for their patients, the only way to get it was by taking their chances within a randomized trial. Thus began a golden era of effective medical science [[7] "Controlled trials: the 1948 watershed" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1114161/ , British Medical Journal, 31 October 1998.], led by a strikingly novel and extraordinarily effective gold standard. What is more, to everyone’s surprise, the streptomycin treatment had limited effectiveness against tuberculosis. Patients improved initially, but then the bacteria evolved resistance to the drug and patients deteriorated again. This phenomenon of drug resistance had never been seen before. The randomized trial allowed this failure to be quickly recognized, leading to the improved and effective treatment protocols we have today.
>
> We have so few doses available, and it is unethical to waste them in unsystematic tests that lack a control group. The US should have led the way by tossing a coin to see which of the two American patients got ZMapp and which got a placebo. And then it should have given its second dose to Africa on the condition that it be randomly distributed to one out of two preselected patients in the same manner. This would have been the ethical thing to do.
>
> If ten patients had been rigorously randomized such that only five of them received the scarce ZMapp treatments and the other five got a placebo, and if ZMapp really were a miracle drug reducing the death rate from 60% to 0%, then there is a 69% probability that we would have been able to conclude in a “statistically significant” fashion, from that tiny but well designed trial, that the drug works. We think of randomized trials as huge affairs. And it is true that to detect subtle differences, we do need huge trials. But when the improvements are not subtle, trials can be quite small. Sixteen patients (eight per group) would be enough to have a 95% chance of detecting the effectiveness of a miracle drug. Even if the drug were slightly less miraculous, dropping the death rate from 60% to 30%, the 10-patient trial that we could and should have done with existing resources would have had a 42% chance of detecting the drug’s effectiveness. Our unsystematic trial of five patients will tell us much less, squandering this opportunity to make best use of the limited supply of ZMapp that we had.
>
> ...What we should learn from the history of randomized trials is that the biggest danger with randomization comes from the urge to cheat. It is only natural for doctors to have special sympathy for particular patients, and to rig the game so that their favorite patients end up in the treatment group rather than the placebo. This is the real historical reason that trials were made “double blind” so that neither patient nor doctor knows who gets what. There is a lot of talk about the power of the placebo effect, and it is important for some conditions such as pain, but for most diseases the placebo effect is overrated. A placebo won’t stop you dying of Ebola just because you believe in it. But a double blind design is still an important precaution to make it impossible for well-meaning doctors to rig the allocations.
http://www.cnn.com/2014/08/17/world/africa/ebola-liberia-attack/index.html?hpt=hp_t2 caption, slideshow photo #6:
> Liberian police depart after firing shots in the air while trying to protect an Ebola burial team in the West Point slum of Monrovia on August 16, 2014. A crowd of several hundred local residents reportedly drove away the burial team and their police escort. The mob then forced open an Ebola isolation ward and took the patients out, many saying that the Ebola epidemic is a hoax.
"Controlled trials: the 1948 watershed" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1114161/ Doll 1998
> When I qualified in medicine in 1937, new treatments were almost always introduced on the grounds that in the hands of professor A or in the hands of a consultant at one of the leading teaching hospitals, the results in a small series of patients (seldom more than 50) had been superior to those recorded by professor B (or some other consultant) or by the same investigator previously. Under these conditions variability of outcome, chance, and the unconscious (leave alone the conscious) in the selection of patients brought about apparently important differences in the results obtained; consequently, there were many competing new treatments. The treatment of peptic ulcer was, perhaps, more susceptible to claims of benefit than most other chronic diseases; so that in 1948, when I began to investigate it, I was soon able to prepare a list of treatments beginning with each letter of the alphabet. Standard treatments, for their part, tended to be passed from one textbook to another without ever being adequately evaluated.
>
> ...One way of avoiding such biases would be to divide the patients into two similar groups before it was known which group would get which treatment and then, at the last minute, allocate one whole group to one treatment and the other to another by tossing a coin. This method was proposed by van Helmont, a medicinal chemist, in 1662 when he challenged the academics of the day to compare their treatments based on theory with his based on experience. “Let us take out of the hospitals, out of the Camps, or from elsewhere, 200, or 500 poor People, that have Fevers, Pleurisies, etc. Let us divide them into half, let us cast lots, that one half of them may fall to my share, and the other to yours ... We shall see how many funerals both of us shall have. But let the reward of the contention or wager, be 300 florens, deposited on both sides.”5 Sadly, the challenge was not accepted. The technique was, however, actually put into practice by Amberson et al 260 years later to assess the value of sodium gold thiosulphate in the treatment of pulmonary tuberculosis.6 Amberson et al divided 24 patients into two groups of 12, the members of each group being “individually matched” in pairs. They then tossed a coin to decide which treatment each group should get. This technique suffers, as Armitage has pointed out,5 not only from the virtual impossibility of truly being able to match cases, but also because it provides no means of measuring the relevant random error. Both difficulties are overcome within quantifiable limits by the randomisation of individuals.
>
> ...He [Bradford Hill] did not recommend the randomisation of individuals then, preferring that the two treatments for comparison be allocated to alternate patients because, as he wrote in 1990, by referring to the randomisation of treatments he might have scared doctors off any use of concurrent controls.9 In 1946, when he judged the time was right, he recommended the randomisation of individual patients and this rapidly gained acceptance among medical scientists.10,11 He advocated it not so much because it provided a proper estimate of random error, which was the principal reason it was advocated by Fisher, but on the practical grounds that it eliminated bias in selection.
>
> ...In the trial of streptomycin, the first issue that had to be faced was whether it was ethical to withhold from any patient a drug that had been effective in animal experiments and had had encouraging clinical results in the few published reports. There was, however, only a small amount of the drug in Britain and it was not possible to buy more from abroad. It was agreed to use the limited supplies to treat patients with two conditions that had previously been invariably fatal: miliary tuberculosis and tuberculous meningitis. The amount of streptomycin left over was insufficient to treat more than a tiny proportion of the people desperately ill with other types of tuberculosis. The Medical Research Council’s Streptomycin in Tuberculosis Trials Committee agreed that “it would have been unethical not to have seized the opportunity to design a strictly controlled trial which could speedily and effectively reveal the value of the treatment.”12 The question of whether it was ethically justifiable to withhold the drug from any patient was, therefore, answered with an unhesitating “Yes.”
>
> ...The spread of randomisation, until it became an essential element of trials submitted to licensing authorities for the approval of new drugs, was initially slow and not without opposition. This was most commonly expressed along the lines of Lewis’s criticism of what he called “the statistical method of testing treatment.”14 Lewis was the doctor in charge of the department of clinical research at University College Hospital, London, and the doyen of clinical research in the United Kingdom in the 1930s. He died in 1945 before randomised trials were introduced but I can imagine what his reaction would have been. Lewis thought that when testing treatments for acute diseases two groups of patients that were as similar as possible should be treated in exactly the same way and concurrently, except that one group should receive the remedy and the other should not. However, he added that “it is to be recognised that the statistical method of testing treatment is never more than a temporary expedient, and that but little progress can come of it directly: for in investigating cases collectively, it does not discriminate between cases that benefit and those that do not, and so fails to determine criteria by which we may know beforehand in any given case that treatment will be successful.”14 Lewis’s objection was repeated many times in the first few years after randomisation was introduced. Bradford Hill would reply: “Tell me the criteria to distinguish patients who will respond from those who don’t and we will build this into the trial”(A Bradford Hill, personal communication). There was never any serious response to Bradford Hill’s challenge
>
> ...Early randomised trials can properly be criticised on the grounds that they were often too small to have any chance of detecting moderate effects...For example, many early trials of the treatment of myocardial infarction, stroke, and cancer, which were not large by modern standards, consequently led to the misleading conclusion that there was no benefit. Bradford Hill and his students, such as myself, were primarily concerned with getting the principle adopted, and to have pressed for trials on thousands of patients would have been self defeating. There were too few physicians, leave alone surgeons, who were willing to expose their theories to cold scientific investigation...It was many years before randomisation was accepted as such a normal procedure. Only then did it become possible to organise the groundbreaking international study of infarct survival (ISIS) trials for the treatment of myocardial infarction, which involved hundreds of centres and randomly allocated tens of thousands of patients, and thereby showed the value of moderate improvements in the treatment of common diseases.17