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Learning from the literature
The leading edge
Learning from the literature The importance of conducting thorough literature searches before initiating clinical trials with investigational drugs, was brought to the fore in July 2001, with the report on the death of a healthy volunteer in a study of hexamethonium at Johns Hopkins University, USA (report available at http://www.jhu.edu). One point that emerged clearly from the resulting investigation was that the researchers had failed to do a comprehensive literature search, which would have revealed published work describing cases of pulmonary side-effects with hexamethonium. The investigators only used one search engine, and this was not even a medical bibliographic database. They took the view – mistakenly, as it turned out – that because the four reports of similar studies they found made no mention of toxic effects, that no such effects had been observed. During the investigation, committee members themselves conducted searches to see how easy it was to find information about the pulmonary side-effects of hexamethonium; some members were unable to find the specific references until several search engines had been used, review articles identified, and detailed analysis of 1950s material reviewed. As MEDLINE alone contains over 10 million references to journal articles, and 400 000 references are added annually from 3900 journals, and since records only began in 1966, this is perhaps not surprising. These findings have prompted Johns Hopkins to provide guidelines for its staff and Institutional Review Boards (IRB) on the standards required for literature searching. The guidelines produced by the committee, which included scientists, librarians, and a pharmacist, have been circulated to external experts in medical information and will soon be made public. The committee concluded that, at Johns Hopkins, the responsibility for doing a comprehensive literature search for drugs that do not have FDA Investigational New Drug status, such as hexamethonium, rests entirely with the investigators and the IRB. The main recommendations are that investigators at Johns Hopkins must work together with a librarian and a pharmacist to do a comprehensive literature search and then collate the material collected into a summary of evidence to be given to the IRB for approval. It is highly likely that key data have been missed in other research studies. As investigators are unlikely to have been trained in literature searching, it seems logical to enlist the help of people qualified in medical
THE LANCET Oncology Vol 2 October 2001
information – surprisingly, there is no evidence that anyone has gone down this route before. Researchers need to work closely with medical information experts, indicating clearly why they need the search, and if possible specifying what they are looking for. If there is a possibility of studies published before 1966 being relevant, they may need to search extra databases, such as OLDMEDLINE. With the vast amount of published work accumulating, reviews of treatment strategies and systematic reviews of randomised clinical trials are essential, and preparation for producing these articles also requires careful searching. The Cochrane Collaboration has been working to increase the accuracy and ease of identifying relevant studies – randomised controlled trials – for systematic reviews. This is an onerous task, especially when, without expert knowledge of search terms and search strategies, many randomised controlled trials will not be picked up. In 1993, only 19 000 reports of controlled trials were easily identifiable in MEDLINE. The UK and New England Cochrane Centres have now identified a further 69 000 reports in MEDLINE, 33 000 reports from EMBASE, and thousands more reports of controlled trials by handsearching journals not indexed in these databases or published before 1966. These reports are all available in The Cochrane Controlled Trials Register. The results of thorough literature searching and systematic review can make a difference to treatment decisions and standard therapies. For example, the importance of adjuvant ovarian ablation for breast cancer has been rediscovered as a consequence of systematic reviews by the Early Breast Cancer Collaborative Group, first published in the 1990s and still being maintained. The first case reports of ovarian ablation were published in The Lancet in 1896 and one of the earliest randomised trials of a treatment of cancer was of ovarian ablation for cancer, started by R Paterson in the UK in 1948. Finally, if researchers fail to do comprehensive literature searches before starting new projects, they run the risk of repeating work that has already been done, thereby wasting valuable time and resources. The vast body of published work, available to most of us at the click of a button, is a vital source of information to learn from and to build on – let’s make sure we use it properly. The Lancet Oncology
587
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Learning from the literature The importance of conducting thorough literature searches before initiating clinical trials with investigational drugs, was brought to the fore in July 2001, with the report on the death of a healthy volunteer in a study of hexamethonium at Johns Hopkins University, USA (report available at http://www.jhu.edu). One point that emerged clearly from the resulting investigation was that the researchers had failed to do a comprehensive literature search, which would have revealed published work describing cases of pulmonary side-effects with hexamethonium. The investigators only used one search engine, and this was not even a medical bibliographic database. They took the view – mistakenly, as it turned out – that because the four reports of similar studies they found made no mention of toxic effects, that no such effects had been observed. During the investigation, committee members themselves conducted searches to see how easy it was to find information about the pulmonary side-effects of hexamethonium; some members were unable to find the specific references until several search engines had been used, review articles identified, and detailed analysis of 1950s material reviewed. As MEDLINE alone contains over 10 million references to journal articles, and 400 000 references are added annually from 3900 journals, and since records only began in 1966, this is perhaps not surprising. These findings have prompted Johns Hopkins to provide guidelines for its staff and Institutional Review Boards (IRB) on the standards required for literature searching. The guidelines produced by the committee, which included scientists, librarians, and a pharmacist, have been circulated to external experts in medical information and will soon be made public. The committee concluded that, at Johns Hopkins, the responsibility for doing a comprehensive literature search for drugs that do not have FDA Investigational New Drug status, such as hexamethonium, rests entirely with the investigators and the IRB. The main recommendations are that investigators at Johns Hopkins must work together with a librarian and a pharmacist to do a comprehensive literature search and then collate the material collected into a summary of evidence to be given to the IRB for approval. It is highly likely that key data have been missed in other research studies. As investigators are unlikely to have been trained in literature searching, it seems logical to enlist the help of people qualified in medical
THE LANCET Oncology Vol 2 October 2001
information – surprisingly, there is no evidence that anyone has gone down this route before. Researchers need to work closely with medical information experts, indicating clearly why they need the search, and if possible specifying what they are looking for. If there is a possibility of studies published before 1966 being relevant, they may need to search extra databases, such as OLDMEDLINE. With the vast amount of published work accumulating, reviews of treatment strategies and systematic reviews of randomised clinical trials are essential, and preparation for producing these articles also requires careful searching. The Cochrane Collaboration has been working to increase the accuracy and ease of identifying relevant studies – randomised controlled trials – for systematic reviews. This is an onerous task, especially when, without expert knowledge of search terms and search strategies, many randomised controlled trials will not be picked up. In 1993, only 19 000 reports of controlled trials were easily identifiable in MEDLINE. The UK and New England Cochrane Centres have now identified a further 69 000 reports in MEDLINE, 33 000 reports from EMBASE, and thousands more reports of controlled trials by handsearching journals not indexed in these databases or published before 1966. These reports are all available in The Cochrane Controlled Trials Register. The results of thorough literature searching and systematic review can make a difference to treatment decisions and standard therapies. For example, the importance of adjuvant ovarian ablation for breast cancer has been rediscovered as a consequence of systematic reviews by the Early Breast Cancer Collaborative Group, first published in the 1990s and still being maintained. The first case reports of ovarian ablation were published in The Lancet in 1896 and one of the earliest randomised trials of a treatment of cancer was of ovarian ablation for cancer, started by R Paterson in the UK in 1948. Finally, if researchers fail to do comprehensive literature searches before starting new projects, they run the risk of repeating work that has already been done, thereby wasting valuable time and resources. The vast body of published work, available to most of us at the click of a button, is a vital source of information to learn from and to build on – let’s make sure we use it properly. The Lancet Oncology
587
For personal use. Only reproduce with permission from The Lancet Publishing Group.