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1.  Information from Pharmaceutical Companies and the Quality, Quantity, and Cost of Physicians' Prescribing: A Systematic Review 
PLoS Medicine  2010;7(10):e1000352.
Geoff Spurling and colleagues report findings of a systematic review looking at the relationship between exposure to promotional material from pharmaceutical companies and the quality, quantity, and cost of prescribing. They fail to find evidence of improvements in prescribing after exposure, and find some evidence of an association with higher prescribing frequency, higher costs, or lower prescribing quality.
Background
Pharmaceutical companies spent $57.5 billion on pharmaceutical promotion in the United States in 2004. The industry claims that promotion provides scientific and educational information to physicians. While some evidence indicates that promotion may adversely influence prescribing, physicians hold a wide range of views about pharmaceutical promotion. The objective of this review is to examine the relationship between exposure to information from pharmaceutical companies and the quality, quantity, and cost of physicians' prescribing.
Methods and Findings
We searched for studies of physicians with prescribing rights who were exposed to information from pharmaceutical companies (promotional or otherwise). Exposures included pharmaceutical sales representative visits, journal advertisements, attendance at pharmaceutical sponsored meetings, mailed information, prescribing software, and participation in sponsored clinical trials. The outcomes measured were quality, quantity, and cost of physicians' prescribing. We searched Medline (1966 to February 2008), International Pharmaceutical Abstracts (1970 to February 2008), Embase (1997 to February 2008), Current Contents (2001 to 2008), and Central (The Cochrane Library Issue 3, 2007) using the search terms developed with an expert librarian. Additionally, we reviewed reference lists and contacted experts and pharmaceutical companies for information. Randomized and observational studies evaluating information from pharmaceutical companies and measures of physicians' prescribing were independently appraised for methodological quality by two authors. Studies were excluded where insufficient study information precluded appraisal. The full text of 255 articles was retrieved from electronic databases (7,185 studies) and other sources (138 studies). Articles were then excluded because they did not fulfil inclusion criteria (179) or quality appraisal criteria (18), leaving 58 included studies with 87 distinct analyses. Data were extracted independently by two authors and a narrative synthesis performed following the MOOSE guidelines. Of the set of studies examining prescribing quality outcomes, five found associations between exposure to pharmaceutical company information and lower quality prescribing, four did not detect an association, and one found associations with lower and higher quality prescribing. 38 included studies found associations between exposure and higher frequency of prescribing and 13 did not detect an association. Five included studies found evidence for association with higher costs, four found no association, and one found an association with lower costs. The narrative synthesis finding of variable results was supported by a meta-analysis of studies of prescribing frequency that found significant heterogeneity. The observational nature of most included studies is the main limitation of this review.
Conclusions
With rare exceptions, studies of exposure to information provided directly by pharmaceutical companies have found associations with higher prescribing frequency, higher costs, or lower prescribing quality or have not found significant associations. We did not find evidence of net improvements in prescribing, but the available literature does not exclude the possibility that prescribing may sometimes be improved. Still, we recommend that practitioners follow the precautionary principle and thus avoid exposure to information from pharmaceutical companies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
A prescription drug is a medication that can be supplied only with a written instruction (“prescription”) from a physician or other licensed healthcare professional. In 2009, 3.9 billion drug prescriptions were dispensed in the US alone and US pharmaceutical companies made US$300 billion in sales revenue. Every year, a large proportion of this revenue is spent on drug promotion. In 2004, for example, a quarter of US drug revenue was spent on pharmaceutical promotion. The pharmaceutical industry claims that drug promotion—visits from pharmaceutical sales representatives, advertisements in journals and prescribing software, sponsorship of meetings, mailed information—helps to inform and educate healthcare professionals about the risks and benefits of their products and thereby ensures that patients receive the best possible care. Physicians, however, hold a wide range of views about pharmaceutical promotion. Some see it as a useful and convenient source of information. Others deny that they are influenced by pharmaceutical company promotion but claim that it influences other physicians. Meanwhile, several professional organizations have called for tighter control of promotional activities because of fears that pharmaceutical promotion might encourage physicians to prescribe inappropriate or needlessly expensive drugs.
Why Was This Study Done?
But is there any evidence that pharmaceutical promotion adversely influences prescribing? Reviews of the research literature undertaken in 2000 and 2005 provide some evidence that drug promotion influences prescribing behavior. However, these reviews only partly assessed the relationship between information from pharmaceutical companies and prescribing costs and quality and are now out of date. In this study, therefore, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) to reexamine the relationship between exposure to information from pharmaceutical companies and the quality, quantity, and cost of physicians' prescribing.
What Did the Researchers Do and Find?
The researchers searched the literature for studies of licensed physicians who were exposed to promotional and other information from pharmaceutical companies. They identified 58 studies that included a measure of exposure to any type of information directly provided by pharmaceutical companies and a measure of physicians' prescribing behavior. They then undertook a “narrative synthesis,” a descriptive analysis of the data in these studies. Ten of the studies, they report, examined the relationship between exposure to pharmaceutical company information and prescribing quality (as judged, for example, by physician drug choices in response to clinical vignettes). All but one of these studies suggested that exposure to drug company information was associated with lower prescribing quality or no association was detected. In the 51 studies that examined the relationship between exposure to drug company information and prescribing frequency, exposure to information was associated with more frequent prescribing or no association was detected. Thus, for example, 17 out of 29 studies of the effect of pharmaceutical sales representatives' visits found an association between visits and increased prescribing; none found an association with less frequent prescribing. Finally, eight studies examined the relationship between exposure to pharmaceutical company information and prescribing costs. With one exception, these studies indicated that exposure to information was associated with a higher cost of prescribing or no association was detected. So, for example, one study found that physicians with low prescribing costs were more likely to have rarely or never read promotional mail or journal advertisements from pharmaceutical companies than physicians with high prescribing costs.
What Do These Findings Mean?
With rare exceptions, these findings suggest that exposure to pharmaceutical company information is associated with either no effect on physicians' prescribing behavior or with adverse affects (reduced quality, increased frequency, or increased costs). Because most of the studies included in the review were observational studies—the physicians in the studies were not randomly selected to receive or not receive drug company information—it is not possible to conclude that exposure to information actually causes any changes in physician behavior. Furthermore, although these findings provide no evidence for any net improvement in prescribing after exposure to pharmaceutical company information, the researchers note that it would be wrong to conclude that improvements do not sometimes happen. The findings support the case for reforms to reduce negative influence to prescribing from pharmaceutical promotion.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000352.
Wikipedia has pages on prescription drugs and on pharmaceutical marketing (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The UK General Medical Council provides guidelines on good practice in prescribing medicines
The US Food and Drug Administration provides information on prescription drugs and on its Bad Ad Program
Healthy Skepticism is an international nonprofit membership association that aims to improve health by reducing harm from misleading health information
The Drug Promotion Database was developed by the World Health Organization Department of Essential Drugs & Medicines Policy and Health Action International Europe to address unethical and inappropriate drug promotion
doi:10.1371/journal.pmed.1000352
PMCID: PMC2957394  PMID: 20976098
2.  A Statistical Model of the International Spread of Wild Poliovirus in Africa Used to Predict and Prevent Outbreaks 
PLoS Medicine  2011;8(10):e1001109.
Using outbreak data from 2003–2010, Kathleen O'Reilly and colleagues develop a statistical model of the spread of wild polioviruses in Africa that can predict polio outbreaks six months in advance.
Background
Outbreaks of poliomyelitis in African countries that were previously free of wild-type poliovirus cost the Global Polio Eradication Initiative US$850 million during 2003–2009, and have limited the ability of the program to focus on endemic countries. A quantitative understanding of the factors that predict the distribution and timing of outbreaks will enable their prevention and facilitate the completion of global eradication.
Methods and Findings
Children with poliomyelitis in Africa from 1 January 2003 to 31 December 2010 were identified through routine surveillance of cases of acute flaccid paralysis, and separate outbreaks associated with importation of wild-type poliovirus were defined using the genetic relatedness of these viruses in the VP1/2A region. Potential explanatory variables were examined for their association with the number, size, and duration of poliomyelitis outbreaks in 6-mo periods using multivariable regression analysis. The predictive ability of 6-mo-ahead forecasts of poliomyelitis outbreaks in each country based on the regression model was assessed. A total of 142 genetically distinct outbreaks of poliomyelitis were recorded in 25 African countries, resulting in 1–228 cases (median of two cases). The estimated number of people arriving from infected countries and <5-y childhood mortality were independently associated with the number of outbreaks. Immunisation coverage based on the reported vaccination history of children with non-polio acute flaccid paralysis was associated with the duration and size of each outbreak, as well as the number of outbreaks. Six-month-ahead forecasts of the number of outbreaks in a country or region changed over time and had a predictive ability of 82%.
Conclusions
Outbreaks of poliomyelitis resulted primarily from continued transmission in Nigeria and the poor immunisation status of populations in neighbouring countries. From 1 January 2010 to 30 June 2011, reduced transmission in Nigeria and increased incidence in reinfected countries in west and central Africa have changed the geographical risk of polio outbreaks, and will require careful immunisation planning to limit onward spread.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
During the first half of the 20th century, polio (poliomyelitis) was one of the most feared infectious diseases in industrialized countries, paralyzing thousands of young children every year. The virus that causes polio enters the human body through ingestion of contaminated water or food, multiplies in the gut, and is shed through the feces (stool) into the environment, where it spreads rapidly if sanitation or personal hygiene is poor. Most people infected with poliovirus have no symptoms, but about one in 200 infected people develop paralytic polio, in which poliovirus invades and destroys the nerve cells that control the arm and leg muscles, leading to acute flaccid paralysis (AFP; limb paralysis). In the worst cases, poliovirus paralyzes the muscles involved in breathing, which can be fatal unless patients are helped to breathe with an “iron lung” or ventilator. There is no cure for paralytic polio, and although AFP usually lasts less than two weeks, some patients never regain full use of their limbs.
Why Was This Study Done?
From 1955 onwards, routine polio vaccination rapidly reduced or eliminated wild polio (polio occurring through natural infection) in developed countries, but the disease remained common in developing countries. Consequently, in 1988, the Global Polio Eradication Initiative was launched. Between 1988 and 2009, routine vaccination and supplementary immunization activities (additional doses of polio vaccine given to all young children on national immunization days) reduced the annual number of children paralyzed by polio from 350,000 to about 1,600 and the number of countries where polio is endemic (always present) from 125 to four. Unfortunately, continued circulation of wild polioviruses in Nigeria and India resulted in reinfection of 19 African countries in 2009 and re-establishment of polio transmission in four countries. A better understanding of the factors that affect the distribution and timing of wild polio outbreaks might help experts prevent such outbreaks and could facilitate global polio eradication. Here, the researchers develop a statistical model of the spread of wild polioviruses in Africa and assess its ability to predict polio outbreaks in individual African countries.
What Did the Researchers Do and Find?
The researchers used routine AFP surveillance to identify children who developed polio in Africa between 2003 and 2010. They determined whether each case was associated with the importation of wild poliovirus based on genetic analysis the polioviruses and then used “multivariable regression analysis” to identify factors associated with the number, size, and duration of polio outbreaks. During the study period, 142 genetically distinct polio outbreaks (involving one to 228 cases) were recorded in 25 African countries, with the average number of outbreaks in each country declining with reduced population movements from each infected country. The estimated number of people migrating into a country from an infected country was associated with the number of outbreaks in that country. Thus, countries with a high rate of immigration from Nigeria and other countries where polio is still endemic had more polio outbreaks than countries with less immigration from these countries. A country's mortality rate for children under 5 years of age (an indicator of sanitary conditions and access to health care) was also associated with the number of outbreaks, and immunization coverage was associated with the size, duration, and number of outbreaks. Finally, in 82% of instances, for a randomly selected country where an outbreak was observed, the statistical model predicted six months ahead of time more outbreaks for that country than for any randomly selected country where there were no outbreaks. That is, the model's predictive ability was 82%.
What Do These Findings Mean?
These findings indicate that outbreaks of polio in Africa over the study period resulted mainly from continued transmission in Nigeria and other countries that reported polio cases and from poor immunization status. They also highlight how the geographical risk of polio is changing over time in Africa. Importantly, the risk factors included by the researchers in their statistical model are sufficient to describe the scale and geographical distribution of polio outbreaks in Africa six months in advance with a high predictive ability. Although the accuracy of the predictions made by the model is limited by the structure of the model and by the data fed into it, the information provided by this and other predictive models should help the Global Polio Eradication Initiative plan its future immunization and surveillance campaigns and should facilitate the elimination of polio from Africa.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001109.
The Global Polio Eradication Initiative provides information about polio and about global efforts to eradicate the disease; its website includes links to videos about global polio elimination efforts
The World Health Organization provides information about polio and attempts to eradicate the disease (in several languages)
The US Centers for Disease Control and Prevention provides information about polio vaccination
The UK National Health Service Choices website has information on polio
MedlinePlus provides links to more resources on polio (in English and Spanish)
Personal stories about polio are available through the British Polio Fellowship Heritage Project; the National Museum of American History Whatever happened to polio? website includes an archive of polio-related pictures
doi:10.1371/journal.pmed.1001109
PMCID: PMC3196484  PMID: 22028632
3.  News at Biochemia Medica: Research integrity corner, updated Guidelines to authors, revised Author statement form and adopted ICMJE Conflict-of-interest form 
Biochemia Medica  2013;23(1):5-6.
From the issue 23(1) we have implemented several major changes in the editorial policies and procedures. We hope that those changes will raise awareness of our potential authors and reviewers for research and publication integrity issues as well as to improve the quality of our submissions and published articles. Among those changes is the launch of a special journal section called Research Integrity Corner. In this section we aim to publish educational articles dealing with different research and publication misconduct issues. Moreover, we have done a comprehensive revision of our Instructions to authors. Whereas our former Instructions to authors have mostly been concerned with recommendations for manuscript preparation and submission, the revised document additionally describes the editorial procedure for all submitted articles and provides exact journal policies towards research integrity, authorship, copyright and conflict of interest. By putting these Guidelines into action, we hope that our main ethical policies and requirements are now visible and available to all our potential authors. We have also revised the former Authorship and copyright form which is now called the Author statement form. This form now contains statements on the authorship, originality of work, research ethics, patient privacy and confidentiality, and copyright transfer. Finally, Journal has adopted the ICMJE Form for Disclosure of Potential Conflicts of Interest. From this issue, for each submitted article, authors are requested to fill out the “ICMJE Form for Disclosure of Potential Conflicts of Interest” as well as the Author statement form and upload those forms during the online manuscript submission process. We honestly believe that our authors and readers will appreciate such endeavors. In this Editorial article we briefly explain the background and the nature of those recent major editorial changes.
doi:10.11613/BM.2013.001
PMCID: PMC3900092  PMID: 23457759
scientific misconduct; plagiarism; editorial policies
4.  Factors Associated with Findings of Published Trials of Drug–Drug Comparisons: Why Some Statins Appear More Efficacious than Others 
PLoS Medicine  2007;4(6):e184.
Background
Published pharmaceutical industry–sponsored trials are more likely than non-industry-sponsored trials to report results and conclusions that favor drug over placebo. Little is known about potential biases in drug–drug comparisons. This study examined associations between research funding source, study design characteristics aimed at reducing bias, and other factors that potentially influence results and conclusions in randomized controlled trials (RCTs) of statin–drug comparisons.
Methods and Findings
This is a cross-sectional study of 192 published RCTs comparing a statin drug to another statin drug or non-statin drug. Data on concealment of allocation, selection bias, blinding, sample size, disclosed funding source, financial ties of authors, results for primary outcomes, and author conclusions were extracted by two coders (weighted kappa 0.80 to 0.97). Univariate and multivariate logistic regression identified associations between independent variables and favorable results and conclusions. Of the RCTs, 50% (95/192) were funded by industry, and 37% (70/192) did not disclose any funding source. Looking at the totality of available evidence, we found that almost all studies (98%, 189/192) used only surrogate outcome measures. Moreover, study design weaknesses common to published statin–drug comparisons included inadequate blinding, lack of concealment of allocation, poor follow-up, and lack of intention-to-treat analyses. In multivariate analysis of the full sample, trials with adequate blinding were less likely to report results favoring the test drug, and sample size was associated with favorable conclusions when controlling for other factors. In multivariate analysis of industry-funded RCTs, funding from the test drug company was associated with results (odds ratio = 20.16 [95% confidence interval 4.37–92.98], p < 0.001) and conclusions (odds ratio = 34.55 [95% confidence interval 7.09–168.4], p < 0.001) that favor the test drug when controlling for other factors. Studies with adequate blinding were less likely to report statistically significant results favoring the test drug.
Conclusions
RCTs of head-to-head comparisons of statins with other drugs are more likely to report results and conclusions favoring the sponsor's product compared to the comparator drug. This bias in drug–drug comparison trials should be considered when making decisions regarding drug choice.
Lisa Bero and colleagues found published trials comparing one statin with another were more likely to report results and conclusions favoring the sponsor's product than the comparison drug.
Editors' Summary
Background.
Randomized controlled trials are generally considered to be the most reliable type of experimental study for evaluating the effectiveness of different treatments. Randomization involves the assignment of participants in the trial to different treatment groups by the play of chance. Properly done, this procedure means that the different groups are comparable at outset, reducing the chance that outside factors could be responsible for treatment effects seen in the trial. When done properly, randomization also ensures that the clinicians recruiting participants into the trial cannot know the treatment group to which a patient will end up being assigned. However, despite these advantages, a large number of factors can still result in bias creeping in. Bias comes about when the findings of research appear to differ in some systematic way from the true result. Other research studies have suggested that funding is a source of bias; studies sponsored by drug companies seem to more often favor the sponsor's drug than trials not sponsored by drug companies
Why Was This Study Done?
The researchers wanted to more precisely understand the impact of different possible sources of bias in the findings of randomized controlled trials. In particular, they wanted to study the outcomes of “head-to-head” drug comparison studies for one particular class of drugs, the statins. Drugs in this class are commonly prescribed to reduce the levels of cholesterol in blood amongst people who are at risk of heart and other types of disease. This drug class is a good example for studying the role of bias in drug–drug comparison trials, because these trials are extensively used in decision making by health-policy makers.
What Did the Researchers Do and Find?
This research study was based on searching PubMed, a biomedical literature database, with the aim of finding all randomized controlled trials of statins carried out between January 1999 and May 2005 (reference lists also were searched). Only trials which compared one statin to another statin or one statin to another type of drug were included. The researchers extracted the following information from each article: the study's source of funding, aspects of study design, the overall results, and the authors' conclusions. The results were categorized to show whether the findings were favorable to the test drug (the newer statin), inconclusive, or not favorable to the test drug. Aspects of each study's design were also categorized in relation to various features, such as how well the randomization was done (in particular, the degree to which the processes used would have prevented physicians from knowing which treatment a patient was likely to receive on enrollment); whether all participants enrolled in the trial were eventually analyzed; and whether investigators or participants knew what treatment an individual was receiving.
One hundred and ninety-two trials were included in this study, and of these, 95 declared drug company funding; 23 declared government or other nonprofit funding while 74 did not declare funding or were not funded. Trials that were properly blinded (where participants and investigators did not know what treatment an individual received) were less likely to have conclusions favoring the test drug. However, large trials were more likely to favor the test drug than smaller trials. When looking specifically at the trials funded by drug companies, the researchers found various factors that predicted whether a result or conclusion favored the test drug. These included the impact of the journal publishing the results; the size of the trial; and whether funding came from the maker of the test drug. However, properly blinded trials were less likely to produce results favoring the test drug. Even once all other factors were accounted for, the funding source for the study was still linked with results and conclusions that favored the maker of the test drug.
What Do These Findings Mean?
This study shows that the type of sponsorship available for randomized controlled trials of statins was strongly linked to the results and conclusions of those studies, even when other factors were taken into account. However, it is not clear from this study why sponsorship has such a strong link to the overall findings. There are many possible reasons why this might be. Some people have suggested that drug companies may deliberately choose lower dosages for the comparison drug when they carry out “head-to-head” trials; this tactic is likely to result in the company's product doing better in the trial. Others have suggested that trials which produce unfavorable results are not published, or that unfavorable outcomes are suppressed. Whatever the reasons for these findings, the implications are important, and suggest that the evidence base relating to statins may be substantially biased.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040184.
The James Lind Library has been created to help people understand fair tests of treatments in health care by illustrating how fair tests have developed over the centuries
The International Committee of Medical Journal Editors has provided guidance regarding sponsorship, authorship, and accountability
The CONSORT statement is a research tool that provides an evidence-based approach for reporting the results of randomized controlled trials
Good Publication Practice guidelines provide standards for responsible publication of research sponsored by pharmaceutical companies
Information from Wikipedia on Statins. Wikipedia is an internet encyclopedia anyone can edit
doi:10.1371/journal.pmed.0040184
PMCID: PMC1885451  PMID: 17550302
5.  Medical Students' Exposure to and Attitudes about the Pharmaceutical Industry: A Systematic Review 
PLoS Medicine  2011;8(5):e1001037.
A systematic review of published studies reveals that undergraduate medical students may experience substantial exposure to pharmaceutical marketing, and that this contact may be associated with positive attitudes about marketing.
Background
The relationship between health professionals and the pharmaceutical industry has become a source of controversy. Physicians' attitudes towards the industry can form early in their careers, but little is known about this key stage of development.
Methods and Findings
We performed a systematic review reported according to PRISMA guidelines to determine the frequency and nature of medical students' exposure to the drug industry, as well as students' attitudes concerning pharmaceutical policy issues. We searched MEDLINE, EMBASE, Web of Science, and ERIC from the earliest available dates through May 2010, as well as bibliographies of selected studies. We sought original studies that reported quantitative or qualitative data about medical students' exposure to pharmaceutical marketing, their attitudes about marketing practices, relationships with industry, and related pharmaceutical policy issues. Studies were separated, where possible, into those that addressed preclinical versus clinical training, and were quality rated using a standard methodology. Thirty-two studies met inclusion criteria. We found that 40%–100% of medical students reported interacting with the pharmaceutical industry. A substantial proportion of students (13%–69%) were reported as believing that gifts from industry influence prescribing. Eight studies reported a correlation between frequency of contact and favorable attitudes toward industry interactions. Students were more approving of gifts to physicians or medical students than to government officials. Certain attitudes appeared to change during medical school, though a time trend was not performed; for example, clinical students (53%–71%) were more likely than preclinical students (29%–62%) to report that promotional information helps educate about new drugs.
Conclusions
Undergraduate medical education provides substantial contact with pharmaceutical marketing, and the extent of such contact is associated with positive attitudes about marketing and skepticism about negative implications of these interactions. These results support future research into the association between exposure and attitudes, as well as any modifiable factors that contribute to attitudinal changes during medical education.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The complex relationship between health professionals and the pharmaceutical industry has long been a subject of discussion among physicians and policymakers. There is a growing body of evidence that suggests that physicians' interactions with pharmaceutical sales representatives may influence clinical decision making in a way that is not always in the best interests of individual patients, for example, encouraging the use of expensive treatments that have no therapeutic advantage over less costly alternatives. The pharmaceutical industry often uses physician education as a marketing tool, as in the case of Continuing Medical Education courses that are designed to drive prescribing practices.
One reason that physicians may be particularly susceptible to pharmaceutical industry marketing messages is that doctors' attitudes towards the pharmaceutical industry may form early in their careers. The socialization effect of professional schooling is strong, and plays a lasting role in shaping views and behaviors.
Why Was This Study Done?
Recently, particularly in the US, some medical schools have limited students' and faculties' contact with industry, but some have argued that these restrictions are detrimental to students' education. Given the controversy over the pharmaceutical industry's role in undergraduate medical training, consolidating current knowledge in this area may be useful for setting priorities for changes to educational practices. In this study, the researchers systematically examined studies of pharmaceutical industry interactions with medical students and whether such interactions influenced students' views on related topics.
What Did the Researchers Do and Find?
The researchers did a comprehensive literature search using appropriate search terms for all relevant quantitative and qualitative studies published before June 2010. Using strict inclusion criteria, the researchers then selected 48 articles (from 1,603 abstracts) for full review and identified 32 eligible for analysis—giving a total of approximately 9,850 medical students studying at 76 medical schools or hospitals.
Most students had some form of interaction with the pharmaceutical industry but contact increased in the clinical years, with up to 90% of all clinical students receiving some form of educational material. The highest level of exposure occurred in the US. In most studies, the majority of students in their clinical training years found it ethically permissible for medical students to accept gifts from drug manufacturers, while a smaller percentage of preclinical students reported such attitudes. Students justified their entitlement to gifts by citing financial hardship or by asserting that most other students accepted gifts. In addition, although most students believed that education from industry sources is biased, students variably reported that information obtained from industry sources was useful and a valuable part of their education.
Almost two-thirds of students reported that they were immune to bias induced by promotion, gifts, or interactions with sales representatives but also reported that fellow medical students or doctors are influenced by such encounters. Eight studies reported a relationship between exposure to the pharmaceutical industry and positive attitudes about industry interactions and marketing strategies (although not all included supportive statistical data). Finally, student opinions were split on whether physician–industry interactions should be regulated by medical schools or the government.
What Do These Findings Mean?
This analysis shows that students are frequently exposed to pharmaceutical marketing, even in the preclinical years, and that the extent of students' contact with industry is generally associated with positive attitudes about marketing and skepticism towards any negative implications of interactions with industry. Therefore, strategies to educate students about interactions with the pharmaceutical industry should directly address widely held misconceptions about the effects of marketing and other biases that can emerge from industry interactions. But education alone may be insufficient. Institutional policies, such as rules regulating industry interactions, can play an important role in shaping students' attitudes, and interventions that decrease students' contact with industry and eliminate gifts may have a positive effect on building the skills that evidence-based medical practice requires. These changes can help cultivate strong professional values and instill in students a respect for scientific principles and critical evidence review that will later inform clinical decision-making and prescribing practices.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001037.
Further information about the influence of the pharmaceutical industry on doctors and medical students can be found at the American Medical Students Association PharmFree campaign and PharmFree Scorecard, Medsin-UKs PharmAware campaign, the nonprofit organization Healthy Skepticism, and the Web site of No Free Lunch.
doi:10.1371/journal.pmed.1001037
PMCID: PMC3101205  PMID: 21629685
6.  Expanding Disease Definitions in Guidelines and Expert Panel Ties to Industry: A Cross-sectional Study of Common Conditions in the United States 
PLoS Medicine  2013;10(8):e1001500.
Background
Financial ties between health professionals and industry may unduly influence professional judgments and some researchers have suggested that widening disease definitions may be one driver of over-diagnosis, bringing potentially unnecessary labeling and harm. We aimed to identify guidelines in which disease definitions were changed, to assess whether any proposed changes would increase the numbers of individuals considered to have the disease, whether potential harms of expanding disease definitions were investigated, and the extent of members' industry ties.
Methods and Findings
We undertook a cross-sectional study of the most recent publication between 2000 and 2013 from national and international guideline panels making decisions about definitions or diagnostic criteria for common conditions in the United States. We assessed whether proposed changes widened or narrowed disease definitions, rationales offered, mention of potential harms of those changes, and the nature and extent of disclosed ties between members and pharmaceutical or device companies.
Of 16 publications on 14 common conditions, ten proposed changes widening and one narrowing definitions. For five, impact was unclear. Widening fell into three categories: creating “pre-disease”; lowering diagnostic thresholds; and proposing earlier or different diagnostic methods. Rationales included standardising diagnostic criteria and new evidence about risks for people previously considered to not have the disease. No publication included rigorous assessment of potential harms of proposed changes.
Among 14 panels with disclosures, the average proportion of members with industry ties was 75%. Twelve were chaired by people with ties. For members with ties, the median number of companies to which they had ties was seven. Companies with ties to the highest proportions of members were active in the relevant therapeutic area. Limitations arise from reliance on only disclosed ties, and exclusion of conditions too broad to enable analysis of single panel publications.
Conclusions
For the common conditions studied, a majority of panels proposed changes to disease definitions that increased the number of individuals considered to have the disease, none reported rigorous assessment of potential harms of that widening, and most had a majority of members disclosing financial ties to pharmaceutical companies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Health professionals generally base their diagnosis of physical and mental disorders among their patients on disease definitions and diagnostic thresholds that are drawn up by expert panels and published as statements or as part of clinical practice guidelines. These disease definitions and diagnostic thresholds are reviewed and updated in response to changes in disease detection methods, treatments, medical knowledge, and, in the case of mental illness, changes in cultural norms. Sometimes, the review process widens disease definitions and lowers diagnostic thresholds. Such changes can be beneficial. For example, they might ensure that life-threatening conditions are diagnosed early when they are still treatable. But the widening of disease definitions can also lead to over-diagnosis—the diagnosis of a condition in a healthy individual that will never cause any symptoms and won't lead to an early death. Over-diagnosis can unnecessarily label people as ill, harm healthy individuals by exposing them to treatments they do not need, and waste resources that could be used to treat or prevent “genuine” illness.
Why Was This Study Done?
In recent years, evidence for widespread financial and non-financial ties between pharmaceutical companies and the health professionals involved in writing clinical practice guidelines has increased, and concern that these links may influence professional judgments has grown. As a result, a 2011 report from the US Institute of Medicine (IOM) recommended that, whenever possible, guideline developers should not have conflicts of interest, that a minority of the panel members involved in guideline development should have conflicts of interest, and that the chairs of these panels should be free of conflicts. Much less is known, however, about the ties between industry and the health professionals involved in reviewing disease definitions and whether these ties might in some way contribute to over-diagnosis. In this cross-sectional study (an investigation that takes a snapshot of a situation at a single time point), the researchers identify panels that have recently made decisions about definitions or diagnostic thresholds for conditions that are common in the US and describe the industry ties among the panel members and the changes in disease definitions proposed by the panels.
What Did the Researchers Do and Find?
The researchers identified 16 publications in which expert panels proposed changes to the disease definitions and diagnostic criteria for 14 conditions that are common in the US such as hypertension (high blood pressure) and Alzheimer disease. The proposed changes widened the disease definition for ten diseases, narrowed it for one disease, and had an unclear impact for five diseases. Reasons included in the publications for changing disease definitions included new evidence of risk for people previously considered normal (pre-hypertension) and the emergence of new biomarkers, tests, or treatments (Alzheimer disease). Only six of the panels mentioned possible harms of the proposed changes and none appeared to rigorously assess the downsides of expanding definitions. Of the 15 panels involved in the publications (one panel produced two publications), 12 included members who disclosed financial ties to multiple companies. Notably, the commonest industrial ties among these panels were to companies marketing drugs for the disease being considered by that panel. On average, 75% of panel members disclosed industry ties (range 0% to 100%) to a median of seven companies each. Moreover, similar proportions of panel members disclosed industry ties in publications released before and after the 2011 IOM report.
What Do These Findings Mean?
These findings show that, for the conditions studied, most panels considering disease definitions and diagnostic criteria proposed changes that widened disease definitions and that financial ties with pharmaceutical companies with direct interests in the therapeutic area covered by the panel were common among panel members. Because this study does not include a comparison group, these findings do not establish a causal link between industry ties and proposals to change disease definitions. Moreover, because the study concentrates on a subset of common diseases in the US setting, the generalizability of these findings is limited. Despite these and other study limitations, these findings provide new information about the ties between industry and influential medical professionals and raise questions about the current processes of disease definition. Future research, the researchers suggest, should investigate how disease definitions change over time, how much money panel members receive from industry, and how panel proposals affect the potential market of sponsors. Finally it should aim to design new processes for reviewing disease definitions that are free from potential conflicts of interest.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001500.
A PLOS Medicine Research Article by Knüppel et al. assesses the representation of ethical issues in general clinical practice guidelines on dementia care
Wikipedia has a page on medical diagnosis (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
An article on over-diagnosis by two of the study authors is available; an international conference on preventing over-diagnosis will take place this September
The 2011 US Institute of Medicine report Clinical Practice Guidelines We Can Trust is available
A PLOS Medicine Essay by Lisa Cosgrove and Sheldon Krimsky discusses the financial ties with industry of panel members involved in the preparation of the latest revision of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM), which provides standard criteria for the classification of mental disorders
doi:10.1371/journal.pmed.1001500
PMCID: PMC3742441  PMID: 23966841
7.  Patented Drug Extension Strategies on Healthcare Spending: A Cost-Evaluation Analysis 
PLoS Medicine  2013;10(6):e1001460.
In a cost-evaluation analysis of pharmacy invoice data in one Canton in Switzerland, Nathalie Vernaz and colleagues find that “evergreening” strategies pursued by drug manufacturers have been successful in maintaining market share and contribute to increased overall healthcare costs.
Please see later in the article for the Editors' Summary
Background
Drug manufacturers have developed “evergreening” strategies to compete with generic medication after patent termination. These include marketing of slightly modified follow-on drugs. We aimed to estimate the financial impact of these drugs on overall healthcare costs and also to examine the impact of listing these drugs in hospital restrictive drug formularies (RDFs) on the healthcare system as a whole (“spillover effect”).
Methods and Findings
We used hospital and community pharmacy invoice office data in the Swiss canton of Geneva to calculate utilisation of eight follow-on drugs in defined daily doses between 2000 and 2008. “Extra costs” were calculated for three different scenarios assuming replacement with the corresponding generic equivalent for prescriptions of (1) all brand (i.e., initially patented) drugs, (2) all follow-on drugs, or (3) brand and follow-on drugs. To examine the financial spillover effect we calculated a monthly follow-on drug market share in defined daily doses for medications prescribed by hospital physicians but dispensed in community pharmacies, in comparison to drugs prescribed by non-hospital physicians in the community.
Estimated “extra costs” over the study period were €15.9 (95% CI 15.5; 16.2) million for scenario 1, €14.4 (95% CI 14.1; 14.7) million for scenario 2, and €30.3 (95% CI 29.8; 30.8) million for scenario 3. The impact of strictly switching all patients using proton-pump inhibitors to esomeprazole at admission resulted in a spillover “extra cost” of €330,300 (95% CI 276,100; 383,800), whereas strictly switching to generic cetirizine resulted in savings of €7,700 (95% CI 4,100; 11,100). Overall we estimated that the RDF resulted in “extra costs” of €503,600 (95% CI 444,500; 563,100).
Conclusions
Evergreening strategies have been successful in maintaining market share in Geneva, offsetting competition by generics and cost containment policies. Hospitals may be contributing to increased overall healthcare costs by listing follow-on drugs in their RDF. Therefore, healthcare providers and policy makers should be aware of the impact of evergreening strategies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The development of a new medical drug—from discovery of a new compound to regulatory approval for its use—can take many years and cost millions of dollars. In 1995 the World Trade Organization adopted an international law (Trade-Related Aspects of Intellectual Property Rights—TRIPS) by which pharmaceutical companies can protect their intellectual property through patents. Under TRIPS, pharmaceutical companies are granted exclusive manufacturing rights for up to 20 years for each new drug, generating large revenues that often exceed initial investments costs, thus providing an incentive for pharmaceutical companies to continue to invest in the research and development of new drugs. However, recent stricter regulatory procedures for drug approval, national price control policies, and increased competition from generic manufacturers (that produce drugs similar to the brand drug once the patent has expired) have meant that pharmaceutical company profits have increasingly come under pressure.
Why Was This Study Done?
One of the tactics that pharmaceutical companies currently use in response to this situation is to extend their market monopoly. This practice is known as “evergreening” and refers to the situation in which pharmaceutical companies slightly change the formulation of their brand drug into “follow on” drugs, for example, by combining formulations or producing slow-release forms, so that they can extend the patent. The impact of such follow-on drugs on overall healthcare costs in high-resource settings is unclear and has received little attention. In this study, the researchers assessed the overall costs associated with the prescribing of follow-on drugs in the Swiss canton of Geneva.
What Did the Researchers Do and Find?
The researchers identified prescriptions of eight follow-on drugs issued by hospital and community pharmacists in Geneva between 2000 and 2008. To analyze the impact of evergreening strategies on healthcare spending, they calculated the market share score (an indicator of market competitiveness) for all prescriptions of the originally patented (brand) drug, the follow-on drug, and generic versions of the drug. The researchers then used hospital and community databases to analyze the costs of replacing brand and/or follow-on drugs with a corresponding generic drug (when available) under three scenarios (1) replacing all brand drug prescriptions, (2) replacing all follow-on drug prescriptions, and (3) replacing both follow-on and brand prescriptions.
Using these methods, the researchers found that over the study period, the number of patients receiving either a brand or follow-on drug increased from 56,686 patients in 2001 to 131,193 patients in 2008. The total cost for all studied drugs was €171.5 million, of which €103.2 million was for brand drugs, €41.1 million was for follow-on drugs, and €27.2 million was for generic drugs. Based on scenario 1 (all brand drugs being replaced by generics) and scenario 2 (all follow-on drugs being replaced by generics), over the study period, the healthcare system could have saved €15.9 million and €14.4 million in extra costs, respectively. The researchers also found some evidence that hospital prescribing patterns (through a restrictive drug formulary) influenced prescribing in the community: over the study period, the influence of hospital prescription patterns on the community resulted in an extra cost of €503,600 (mainly attributable to two drugs, esomeprazole and escitalopram). However, this influence also resulted in some savings because of a generic drug listed in the hospital formulary: use of the generic version of the drug cetirizine resulted in savings of €7,700.
What Do These Findings Mean?
These findings show that in a high-income setting, evergreening strategies developed by pharmaceutical companies for follow-on drugs substantially contributed to an increase in overall healthcare costs. These findings also provide further evidence that policies encouraging prescribing of generic medicines could have substantial savings on healthcare expenditure and, if implemented in hospital formularies, could also influence prescribing outside of the hospital setting, resulting in further savings. However, in their analysis, the researchers assumed that the health outcomes of patients would be the same whatever type of drug they used (brand, generic, or follow-on), as they had no information on health outcomes. Nevertheless, this study provides useful information for healthcare providers and policy makers about the cost implications of the evergreening strategies used by the pharmaceutical industry, particularly for follow-on drugs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001460.
This study is further discussed in a PLOS Medicine Perspective by Aaron Kesselheim
Wikipedia provides an explanation of evergreening (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Trade Organization has detailed information on TRIPS
doi:10.1371/journal.pmed.1001460
PMCID: PMC3672218  PMID: 23750120
8.  Impact of current good manufacturing practices and emission regulations and guidances on the discharge of pharmaceutical chemicals into the environment from manufacturing, use, and disposal. 
Environmental Health Perspectives  2002;110(3):213-220.
The current Good Manufacturing Practice (cGMP) and effluent emission (use and disposal) regulations of the U.S. Food and Drug Administration (FDA) and manufacturing effluent discharge and emission regulations of the U.S. Environmental Protection Agency (U.S. EPA) require contained manufacture, use, and disposal of pharmaceuticals with the goal of minimizing the release of pharmaceutical chemicals into the environment. However, debate has recently arisen in several scientific forums over whether these regulations adequately protect human and environmental health from the new pharmaceutical drugs introduced each year into the marketplace and the multitude of existing products, each with many distinct biochemical modes of actions. To address this issue, it is important to understand the relevance of current cGMP regulations and emission regulations that have a direct bearing on the releases of pharmaceutical chemicals into the environment during the manufacture, use, and disposal of active pharmaceutical ingredients (drug substances) and drug products. This knowledge may help us assess the quantity of residues that may be released into the environment. Additionally, the information on physical, chemical, and degradation and sorption properties of the pharmaceutical chemicals may help determine the net residue levels that could persist in the environment to evaluate if such residues have any bearing on human and environmental health. The scientific and regulatory aspects of issues related to the manufacture, use, and disposal of pharmaceutical chemicals are discussed in this article, with special emphasis on potential environmental exposure pathways during the life cycle of an active pharmaceutical ingredient or drug product. The mechanisms of degradation (transformation or depletion) and dilution of pharmaceutical residues that may be released into aquatic or terrestrial environmental compartments are described. Such degradation and dilution of pharmaceutical chemicals in the environment may significantly reduce the residues. It is important to evaluate whether such residue levels have any measurable impact on human and/or environmental health.
PMCID: PMC1240759  PMID: 11882470
9.  Evaluation of the Erosive Potential of Various Pediatric Liquid Medicaments: An in-vitro Study 
Background: The present in-vitro study was a scanning electron microscope (SEM) study conducted in primary teeth in order to evaluate the erosive potential of ten commonly used pediatric liquid medications (PLMs).
Materials & Methods: 10 commonly used PLMs and 33 exfoliated or extracted primary teeth were collected. The 33 teeth were divided into two groups, the control group (n=3) and the study group (n=30). The endogenous pH of all the teeth was measured using a pH electrode meter. The control group teeth were immersed in artificial saliva for three different time intervals- 1 minute, 10 minutes and 8 hours. The study group teeth were also maintained for 1 minute, 10 minutes and 8 hours in various selected PLMs. The primary enamel surface (PES) changes were then observed under the SEM for all the teeth of both groups.
Results: All the PLMs used in the study showed an erosive effect on the PES when viewed under SEM. Majority of the medications caused etched prism pattern followed by crater formation and sporadic rod ends in that order on PES.
Conclusion: There is a need to educate parents and professionals about the association between dental erosion and PLMs which predisposes to dental caries.
How to cite the article: Tupalli AR, Satish B, Shetty BR, Battu S, Kumar JP, Nagaraju B. Evaluation of the Erosive Potential of Various Pediatric Liquid Medicaments: An In-vitro Study. J Int Oral Health 2014;6(1):59-65.
PMCID: PMC3959139  PMID: 24653605
Acids; dental caries; dental erosion; enamel surface changes; pediatric liquid medications; scanning electron microscope
10.  Conflict of Interest Reporting by Authors Involved in Promotion of Off-Label Drug Use: An Analysis of Journal Disclosures 
PLoS Medicine  2012;9(8):e1001280.
Aaron Kesselheim and colleagues investigate conflict of interest disclosures in articles authored by physicians and scientists identified in whistleblower complaints alleging illegal off-label marketing by pharmaceutical companies.
Background
Litigation documents reveal that pharmaceutical companies have paid physicians to promote off-label uses of their products through a number of different avenues. It is unknown whether physicians and scientists who have such conflicts of interest adequately disclose such relationships in the scientific publications they author.
Methods and Findings
We collected whistleblower complaints alleging illegal off-label marketing from the US Department of Justice and other publicly available sources (date range: 1996–2010). We identified physicians and scientists described in the complaints as having financial relationships with defendant manufacturers, then searched Medline for articles they authored in the subsequent three years. We assessed disclosures made in articles related to the off-label use in question, determined the frequency of adequate disclosure statements, and analyzed characteristics of the authors (specialty, author position) and articles (type, connection to off-label use, journal impact factor, citation count/year). We identified 39 conflicted individuals in whistleblower complaints. They published 404 articles related to the drugs at issue in the whistleblower complaints, only 62 (15%) of which contained an adequate disclosure statement. Most articles had no disclosure (43%) or did not mention the pharmaceutical company (40%). Adequate disclosure rates varied significantly by article type, with commentaries less likely to have adequate disclosure compared to articles reporting original studies or trials (adjusted odds ratio [OR] = 0.10, 95%CI = 0.02–0.67, p = 0.02). Over half of the authors (22/39, 56%) made no adequate disclosures in their articles. However, four of six authors with ≥25 articles disclosed in about one-third of articles (range: 10/36–8/25 [28%–32%]).
Conclusions
One in seven authors identified in whistleblower complaints as involved in off-label marketing activities adequately disclosed their conflict of interest in subsequent journal publications. This is a much lower rate of adequate disclosure than has been identified in previous studies. The non-disclosure patterns suggest shortcomings with authors and the rigor of journal practices.
Please see later in the article for the Editors' Summary
Editor's Summary
Background
Off-label use of pharmaceuticals is the practice of prescribing a drug for a condition or age group, or in a dose or form of administration, that has not been specifically approved by a formal regulatory body, such as the US Food and Drug Administration (FDA). Off-label prescribing is common all over the world. In the US, although it is legal for doctors to prescribe drugs off-label and discuss such clinical uses with colleagues, it is illegal for pharmaceutical companies to directly promote off-label uses of any of their products. Revenue from off-label uses can be lucrative for drug companies and even surpass the income from approved uses. Therefore, many pharmaceutical companies have paid physicians and scientists to promote off-label use of their products as part of their marketing programs.
Why Was This Study Done?
Recently, a number of pharmaceutical companies have been investigated in the US for illegal marketing programs that promote off-label uses of their products and have had to pay billions of dollars in court settlements. As part of these investigations, doctors and scientists were identified who were paid by the companies to deliver lectures and conduct other activities to support off-label uses. When the same physicians and scientists also wrote articles about these drugs for medical journals, their financial relationships would have constituted clear conflicts of interest that should have been declared alongside the journal articles. So, in this study, the researchers identified such authors, examined their publications, and assessed the adequacy of conflict of interest disclosures made in these publications.
What Did the Researchers Do and Find?
The researchers used disclosed information from the US Department of Justice, media reports, and data from a non-governmental organization that tracks federal fraud actions, to find whistleblower complaints alleging illegal off-label promotion. Then they identified the doctors and scientists described in the complaints as having financial relationships with the defendant drug companies and searched Medline for articles authored by these experts in the subsequent three years. Using a four step approach, the researchers assessed the adequacy of conflict of interest disclosures made in articles relating to the off-label uses in question.
Using these methods, the researchers examined 26 complaints alleging illegal off-label promotion and identified the 91 doctors and scientists recorded as being involved in this practice. The researchers found 39 (43%) of these 91 experts had authored 404 related publications. In the complaints, these 39 experts were alleged to have engaged in 42 relationships with the relevant drug company: the most common activity was acting as a paid speaker (n = 26, 62%) but also writing reviews or articles on behalf of the company (n = 7), acting as consultants or advisory board members (n = 3), and receiving gifts/honoraria (n = 3), research support funds (n = 2), and educational support funds (n = 1). However, the researchers found that only 62 (15%) of the 404 related articles had adequate disclosures—43% (148) had no disclosure at all, 4% had statements denying any conflicts of interest, 40% had disclosures that did not mention the drug manufacturer, and 13% had disclosures that mentioned the manufacturer but inadequately conveyed the nature of the relationship between author and drug manufacturer reported in the complaint. The researchers also found that adequate disclosure rates varied significantly by article type, with commentaries significantly less likely to have adequate disclosure compared to articles reporting studies or trials.
What Do These Findings Mean?
These findings show the substantial deficiencies in the adequacy of conflict-of-interest disclosures made by authors who had been paid by pharmaceutical manufacturers as part of off-label marketing activities: only one in seven authors fully disclosed their conflict of interest in their published articles. This low figure is troubling and suggests that approaches to controlling the effects of conflicts of interest that rely on author candidness are inadequate and furthermore, journal practices are not robust enough and need to be improved. In the meantime, readers have no option but to interpret conflict of interest disclosures, particularly in relation to off-label uses, with caution.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001280.
The US FDA provides a guide on the use of off-label drugs
The US Agency for Healthcare Research and Quality offers a patient guide to off-label drugs
ProPublica offers a web-based tool to identify physicians who have financial relationships with certain pharmaceutical companies
Wikipedia has a good description of off-label drug use (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The Institute for Medicine as a Profession maintains a list of policies regulating physicians' financial relationships that are in place at US-based academic medical centers
doi:10.1371/journal.pmed.1001280
PMCID: PMC3413710  PMID: 22899894
11.  Trends in Compulsory Licensing of Pharmaceuticals Since the Doha Declaration: A Database Analysis 
PLoS Medicine  2012;9(1):e1001154.
Reed Beall and Randall Kuhn describe their findings from an analysis of use of compulsory licenses for pharmaceutical products by World Trade Organization members since 1995.
Background
It is now a decade since the World Trade Organization (WTO) adopted the “Declaration on the TRIPS Agreement and Public Health” at its 4th Ministerial Conference in Doha. Many anticipated that these actions would lead nations to claim compulsory licenses (CLs) for pharmaceutical products with greater regularity. A CL is the use of a patented innovation that has been licensed by a state without the permission of the patent title holder. Skeptics doubted that many CLs would occur, given political pressure against CL activity and continued health system weakness in poor countries. The subsequent decade has seen little systematic assessment of the Doha Declaration's impact.
Methods and Findings
We assembled a database of all episodes in which a CL was publically entertained or announced by a WTO member state since 1995. Broad searches of CL activity were conducted using media, academic, and legal databases, yielding 34 potential CL episodes in 26 countries. Country- and product-specific searches were used to verify government participation, resulting in a final database of 24 verified CLs in 17 nations. We coded CL episodes in terms of outcome, national income, and disease group over three distinct periods of CL activity. Most CL episodes occurred between 2003 and 2005, involved drugs for HIV/AIDS, and occurred in upper-middle-income countries (UMICs). Aside from HIV/AIDS, few CL episodes involved communicable disease, and none occurred in least-developed or low-income countries.
Conclusions
Given skepticism about the Doha Declaration's likely impact, we note the relatively high occurrence of CLs, yet CL activity has diminished markedly since 2006. While UMICs have high CL activity and strong incentives to use CLs compared to other countries, we note considerable countervailing pressures against CL use even in UMICs. We conclude that there is a low probability of continued CL activity. We highlight the need for further systematic evaluation of global health governance actions.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The development of a new drug is a time-consuming and expensive process. To stimulate investment in drug development, the creators of new drugs (including the pharmaceutical companies that undertake the development and testing that is needed before any drug can be used in patients) can apply for “intellectual property rights” (a patent). Intellectual property rights protect the investments made by companies during drug development by preventing other companies from making the new drug for a fixed period of time and by providing a means by which creators of new drugs can negotiate payment from other companies for the use of their creation. Until recently, the extent and enforcement of intellectual property rights varied widely around the world. Then, in 1995, the World Trade Organization (WTO) was established. By providing a set of ground rules for trade among nations, the WTO aims to ensure that trade flows as smoothly, predictably, and freely as possible around the world. One of the founding documents of the WTO is the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement), which attempts to bring the protection of intellectual property rights (including patents) under common international rules.
Why Was This Study Done?
Unfortunately, patent protection for drugs (pharmaceuticals) means that many medicines are too expensive for use in developing countries. While maintaining incentives for drug development, the TRIPS Agreement allows governments to license the use of patented inventions to someone else without the consent of the patent owner. Such “compulsory licensing” normally occurs only after negotiations for a voluntary license have failed, and the patent owner still receives an appropriate payment. It soon became clear that some governments were unsure of their right to use compulsory licensing and other flexibilities in the TRIPS Agreement, a situation likely to affect public health in poor countries by hindering universal access to medicines. Consequently, the WTO issued the “Declaration on the TRIPS Agreement and Public Health” at its 4th Ministerial Conference in Doha in November 2001. Reaction to the Doha Declaration, which reaffirms that the “TRIPS Agreement does not and should not prevent members from taking measures to protect public health,” has been mixed. Some experts predicted that it would increase compulsory licensing of pharmaceuticals, but others suggested that political pressure against compulsory licensing and health system weaknesses in poor countries would limit claims for compulsory licenses. In this database analysis, the researchers systematically assess the impact of the Doha Declaration on the compulsory licensing of pharmaceuticals.
What Did the Researchers Do and Find?
By systematically searching media archives for reports of WTO member states considering or announcing compulsory licensing of pharmaceuticals, the researchers identified 24 verified compulsory licensing episodes in 17 nations that occurred between January 1995 and June 2011. Half of these episodes ended with an announcement of a compulsory license, and the majority ended in a price reduction for a specific pharmaceutical product for the potential issuing nation through a compulsory license, a voluntary license, or a negotiated discount. Sixteen of the compulsory licensing episodes involved drugs for HIV/AIDS, four involved drugs for other communicable diseases, and four involved drugs for non-communicable diseases such as cancer. More than half the compulsory licensing episodes occurred in upper-middle-income countries (including Brazil and Thailand). Finally, most compulsory licensing episodes occurred between 2003 and 2005. There was a smaller peak of activity in the months leading up to the Doha conference, but after 2006 activity declined substantially.
What Do These Findings Mean?
Given these findings, the researchers suggest that the Doha Declaration is unlikely to have an important long-term impact on the use of compulsory licensing or on access to pharmaceuticals for communicable diseases other than HIV/AIDS in developing and low-income countries. Most notably, the researchers found no evidence of a spike in compulsory licensing episodes immediately after the Doha Declaration, and they note that the lagged spike that occurred between 2003 and 2005 could have resulted in large part from the global antiretroviral advocacy campaign. Moreover, compulsory licensing activity has diminished greatly since 2006. Thus, the researchers conclude, health advocates who pushed for the Doha Declaration reforms have had little success in engaging trade as a positive, proactive force for addressing health gaps.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001154.
The World Trade Organization provides information on intellectual property rights, on the TRIPS Agreement, on TRIPS and pharmaceutical patents, and on compulsory licensing of pharmaceuticals and TRIPS (in English, French, and Spanish); the Doha Declaration on the TRIPS Agreement and Public Health is also available
The World Health Organization provides information on the Doha Declaration on the TRIPS Agreement and Public Health and an analysis of the implications of the Doha Declaration
Wikipedia has pages on intellectual property rights, on the TRIPS Agreement, and on the Doha Declaration (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001154
PMCID: PMC3254665  PMID: 22253577
12.  Interactions between Non-Physician Clinicians and Industry: A Systematic Review 
PLoS Medicine  2013;10(11):e1001561.
In a systematic review of studies of interactions between non-physician clinicians and industry, Quinn Grundy and colleagues found that many of the issues identified for physicians' industry interactions exist for non-physician clinicians.
Please see later in the article for the Editors' Summary
Background
With increasing restrictions placed on physician–industry interactions, industry marketing may target other health professionals. Recent health policy developments confer even greater importance on the decision making of non-physician clinicians. The purpose of this systematic review is to examine the types and implications of non-physician clinician–industry interactions in clinical practice.
Methods and Findings
We searched MEDLINE and Web of Science from January 1, 1946, through June 24, 2013, according to PRISMA guidelines. Non-physician clinicians eligible for inclusion were: Registered Nurses, nurse prescribers, Physician Assistants, pharmacists, dieticians, and physical or occupational therapists; trainee samples were excluded. Fifteen studies met inclusion criteria. Data were synthesized qualitatively into eight outcome domains: nature and frequency of industry interactions; attitudes toward industry; perceived ethical acceptability of interactions; perceived marketing influence; perceived reliability of industry information; preparation for industry interactions; reactions to industry relations policy; and management of industry interactions. Non-physician clinicians reported interacting with the pharmaceutical and infant formula industries. Clinicians across disciplines met with pharmaceutical representatives regularly and relied on them for practice information. Clinicians frequently received industry “information,” attended sponsored “education,” and acted as distributors for similar materials targeted at patients. Clinicians generally regarded this as an ethical use of industry resources, and felt they could detect “promotion” while benefiting from industry “information.” Free samples were among the most approved and common ways that clinicians interacted with industry. Included studies were observational and of varying methodological rigor; thus, these findings may not be generalizable. This review is, however, the first to our knowledge to provide a descriptive analysis of this literature.
Conclusions
Non-physician clinicians' generally positive attitudes toward industry interactions, despite their recognition of issues related to bias, suggest that industry interactions are normalized in clinical practice across non-physician disciplines. Industry relations policy should address all disciplines and be implemented consistently in order to mitigate conflicts of interest and address such interactions' potential to affect patient care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Making and selling health care goods (including drugs and devices) and services is big business. To maximize the profits they make for their shareholders, companies involved in health care build relationships with physicians by providing information on new drugs, organizing educational meetings, providing samples of their products, giving gifts, and holding sponsored events. These relationships help to keep physicians informed about new developments in health care but also create the potential for causing harm to patients and health care systems. These relationships may, for example, result in increased prescription rates of new, heavily marketed medications, which are often more expensive than their generic counterparts (similar unbranded drugs) and that are more likely to be recalled for safety reasons than long-established drugs. They may also affect the provision of health care services. Industry is providing an increasingly large proportion of routine health care services in many countries, so relationships built up with physicians have the potential to influence the commissioning of the services that are central to the treatment and well-being of patients.
Why Was This Study Done?
As a result of concerns about the tension between industry's need to make profits and the ethics underlying professional practice, restrictions are increasingly being placed on physician–industry interactions. In the US, for example, the Physician Payments Sunshine Act now requires US manufacturers of drugs, devices, and medical supplies that participate in federal health care programs to disclose all payments and gifts made to physicians and teaching hospitals. However, other health professionals, including those with authority to prescribe drugs such as pharmacists, Physician Assistants, and nurse practitioners are not covered by this legislation or by similar legislation in other settings, even though the restructuring of health care to prioritize primary care and multidisciplinary care models means that “non-physician clinicians” are becoming more numerous and more involved in decision-making and medication management. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers examine the nature and implications of the interactions between non-physician clinicians and industry.
What Did the Researchers Do and Find?
The researchers identified 15 published studies that examined interactions between non-physician clinicians (Registered Nurses, nurse prescribers, midwives, pharmacists, Physician Assistants, and dieticians) and industry (corporations that produce health care goods and services). They extracted the data from 16 publications (representing 15 different studies) and synthesized them qualitatively (combined the data and reached word-based, rather than numerical, conclusions) into eight outcome domains, including the nature and frequency of interactions, non-physician clinicians' attitudes toward industry, and the perceived ethical acceptability of interactions. In the research the authors identified, non-physician clinicians reported frequent interactions with the pharmaceutical and infant formula industries. Most non-physician clinicians met industry representatives regularly, received gifts and samples, and attended educational events or received educational materials (some of which they distributed to patients). In these studies, non-physician clinicians generally regarded these interactions positively and felt they were an ethical and appropriate use of industry resources. Only a minority of non-physician clinicians felt that marketing influenced their own practice, although a larger percentage felt that their colleagues would be influenced. A sizeable proportion of non-physician clinicians questioned the reliability of industry information, but most were confident that they could detect biased information and therefore rated this information as reliable, valuable, or useful.
What Do These Findings Mean?
These and other findings suggest that non-physician clinicians generally have positive attitudes toward industry interactions but recognize issues related to bias and conflict of interest. Because these findings are based on a small number of studies, most of which were undertaken in the US, they may not be generalizable to other countries. Moreover, they provide no quantitative assessment of the interaction between non-physician clinicians and industry and no information about whether industry interactions affect patient care outcomes. Nevertheless, these findings suggest that industry interactions are normalized (seen as standard) in clinical practice across non-physician disciplines. This normalization creates the potential for serious risks to patients and health care systems. The researchers suggest that it may be unrealistic to expect that non-physician clinicians can be taught individually how to interact with industry ethically or how to detect and avert bias, particularly given the ubiquitous nature of marketing and promotional materials. Instead, they suggest, the environment in which non-physician clinicians practice should be structured to mitigate the potentially harmful effects of interactions with industry.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001561.
This study is further discussed in a PLOS Medicine Perspective by James S. Yeh and Aaron S. Kesselheim
The American Medical Association provides guidance for physicians on interactions with pharmaceutical industry representatives, information about the Physician Payments Sunshine Act, and a toolkit for preparing Physician Payments Sunshine Act reports
The International Council of Nurses provides some guidance on industry interactions in its position statement on nurse-industry relations
The UK General Medical Council provides guidance on financial and commercial arrangements and conflicts of interest as part of its good medical practice website, which describes what is required of all registered doctors in the UK
Understanding and Responding to Pharmaceutical Promotion: A Practical Guide is a manual prepared by Health Action International and the World Health Organization that schools of medicine and pharmacy can use to train students how to recognize and respond to pharmaceutical promotion.
The Institute of Medicine's Report on Conflict of Interest in Medical Research, Education, and Practice recommends steps to identify, limit, and manage conflicts of interest
The University of California, San Francisco, Office of Continuing Medical Education offers a course called Marketing of Medicines
doi:10.1371/journal.pmed.1001561
PMCID: PMC3841103  PMID: 24302892
13.  Analysis of multiple compound–protein interactions reveals novel bioactive molecules 
The authors use machine learning of compound-protein interactions to explore drug polypharmacology and to efficiently identify bioactive ligands, including novel scaffold-hopping compounds for two pharmaceutically important protein families: G-protein coupled receptors and protein kinases.
We have demonstrated that machine learning of multiple compound–protein interactions is useful for efficient ligand screening and for assessing drug polypharmacology.This approach successfully identified novel scaffold-hopping compounds for two pharmaceutically important protein families: G-protein-coupled receptors and protein kinases.These bioactive compounds were not detected by existing computational ligand-screening methods in comparative studies.The results of this study indicate that data derived from chemical genomics can be highly useful for exploring chemical space, and this systems biology perspective could accelerate drug discovery processes.
The discovery of novel bioactive molecules advances our systems-level understanding of biological processes and is crucial for innovation in drug development. Perturbations of biological systems by chemical probes provide broader applications not only for analysis of complex systems but also for intentional manipulations of these systems. Nevertheless, the lack of well-characterized chemical modulators has limited their use. Recently, chemical genomics has emerged as a promising area of research applicable to the exploration of novel bioactive molecules, and researchers are currently striving toward the identification of all possible ligands for all target protein families (Wang et al, 2009). Chemical genomics studies have shown that patterns of compound–protein interactions (CPIs) are too diverse to be understood as simple one-to-one events. There is an urgent need to develop appropriate data mining methods for characterizing and visualizing the full complexity of interactions between chemical space and biological systems. However, no existing screening approach has so far succeeded in identifying novel bioactive compounds using multiple interactions among compounds and target proteins.
High-throughput screening (HTS) and computational screening have greatly aided in the identification of early lead compounds for drug discovery. However, the large number of assays required for HTS to identify drugs that target multiple proteins render this process very costly and time-consuming. Therefore, interest in using in silico strategies for screening has increased. The most common computational approaches, ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS; Oprea and Matter, 2004; Muegge and Oloff, 2006; McInnes, 2007; Figure 1A), have been used for practical drug development. LBVS aims to identify molecules that are very similar to known active molecules and generally has difficulty identifying compounds with novel structural scaffolds that differ from reference molecules. The other popular strategy, SBVS, is constrained by the number of three-dimensional crystallographic structures available. To circumvent these limitations, we have shown that a new computational screening strategy, chemical genomics-based virtual screening (CGBVS), has the potential to identify novel, scaffold-hopping compounds and assess their polypharmacology by using a machine-learning method to recognize conserved molecular patterns in comprehensive CPI data sets.
The CGBVS strategy used in this study was made up of five steps: CPI data collection, descriptor calculation, representation of interaction vectors, predictive model construction using training data sets, and predictions from test data (Figure 1A). Importantly, step 1, the construction of a data set of chemical structures and protein sequences for known CPIs, did not require the three-dimensional protein structures needed for SBVS. In step 2, compound structures and protein sequences were converted into numerical descriptors. These descriptors were used to construct chemical or biological spaces in which decreasing distance between vectors corresponded to increasing similarity of compound structures or protein sequences. In step 3, we represented multiple CPI patterns by concatenating these chemical and protein descriptors. Using these interaction vectors, we could quantify the similarity of molecular interactions for compound–protein pairs, despite the fact that the ligand and protein similarity maps differed substantially. In step 4, concatenated vectors for CPI pairs (positive samples) and non-interacting pairs (negative samples) were input into an established machine-learning method. In the final step, the classifier constructed using training sets was applied to test data.
To evaluate the predictive value of CGBVS, we first compared its performance with that of LBVS by fivefold cross-validation. CGBVS performed with considerably higher accuracy (91.9%) than did LBVS (84.4%; Figure 1B). We next compared CGBVS and SBVS in a retrospective virtual screening based on the human β2-adrenergic receptor (ADRB2). Figure 1C shows that CGBVS provided higher hit rates than did SBVS. These results suggest that CGBVS is more successful than conventional approaches for prediction of CPIs.
We then evaluated the ability of the CGBVS method to predict the polypharmacology of ADRB2 by attempting to identify novel ADRB2 ligands from a group of G-protein-coupled receptor (GPCR) ligands. We ranked the prediction scores for the interactions of 826 reported GPCR ligands with ADRB2 and then analyzed the 50 highest-ranked compounds in greater detail. Of 21 commercially available compounds, 11 showed ADRB2-binding activity and were not previously reported to be ADRB2 ligands. These compounds included ligands not only for aminergic receptors but also for neuropeptide Y-type 1 receptors (NPY1R), which have low protein homology to ADRB2. Most ligands we identified were not detected by LBVS and SBVS, which suggests that only CGBVS could identify this unexpected cross-reaction for a ligand developed as a target to a peptidergic receptor.
The true value of CGBVS in drug discovery must be tested by assessing whether this method can identify scaffold-hopping lead compounds from a set of compounds that is structurally more diverse. To assess this ability, we analyzed 11 500 commercially available compounds to predict compounds likely to bind to two GPCRs and two protein kinases. Functional assays revealed that nine ADRB2 ligands, three NPY1R ligands, five epidermal growth factor receptor (EGFR) inhibitors, and two cyclin-dependent kinase 2 (CDK2) inhibitors were concentrated in the top-ranked compounds (hit rate=30, 15, 25, and 10%, respectively). We also evaluated the extent of scaffold hopping achieved in the identification of these novel ligands. One ADRB2 ligand, two NPY1R ligands, and one CDK2 inhibitor exhibited scaffold hopping (Figure 4), indicating that CGBVS can use this characteristic to rationally predict novel lead compounds, a crucial and very difficult step in drug discovery. This feature of CGBVS is critically different from existing predictive methods, such as LBVS, which depend on similarities between test and reference ligands, and focus on a single protein or highly homologous proteins. In particular, CGBVS is useful for targets with undefined ligands because this method can use CPIs with target proteins that exhibit lower levels of homology.
In summary, we have demonstrated that data mining of multiple CPIs is of great practical value for exploration of chemical space. As a predictive model, CGBVS could provide an important step in the discovery of such multi-target drugs by identifying the group of proteins targeted by a particular ligand, leading to innovation in pharmaceutical research.
The discovery of novel bioactive molecules advances our systems-level understanding of biological processes and is crucial for innovation in drug development. For this purpose, the emerging field of chemical genomics is currently focused on accumulating large assay data sets describing compound–protein interactions (CPIs). Although new target proteins for known drugs have recently been identified through mining of CPI databases, using these resources to identify novel ligands remains unexplored. Herein, we demonstrate that machine learning of multiple CPIs can not only assess drug polypharmacology but can also efficiently identify novel bioactive scaffold-hopping compounds. Through a machine-learning technique that uses multiple CPIs, we have successfully identified novel lead compounds for two pharmaceutically important protein families, G-protein-coupled receptors and protein kinases. These novel compounds were not identified by existing computational ligand-screening methods in comparative studies. The results of this study indicate that data derived from chemical genomics can be highly useful for exploring chemical space, and this systems biology perspective could accelerate drug discovery processes.
doi:10.1038/msb.2011.5
PMCID: PMC3094066  PMID: 21364574
chemical genomics; data mining; drug discovery; ligand screening; systems chemical biology
14.  United States Private-Sector Physicians and Pharmaceutical Contract Research: A Qualitative Study 
PLoS Medicine  2012;9(7):e1001271.
Jill Fisher and Corey Kalbaugh describe their findings from a qualitative research study evaluating the motivations of private-sector physicians conducting contract research for the pharmaceutical industry.
Background
There have been dramatic increases over the past 20 years in the number of nonacademic, private-sector physicians who serve as principal investigators on US clinical trials sponsored by the pharmaceutical industry. However, there has been little research on the implications of these investigators' role in clinical investigation. Our objective was to study private-sector clinics involved in US pharmaceutical clinical trials to understand the contract research arrangements supporting drug development, and specifically how private-sector physicians engaged in contract research describe their professional identities.
Methods and Findings
We conducted a qualitative study in 2003–2004 combining observation at 25 private-sector research organizations in the southwestern United States and 63 semi-structured interviews with physicians, research staff, and research participants at those clinics. We used grounded theory to analyze and interpret our data. The 11 private-sector physicians who participated in our study reported becoming principal investigators on industry clinical trials primarily because contract research provides an additional revenue stream. The physicians reported that they saw themselves as trial practitioners and as businesspeople rather than as scientists or researchers.
Conclusions
Our findings suggest that in addition to having financial motivation to participate in contract research, these US private-sector physicians have a professional identity aligned with an industry-based approach to research ethics. The generalizability of these findings and whether they have changed in the intervening years should be addressed in future studies.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Before a new drug can be used routinely by physicians, it must be investigated in clinical trials—studies that test the drug's safety and effectiveness in people. In the past, clinical trials were usually undertaken in academic medical centers (institutes where physicians provide clinical care, do research, and teach), but increasingly, clinical trials are being conducted in the private sector as part of a growing contract research system. In the US, for example, most clinical trials completed in the 1980s took place in academic medical centers, but nowadays, more than 70% of trials are conducted by nonacademic (community) physicians working under contract to pharmaceutical companies. The number of private-sector nonacademic physicians serving as principal investigators (PIs) for US clinical trials (the PI takes direct responsibility for completion of the trial) increased from 4,000 in 1990 to 20,250 in 2010, and research contracts for clinical trials are now worth more than USṩ11 billion annually.
Why Was This Study Done?
To date, there has been little research on the implications of this change in the conduct of clinical trials. Academic PIs are often involved in both laboratory and clinical research and are therefore likely to identify closely with the science of trials. By contrast, nonacademic PIs may see clinical trials more as a business opportunity—pharmaceutical contract research is profitable to US physicians because they get paid for every step of the trial process. As a result, pharmaceutical companies may now have more control over clinical trial data and more opportunities to suppress negative data through selective publication of study results than previously. In this qualitative study, the researchers explore the outsourcing of clinical trials to private-sector research clinics through observations of, and in-depth interviews with, physicians and other research staff involved in the US clinical trials industry. A qualitative study collects non-quantitative data such as how physicians feel about doing contract research and about their responsibilities to their patients.
What Did the Researchers Do and Find?
Between October 2003 and September 2004, the researchers observed the interactions between PIs, trial coordinators (individuals who undertake many of the trial activities such as blood collection), and trial participants at 25 US research organizations in the southwestern US and interviewed 63 informants (including 12 PIs) about the trials they were involved in and their reasons for becoming involved. The researchers found that private-sector physicians became PIs on industry-sponsored clinical trials primarily because contract research was financially lucrative. The physicians perceived their roles in terms of business rather than science and claimed that they offered something to the pharmaceutical industry that academics do not—the ability to carry out a diverse range of trials quickly and effectively, regardless of their medical specialty. Finally, the physicians saw their primary ethical responsibility as providing accurate data to the companies that hired them and did not explicitly refer to their ethical responsibility to trial participants. One possible reason for this shift in ethical concerns is the belief among private-sector physicians that pharmaceutical companies must be making scientifically and ethically sound decisions when designing trials because of the amount of money they invest in them.
What Do These Findings Mean?
These findings suggest that private-sector physicians participate as PIs in pharmaceutical clinical trials primarily for financial reasons and see themselves as trial practitioners and businesspeople rather than as scientists. The accuracy of these findings is likely to be limited by the small number of PIs interviewed and by the time that has elapsed since the researchers collected their qualitative data. Moreover, these findings may not be generalizable to other regions of the US or to other countries. Nevertheless, they have potentially troubling implications for drug development. By hiring private-sector physicians who see themselves as involved more with the business than the science of contract research, pharmaceutical companies may be able to exert more control over the conduct of clinical trials and the publication of trial results than previously. Compared to the traditional investigatorinitiated system of clinical research, this new system of contract research means that clinical trials now lack the independence that is at the heart of best science practices, a development that casts doubt on the robustness of the knowledge being produced about the safety and effectiveness of new drugs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001271.
The ClinicalTrials.gov website is a searchable register of federally and privately supported clinical trials in the US; it provides information about all aspects of clinical trials
The US National Institutes of Health provides information about clinical trials, including personal stories about clinical trials from patients and researchers
The UK National Health Service Choices website has information for patients about clinical trials and medical research, including personal stories about participating in clinical trials
The UK Medical Research Council Clinical Trials Unit also provides information for patients about clinical trials and links to information on clinical trials provided by other organizations
MedlinePlus has links to further resources on clinical trials (in English and Spanish)
doi:10.1371/journal.pmed.1001271
PMCID: PMC3404112  PMID: 22911055
15.  Association of Medical Students' Reports of Interactions with the Pharmaceutical and Medical Device Industries and Medical School Policies and Characteristics: A Cross-Sectional Study 
PLoS Medicine  2014;11(10):e1001743.
Aaron Kesselheim and colleagues compared US medical students' survey responses regarding pharmaceutical company interactions with the schools' AMSA PharmFree scorecard and Institute on Medicine as a Profession's (IMAP) scores.
Please see later in the article for the Editors' Summary
Background
Professional societies use metrics to evaluate medical schools' policies regarding interactions of students and faculty with the pharmaceutical and medical device industries. We compared these metrics and determined which US medical schools' industry interaction policies were associated with student behaviors.
Methods and Findings
Using survey responses from a national sample of 1,610 US medical students, we compared their reported industry interactions with their schools' American Medical Student Association (AMSA) PharmFree Scorecard and average Institute on Medicine as a Profession (IMAP) Conflicts of Interest Policy Database score. We used hierarchical logistic regression models to determine the association between policies and students' gift acceptance, interactions with marketing representatives, and perceived adequacy of faculty–industry separation. We adjusted for year in training, medical school size, and level of US National Institutes of Health (NIH) funding. We used LASSO regression models to identify specific policies associated with the outcomes. We found that IMAP and AMSA scores had similar median values (1.75 [interquartile range 1.50–2.00] versus 1.77 [1.50–2.18], adjusted to compare scores on the same scale). Scores on AMSA and IMAP shared policy dimensions were not closely correlated (gift policies, r = 0.28, 95% CI 0.11–0.44; marketing representative access policies, r = 0.51, 95% CI 0.36–0.63). Students from schools with the most stringent industry interaction policies were less likely to report receiving gifts (AMSA score, odds ratio [OR]: 0.37, 95% CI 0.19–0.72; IMAP score, OR 0.45, 95% CI 0.19–1.04) and less likely to interact with marketing representatives (AMSA score, OR 0.33, 95% CI 0.15–0.69; IMAP score, OR 0.37, 95% CI 0.14–0.95) than students from schools with the lowest ranked policy scores. The association became nonsignificant when fully adjusted for NIH funding level, whereas adjusting for year of education, size of school, and publicly versus privately funded school did not alter the association. Policies limiting gifts, meals, and speaking bureaus were associated with students reporting having not received gifts and having not interacted with marketing representatives. Policy dimensions reflecting the regulation of industry involvement in educational activities (e.g., continuing medical education, travel compensation, and scholarships) were associated with perceived separation between faculty and industry. The study is limited by potential for recall bias and the cross-sectional nature of the survey, as school curricula and industry interaction policies may have changed since the time of the survey administration and study analysis.
Conclusions
As medical schools review policies regulating medical students' industry interactions, limitations on receipt of gifts and meals and participation of faculty in speaking bureaus should be emphasized, and policy makers should pay greater attention to less research-intensive institutions.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Making and selling prescription drugs and medical devices is big business. To promote their products, pharmaceutical and medical device companies build relationships with physicians by providing information on new drugs, by organizing educational meetings and sponsored events, and by giving gifts. Financial relationships begin early in physicians' careers, with companies providing textbooks and other gifts to first-year medical students. In medical school settings, manufacturers may help to inform trainees and physicians about developments in health care, but they also create the potential for harm to patients and health care systems. These interactions may, for example, reduce trainees' and trained physicians' skepticism about potentially misleading promotional claims and may encourage physicians to prescribe new medications, which are often more expensive than similar unbranded (generic) drugs and more likely to be recalled for safety reasons than older drugs. To address these and other concerns about the potential career-long effects of interactions between medical trainees and industry, many teaching hospitals and medical schools have introduced policies to limit such interactions. The development of these policies has been supported by expert professional groups and medical societies, some of which have created scales to evaluate the strength of the implemented industry interaction policies.
Why Was This Study Done?
The impact of policies designed to limit interactions between students and industry on student behavior is unclear, and it is not known which aspects of the policies are most predictive of student behavior. This information is needed to ensure that the policies are working and to identify ways to improve them. Here, the researchers investigate which medical school characteristics and which aspects of industry interaction policies are most predictive of students' reported behaviors and beliefs by comparing information collected in a national survey of US medical students with the strength of their schools' industry interaction policies measured on two scales—the American Medical Student Association (AMSA) PharmFree Scorecard and the Institute on Medicine as a Profession (IMAP) Conflicts of Interest Policy Database.
What Did the Researchers Do and Find?
The researchers compared information about reported gift acceptance, interactions with marketing representatives, and the perceived adequacy of faculty–industry separation collected from 1,610 medical students at 121 US medical schools with AMSA and IMAP scores for the schools evaluated a year earlier. Students at schools with the highest ranked interaction policies based on the AMSA score were 63% less likely to accept gifts as students at the lowest ranked schools. Students at the highest ranked schools based on the IMAP score were about half as likely to accept gifts as students at the lowest ranked schools, although this finding was not statistically significant (it could be a chance finding). Similarly, students at the highest ranked schools were 70% less likely to interact with sales representatives as students at the lowest ranked schools. These associations became statistically nonsignificant after controlling for the amount of research funding each school received from the US National Institutes of Health (NIH). Policies limiting gifts, meals, and being a part of speaking bureaus (where companies pay speakers to present information about the drugs for dinners and other events) were associated with students' reports of receiving no gifts and of non-interaction with sales representatives. Finally, policies regulating industry involvement in educational activities were associated with the perceived separation between faculty and industry, which was regarded as adequate by most of the students at schools with such policies.
What Do These Findings Mean?
These findings suggest that policies designed to limit industry interactions with medical students need to address multiple aspects of these interactions to achieve changes in the behavior and attitudes of trainees, but that policies limiting gifts, meals, and speaking bureaus may be particularly important. These findings also suggest that the level of NIH funding plays an important role in students' self-reported behaviors and their perceptions of industry, possibly because institutions with greater NIH funding have the resources needed to implement effective policies. The accuracy of these findings may be limited by recall bias (students may have reported their experiences inaccurately), and by the possibility that industry interaction policies may have changed in the year that elapsed between policy grading and the student survey. Nevertheless, these findings suggest that limitations on gifts should be emphasized when academic medical centers refine their policies on interactions between medical students and industry and that particular attention should be paid to the design and implementation of policies that regulate industry interactions in institutions with lower levels of NIH funding.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001743.
The UK General Medical Council provides guidance on financial and commercial arrangements and conflicts of interest as part of its good medical practice document, which describes what is required of all registered doctors in the UK
Information about the American Medical Student Association (AMSA) Just Medicine campaign (formerly the PharmFree campaign) and about the AMSA Scorecard is available
Information about the Institute on Medicine as a Profession (IMAP) and about its Conflicts of Interest Policy Database is also available
“Understanding and Responding to Pharmaceutical Promotion: A Practical Guide” is a manual prepared by Health Action International and the World Health Organization that medical schools can use to train students how to recognize and respond to pharmaceutical promotion
The US Institute of Medicine's report “Conflict of Interest in Medical Research, Education, and Practice” recommends steps to identify, limit, and manage conflicts of interest
The ALOSA Foundation provides evidence-based, non-industry-funded education about treating common conditions and using prescription drugs
doi:10.1371/journal.pmed.1001743
PMCID: PMC4196737  PMID: 25314155
16.  Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints 
PLoS Medicine  2011;8(4):e1000431.
Aaron Kesselheim and colleagues analyzed unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing, and develop a taxonomy of the various off-label practices.
Background
Despite regulatory restrictions, off-label marketing of pharmaceutical products has been common in the US. However, the scope of off-label marketing remains poorly characterized. We developed a typology for the strategies and practices that constitute off-label marketing.
Methods and Findings
We obtained unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing (January 1996–October 2010) and conducted structured reviews of them. We coded and analyzed the strategic goals of each off-label marketing scheme and the practices used to achieve those goals, as reported by the whistleblowers. We identified 41 complaints arising from 18 unique cases for our analytic sample (leading to US$7.9 billion in recoveries). The off-label marketing schemes described in the complaints had three non–mutually exclusive goals: expansions to unapproved diseases (35/41, 85%), unapproved disease subtypes (22/41, 54%), and unapproved drug doses (14/41, 34%). Manufacturers were alleged to have pursued these goals using four non–mutually exclusive types of marketing practices: prescriber-related (41/41, 100%), business-related (37/41, 90%), payer-related (23/41, 56%), and consumer-related (18/41, 44%). Prescriber-related practices, the centerpiece of company strategies, included self-serving presentations of the literature (31/41, 76%), free samples (8/41, 20%), direct financial incentives to physicians (35/41, 85%), and teaching (22/41, 54%) and research activities (8/41, 20%).
Conclusions
Off-label marketing practices appear to extend to many areas of the health care system. Unfortunately, the most common alleged off-label marketing practices also appear to be the most difficult to control through external regulatory approaches.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Before a pharmaceutical company can market a new prescription drug in the US, the drug has to go through a long approval process. After extensive studies in the laboratory and in animals, the pharmaceutical company must test the drug's safety and efficacy in a series of clinical trials in which groups of patients with specific diseases are given the drug according to strict protocols. The results of these trials are reviewed by Federal Drug Administration (FDA, the body that regulates drugs in the US) and, when the FDA is satisfied that the drug is safe and effective for the conditions in which it is tested, it approves the drug for sale. An important part of the approval process is the creation of the “drug label,” a detailed report that specifies the exact diseases and patient groups in which the drug can be used and the approved doses of the drug.
Why Was This Study Done?
Physicians can, however, legally use FDA-approved drugs “off-label.” That is, they can prescribe drugs for a different disease, in a different group of patients, or at a different dose to that specified in the drug's label. However, because drugs' manufacturers stand to benefit financially from off-label use through increased drugs sales, the FDA prohibits them from directly promoting unapproved uses. The fear is that such marketing would encourage the widespread use of drugs in settings where their efficacy and safety has not been rigorously tested, exposing patients to uncertain benefits and possible adverse effects. Despite the regulatory restrictions, off-label marketing seems to be common. In 2010, for example, at least six pharmaceutical companies settled US government investigations into alleged off-label marketing programs. Unfortunately, the tactics used by pharmaceutical companies for off-label marketing have been poorly understood in the medical community, in part because pharmaceutical industry insiders (“whistleblowers”) are the only ones who can present in-depth knowledge of these tactics. In recent years, as more whistleblowers have come forward to allege off-label marketing, developing a more complete picture of the practice is now possible. In this study, the researchers attempt to systematically classify the strategies and practices used in off-labeling marketing by examining complaints filed by whistleblowers in federal enforcement actions where off-label marketing by pharmaceutical companies has been alleged.
What Did the Researchers Do and Find?
In their analysis of 41 whistleblower complaints relating to 18 alleged cases of off-label marketing in federal fraud cases unsealed between January 1996 and October 2010, the researchers identified three non–mutually exclusive goals of off-label marketing schemes. The commonest goal (85% of cases) was expansion of drug use to unapproved diseases (for example, gabapentin, which is approved for the treatment of specific types of epilepsy, was allegedly promoted as a therapy for patients with psychiatric diseases such as depression). The other goals were expansion to unapproved disease subtypes (for example, some antidepressant drugs approved for adults were allegedly promoted to pediatricians for use in children) and expansion to unapproved drug dosing strategies, typically higher doses. The researchers also identified four non–mutually exclusive types of marketing practices designed to achieve these goals. All of the whistleblowers alleged prescriber-related practices (including providing financial incentives and free samples to physicians), and most alleged internal practices intended to bolster off-label marketing, such as sales quotas that could only be met if the manufacturer's sales representatives promoted off-label drug use. Payer-related practices (for example, discussions with prescribers about ways to ensure insurance reimbursement for off-label prescriptions) and consumer-related practices (most commonly, the review of confidential patient charts to identify consumers who could be off-label users) were also alleged.
What Do These Findings Mean?
These findings suggest that off-labeling marketing practices extend to many parts of the health care delivery system. Because these practices were alleged by whistleblowers and were not the subject of testimony in a full trial, some of the practices identified by the researchers were not confirmed. Conversely, because most of the whistleblowers were US-based sales representatives, there may be other goals and strategies that this study has not identified. Nevertheless, these findings provide a useful snapshot of off-label marketing strategies and practices allegedly employed in the US over the past 15 years, which can now be used to develop new regulatory strategies aimed at effective oversight of off-label marketing. Importantly, however, these findings suggest that no regulatory strategy will be complete and effective unless physicians themselves fully understand the range of off-label marketing practices and their consequences for public health and act as a bulwark against continued efforts to engage in off-label promotion.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000431.
The US Food and Drug Administration provides detailed information about drug approval in the US for consumers and for health professionals; its Bad Ad Program aims to educate health care providers about the role they can play in ensuring that prescription drug advertising and promotion is truthful and not misleading.
The American Cancer Society has a page about off-label drug use
Wikipedia has pages on prescription drugs, on pharmaceutical marketing, and on off-label drug use (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Taxpayers Against Fraud is a nonprofit organization dedicated to helping whistleblowers, and it presents up-to-date information about False Claims Act cases
The Government Accountability Project is a nonprofit organization that seeks to promote corporate and government accountability by protecting whistleblowers, advancing occupational free speech, and empowering citizen activists
Healthy Skepticism is an international nonprofit membership association that aims to improve health by reducing harm from misleading health information
doi:10.1371/journal.pmed.1000431
PMCID: PMC3071370  PMID: 21483716
17.  Practical recommendations for statistical analysis and data presentation in Biochemia Medica journal 
Biochemia Medica  2012;22(1):15-23.
The aim of this article is to highlight practical recommendations based on our experience as reviewers and journal editors and refer to some most common mistakes in manuscripts submitted to Biochemia Medica. One of the most important parts of the article is the Abstract. Authors quite often forget that Abstract is sometimes the first (and only) part of the article read by the readers. The article Abstract must therefore be comprehensive and provide key results of your work. Problematic part of the article, also often neglected by authors is the subheading Statistical analysis, within Materials and methods, where authors must explain which statistical tests were used in their data analysis and the rationale for using those tests. They also need to make sure that all tests used are listed under Statistical analysis section, as well as that all tests listed are indeed used in the study. When writing Results section there are several key points to keep in mind, such as: are results presented with adequate precision and accurately; is descriptive analysis appropriate; is the measure of confidence provided for all estimates; if necessary and applicable, are correct statistical tests used for analysis; is P value provided for all tests, etc. Especially important is not to make any conclusions on the causal relationship unless the study is an experiment or clinical trial. We believe that the use of the proposed checklist might increase the quality of the submitted work and speed up the peer-review and publication process for published articles.
PMCID: PMC4062332  PMID: 22384516
biostatistics; errors; data analysis; research ethics
18.  Antibody to Aquaporin 4 in the Diagnosis of Neuromyelitis Optica 
PLoS Medicine  2007;4(4):e133.
Background
Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system (CNS) of putative autoimmune aetiology. Early discrimination between multiple sclerosis (MS) and NMO is important, as optimum treatment for both diseases may differ considerably. Recently, using indirect immunofluorescence analysis, a new serum autoantibody (NMO-IgG) has been detected in NMO patients. The binding sites of this autoantibody were reported to colocalize with aquaporin 4 (AQP4) water channels. Thus we hypothesized that AQP4 antibodies in fact characterize NMO patients.
Methods and Findings
Based on these observations we cloned human water channel AQP4, expressed the protein in a eukaryotic transcription/translation system, and employed the recombinant AQP4 to establish a new radioimmunoprecipitation assay (RIPA). Indeed, application of this RIPA showed that antibodies against AQP4 exist in the majority of patients with NMO (n = 37; 21 positive) as well as in patients with isolated longitudinally extensive transverse myelitis (n = 6; six positive), corresponding to a sensitivity of 62.8% and a specificity of 98.3%. By contrast, AQP4 antibodies were virtually absent in 291 other participants, which included patients with MS (n = 144; four positive), patients with other inflammatory and noninflammatory neurological diseases (n = 73; one positive), patients with systemic autoimmune diseases (n = 45; 0 positive), and healthy participants (n = 29; 0 positive).
Conclusions
In the largest series reported so far to our knowledge, we quantified AQP4 antibodies in patients with NMO versus various other diseases, and showed that the aquaporin 4 water channel is a target antigen in a majority of patients with NMO. The newly developed assay represents a highly specific, observer-independent, and easily reproducible detection method facilitating clinically relevant discrimination between NMO, MS, and other inflammatory diseases.
A newly developed method to detect antibodies to the aquaporin 4 water channel can help discriminate between neuromyelitis optica, multiple sclerosis, and other inflammatory diseases.
Editors' Summary
Background.
Neuromyelitis optica (NMO or Devic syndrome) is a rare disease in which the immune system destroys the myelin (fatty material that insulates nerve fibers so that the body and the brain can communicate using electrical messages) in the optic nerve and spinal cord. Myelin destruction (demyelination) in these parts of the central nervous system (CNS) causes pain and swelling (inflammation) of the optic nerve (optic neuritis) and spinal cord (myelitis). The resultant disruption of communication along these nerves means that patients with NMO experience temporary or permanent blindness in one or both eyes that is preceded or followed by limb weakness or paralysis and loss of bladder and bowel control. These two sets of symptoms can occur many months apart and may happen once during a person's lifetime or recur at intervals. There is no cure for NMO, but corticosteroids or plasmapheresis reduce inflammation during acute attacks and, because NMO is an autoimmune disease (one in which the immune system attacks the body's own tissues instead of foreign organisms), long-term immunosuppression may prevent further attacks.
Why Was This Study Done?
There are many inflammatory/demyelinating diseases of the CNS with clinical symptoms similar to those of NMO. It is particularly hard to distinguish between NMO and multiple sclerosis, an autoimmune disease that involves widespread demyelination. Neurologists need to make a correct diagnosis before starting any treatment and usually use clinical examination and magnetic resonance imaging (to detect sites of inflammation) to help them in this task. Recently, however, a biomarker for NMO was identified. Many patients with NMO make autoantibodies (proteins that recognize a component of a person's own tissues) called NMO-IgGs. These recognize aquaporin 4 (AQP4), a protein that allows water to move through cell membranes. It is not known how often patients with NMO or other demyelinating diseases make antibodies to AQP4, so it is unclear whether testing for these antibodies would help in the diagnosis of NMO. In this study, the researchers have developed a new assay for antibodies to AQP4 and then quantified the antibodies in patients with NMO and other demyelinating diseases.
What Did the Researchers Do and Find?
The researchers made radioactively labeled AQP4 in a test tube, then incubated samples of this with serum (the liquid portion of blood), added small beads coated with protein A (a bacterial protein that binds to antibodies) and allowed the beads to settle. The amount of radioactivity attached to the beads indicates the amount of antibody to AQP4 in the original serum. The researchers used this radioimmunoprecipitation assay to measure antibodies to AQP4 in sera from 37 patients with NMO and from six with another neurological condition, longitudinally extensive transverse myelitis (LETM), which is characterized by large demyelinated lesions across the width of the spinal cord but no optic neuritis; these patients often develop NMO. They also measured antibodies to AQP4 in the sera of nearly 300 other people including patients with multiple sclerosis, other neurological conditions, various autoimmune diseases, and healthy individuals. Nearly two-thirds of the patients with NMO and all those with LETM made antibodies against AQP4; very few of the other study participants made these antibodies. In particular, only four of the 144 patients with multiple sclerosis made AQP4 antibodies.
What Do These Findings Mean?
These findings indicate that testing for antibodies to AQP4 could help neurologists distinguish between NMO and multiple sclerosis and between NMO and other demyelinating diseases of the CNS. In addition, the new radioimmunoprecipitation assay provides a standardized, high-throughput way to quantitatively test for these antibodies, whereas the indirect immune fluorescence assay for measurement of unspecific NMO-IgG is observer-dependent and nonquantitative. Although these findings need to be confirmed in more patients and the assay's reliability demonstrated in different settings, the measurement of antibodies to AQP4 by radioimmunoprecipitation may become a standard part of the differential diagnosis of NMO. Additional research will determine whether AQP4 is the only protein targeted by autoantibodies in NMO and whether this targeting is a critical part of the disease process.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040133.
US National Institute of Neurological Disorders and Stroke has information for patients who have neuromyelitis optica, transverse myelitis, and multiple sclerosis
The Transverse Myelitis Association offers information and useful links for patients and their carers about transverse myelitis and neuromyelitis optica (in several languages, including English and Spanish)
Mayo Clinic information for patients on Devic's syndrome
Medline Plus encyclopedia pages discuss autoimmune disorders (in English and Spanish)
A brief overview of aquaporins is available from the University of Miami
The American MS Society has information on MS
doi:10.1371/journal.pmed.0040133
PMCID: PMC1852124  PMID: 17439296
19.  “I’m not afraid of those ones just 'cause they’ve been prescribed”: Perceptions of risk among illicit users of pharmaceutical opioids 
Background
There has been a rise in the illicit use of pharmaceutical opioids (”pain pills”) in the United States. Conducted with young adult non-medical users of pharmaceutical opioids, this study uses qualitative methods and cultural consensus analysis to describe risk perceptions associated with pharmaceutical opioids and to determine patterns of cultural sharing and intra-cultural variation of these views.
Methods
The qualitative sub-sample (n=47) was selected from a larger sample of 396 young adults (18–23 years old), who were participating in a natural history study of illicit pharmaceutical opioid use. Qualitative life history interviews, drug ranking task, and cultural consensus analysis were used to elicit participant views about risks and harms associated with pain pills and other drugs, as well as alcohol and tobacco.
Results
Cultural consensus analysis revealed that the participants shared a single cultural model of drug risks, but the level of agreement decreased with the increasing range of drugs ever used. Further, those with more extensive drug use histories differed from less “experienced” users in their views about OxyContin and some other drugs. Overall, pain pills were viewed as addicting and potentially deadly substances, but these properties were linked to the patterns and methods of use, as well as characteristics of an individual user. Further, risks associated with pharmaceutical opioids were further curtailed because they “came from the doctor,” and thus had a legitimate aspect to their use.
Conclusions
This study highlights potential problems with universal approaches to substance use prevention and intervention among young people since such approaches ignore the fact that substance use education messages may be experienced differently depending on an individual’s drug use history and his/her perceptions of drug risks. Findings reported here may be useful in the development of prevention and intervention programs aimed at reducing the harm associated with illicit use of pain pills.
doi:10.1016/j.drugpo.2012.01.012
PMCID: PMC3387517  PMID: 22417823
20.  European Materia Medica in Historical Texts: Longevity of a Tradition and Implications for Future Use 
Journal of ethnopharmacology  2010;132(1):28-47.
Recent research in the area of new drug discovery has shown the continued promise of looking to natural products for bioactive compounds. Researchers have thus turned to traditional medicine, which is still used widely throughout the world and increasingly in industrialized countries as well, to provide clues as to which products to investigate. The oral traditions on which much of this medical knowledge rests, however, are unstable, prompting researchers to turn to textual sources for potential drugs. This study uses Mediterranean/European medical texts from the 5th century BC to the 19th century A.D. to compile a list of the most commonly used “simples” – or single action drug substances – used in therapeutics in traditional European medicine. It finds that traditional European materia medica was based on a Dioscordean tradition that lasted through the 19th century with remarkably little variation, but is significantly different from the present-day herbal pharmacopoeia as represented by the National Institutes of Health. The most prominent simples of that tradition can thus provide clues to further bioactive compounds that have not as of yet been fully exploited for their potential, but were clearly of great use in the past.
doi:10.1016/j.jep.2010.05.035
PMCID: PMC2956839  PMID: 20561577
materia medica; new drug discovery; Dioscorides; history; traditional medicine; bioprospecting
21.  Physician Awareness of Drug Cost: A Systematic Review 
PLoS Medicine  2007;4(9):e283.
Background
Pharmaceutical costs are the fastest-growing health-care expense in most developed countries. Higher drug costs have been shown to negatively impact patient outcomes. Studies suggest that doctors have a poor understanding of pharmaceutical costs, but the data are variable and there is no consistent pattern in awareness. We designed this systematic review to investigate doctors' knowledge of the relative and absolute costs of medications and to determine the factors that influence awareness.
Methods and Findings
Our search strategy included The Cochrane Library, EconoLit, EMBASE, and MEDLINE as well as reference lists and contact with authors who had published two or more articles on the topic or who had published within 10 y of the commencement of our review. Studies were included if: either doctors, trainees (interns or residents), or medical students were surveyed; there were more than ten survey respondents; cost of pharmaceuticals was estimated; results were expressed quantitatively; there was a clear description of how authors defined “accurate estimates”; and there was a description of how the true cost was determined. Two authors reviewed each article for eligibility and extracted data independently. Cost accuracy outcomes were summarized, but data were not combined in meta-analysis because of extensive heterogeneity. Qualitative data related to physicians and drug costs were also extracted. The final analysis included 24 articles. Cost accuracy was low; 31% of estimates were within 20% or 25% of the true cost, and fewer than 50% were accurate by any definition of cost accuracy. Methodological weaknesses were common, and studies of low methodological quality showed better cost awareness. The most important factor influencing the pattern and accuracy of estimation was the true cost of therapy. High-cost drugs were estimated more accurately than inexpensive ones (74% versus 31%, Chi-square p < 0.001). Doctors consistently overestimated the cost of inexpensive products and underestimated the cost of expensive ones (binomial test, 89/101, p < 0.001). When asked, doctors indicated that they want cost information and feel it would improve their prescribing but that it is not accessible.
Conclusions
Doctors' ignorance of costs, combined with their tendency to underestimate the price of expensive drugs and overestimate the price of inexpensive ones, demonstrate a lack of appreciation of the large difference in cost between inexpensive and expensive drugs. This discrepancy in turn could have profound implications for overall drug expenditures. Much more focus is required in the education of physicians about costs and the access to cost information. Future research should focus on the accessibility and reliability of medical cost information and whether the provision of this information is used by doctors and makes a difference to physician prescribing. Additionally, future work should strive for higher methodological standards to avoid the biases we found in the current literature, including attention to the method of assessing accuracy that allows larger absolute estimation ranges for expensive drugs.
From a review of data from 24 studies, Michael Allan and colleagues conclude that doctors often underestimate the price of expensive drugs and overestimate the price of those that are inexpensive.
Editors' Summary
Background.
Many medicines are extremely expensive, and the cost of buying them is a major (and increasing) proportion of the total cost of health care. Governments and health-care organizations try to find ways of keeping down costs without reducing the effectiveness of the health care they provide, but their efforts to control what is spent on medicines have not been very successful. There are often two or more equally effective drugs available for treating the same condition, and it would obviously help keep costs down if, when a doctor prescribes a medicine, he or she chose the cheapest of the effective drugs available. This choice could result in savings for whoever is paying for the drugs, be it the government, the patient, or a medical insurance organization.
Why Was This Study Done?
Doctors who prescribe drugs cannot be expected to know the exact cost of each drug on the market, but it would he helpful if they had some impression of the cost of a treatment and how the various alternatives compare in price. However, systems deciding how drugs are priced are often very complex. (This is particularly the case in the US.) The researchers wanted to find out how aware doctors are regarding drug costs and the difference between the alternatives. They also wanted to know what factors affected their awareness.
What Did the Researchers Do and Find?
They decided to do a systematic review of all the research already conducted that addressed this issue so that the evidence from all of them could be considered together. In order to do such a review they had to specify precise requirements for the type of study that they would include and then comprehensively search the medical literature for such studies. They found 24 studies that met their requirements. From these studies, they concluded that doctors were usually not accurate when asked to estimate the cost of drugs; doctors came up with estimates that were within 25% of the true cost less than one-third of the time. In particular doctors tended to underestimate the cost of expensive drugs and overestimate the cost of the cheaper alternatives. A further analysis of the studies showed that many doctors said they would appreciate more accurate information on costs to help them choose which drugs to prescribe but that such information was not readily available.
What Do These Findings Mean?
The researchers concluded that their systematic review demonstrates a lack of appreciation by prescribing doctors of the large difference in cost between inexpensive and expensive drugs, and that this finding has serious implications for overall spending on drugs. They call for more education and information to be provided to doctors on the cost of medicines together with better processes to help doctors in making such decisions.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040283.
A brief guide to systematic reviews has been published by the BMJ (British Medical Journal)
The Web site of the Cochrane Collaboration is a more detailed source of information on systematic reviews; in particular there is a newcomers' guide and information for health-care consumers
The Kaiser Family Foundation, a nonprofit, private operating foundation focusing on the major health care issues in the US, has a section on prescription drugs and their costs
doi:10.1371/journal.pmed.0040283
PMCID: PMC1989748  PMID: 17896856
22.  Discoloration of Roots Caused by Residual Endodontic Intracanal Medicaments 
The Scientific World Journal  2014;2014:404676.
Aims. This study examined the extent to which intervisit corticosteroid-based antibiotic pastes (CAP) medicaments contribute to staining of tooth structure after attempted removal by irrigation techniques. Methods. A total of 140 roots were prepared and the canals were filled with Ledermix paste (demeclocycline), Odontopaste (clindamycin), and Doxypaste (doxycycline). The pastes were removed after 2 or 4 weeks of storage in the dark using EDTA and NaOCl with either a 27-gauge-slotted needle or an EndoActivator (Dentsply). The roots were then exposed to an intense light source for 30 minutes each week and photographed after a further 1, 3, or 6 months. Digital images were standardized and data for changes in luminosity were analysed using repeated measures ANOVA and a post hoc test. Results. Removal of the medicament did not prevent later discolouration. There was no significant difference between the paste removal methods. Ledermix paste caused the greatest darkening compared to the untreated controls, for both application periods and both methods of removal. Doxypaste and Odontopaste caused less darkening than Ledermix. Conclusion. Medicaments that stain teeth may continue to discolour teeth despite best attempts to remove them. This study stresses the importance of material selection and minimising contact of Ledermix within the coronal aspects of teeth.
doi:10.1155/2014/404676
PMCID: PMC3934450  PMID: 24688386
23.  A Collaborative Epidemiological Investigation into the Criminal Fake Artesunate Trade in South East Asia  
PLoS Medicine  2008;5(2):e32.
Background
Since 1998 the serious public health problem in South East Asia of counterfeit artesunate, containing no or subtherapeutic amounts of the active antimalarial ingredient, has led to deaths from untreated malaria, reduced confidence in this vital drug, large economic losses for the legitimate manufacturers, and concerns that artemisinin resistance might be engendered.
Methods and Findings
With evidence of a deteriorating situation, a group of police, criminal analysts, chemists, palynologists, and health workers collaborated to determine the source of these counterfeits under the auspices of the International Criminal Police Organization (INTERPOL) and the Western Pacific World Health Organization Regional Office. A total of 391 samples of genuine and counterfeit artesunate collected in Vietnam (75), Cambodia (48), Lao PDR (115), Myanmar (Burma) (137) and the Thai/Myanmar border (16), were available for analysis. Sixteen different fake hologram types were identified. High-performance liquid chromatography and/or mass spectrometry confirmed that all specimens thought to be counterfeit (195/391, 49.9%) on the basis of packaging contained no or small quantities of artesunate (up to 12 mg per tablet as opposed to ∼ 50 mg per genuine tablet). Chemical analysis demonstrated a wide diversity of wrong active ingredients, including banned pharmaceuticals, such as metamizole, and safrole, a carcinogen, and raw material for manufacture of methylenedioxymethamphetamine (‘ecstasy'). Evidence from chemical, mineralogical, biological, and packaging analysis suggested that at least some of the counterfeits were manufactured in southeast People's Republic of China. This evidence prompted the Chinese Government to act quickly against the criminal traders with arrests and seizures.
Conclusions
An international multi-disciplinary group obtained evidence that some of the counterfeit artesunate was manufactured in China, and this prompted a criminal investigation. International cross-disciplinary collaborations may be appropriate in the investigation of other serious counterfeit medicine public health problems elsewhere, but strengthening of international collaborations and forensic and drug regulatory authority capacity will be required.
Paul Newton and colleagues' international, collaborative study found evidence that counterfeit artesunate was being manufactured in China, which prompted a criminal investigation.
Editors' Summary
Background
Malaria is one of the world's largest public health problems, causing around 500 million cases of illness and at least one million deaths per year (the estimates vary widely). The most serious form of malaria is caused by the parasite Plasmodium falciparum, which has become resistant to multiple drugs that had previously been the cornerstones of antimalarial regimens. One group of drugs for treating malaria, the artemisinin therapies including artesunate, are based upon a Chinese herb called qinghaosu; these have now become vital to the treatment of P. falciparum malaria. But counterfeit artesunate, containing none or too little (“subtherapeutic levels”) of the active ingredient, is a growing problem especially in South and East Asia. Fake artesunate is devastating for malaria control: it causes avoidable death, reduces confidence in the drug, and takes away profit from legitimate manufacturers. Of major concern also is the potential for subtherapeutic counterfeit artesunate to fuel the parasite's resistance to the artemisinin group of drugs.
Previous estimates have suggested that between 33% and 53% of artesunate tablets in mainland South East Asia are counterfeit. In this paper the authors report on an unprecedented international collaboration and criminal investigation that attempted to quantify and source counterfeit artesunate among some of the most malarious countries in Asia.
Why Was This Study Done?
Previous reports have identified the problem of fake artesunate, but as of yet there have been few reports on the potential solutions. Concerned health workers and scientists, the regional World Health Organization (WHO) office and the International Criminal Police Organization (INTERPOL) got together to discuss what could be done in May 2005 when it became clear the counterfeit artesunate situation was worsening in the Greater Mekong Sub-Region of South East Asia (comprising Cambodia, Lao People's Democratic Republic, Myanmar, Thailand, Vietnam, and Yunnan Province in the People's Republic of China). Their subsequent investigation combined the goals and methods of a range of concerned parties—police, scientists, and health workers—to identify the source of counterfeit artesunate in South East Asia and to supply the evidence to help arrest and prosecute the perpetrators.
What Did the Researchers Do and Find?
The researchers conducted forensic analyses of samples of genuine and counterfeit artesunate. They selected these samples from larger surveys and investigations that had been conducted in the region beginning in the year 2000. Genuine samples were supplied by a manufacturer to provide a comparator. The authors examined the physical appearance of the packages and subjected the tablets to a wide range of chemical and biological tests that allowed an analysis of the components contained in the tablets.
When comparing the collected packages and tablets against the genuine samples, the researchers found considerable diversity of fake artesunate in SE Asia. Sixteen different fake hologram types (the stickers contained on packages meant to identify them as genuine) were found. Chemical analysis revealed that all tablets thought to be fake contained no or very small quantities of artesunate. Other ingredients found in the artesunate counterfeit tablets included paracetamol, antibiotics, older antimalarial drugs, and a range of minerals, and there were a variety of gases surrounding the tablets inside the packaging. Biological analyses of pollen grains inside the packaging suggested that the packages originated in the parts of South East Asia along the Chinese border.
What Do these Findings Mean?
The results were crucial in helping the authorities establish the origin of the fake artesunate. For example, the authors identified two regional clusters where the counterfeit tablets appeared to be coming from, thus flagging a potential manufacturing site or distribution network. The presence of wrong active pharmaceutical ingredients (such as the older antimalarial drugs) suggested the counterfeiters had access to a variety of active pharmaceutical ingredients. The presence of safrole, a precursor to the illicit drug ecstasy, suggested the counterfeits may be coming from factories that manufacture ecstasy. And the identification of minerals indigenous to certain regions also helped identify the counterfeits' origin. The researchers concluded that at least some of the counterfeit artesunate was coming from southern China. The Secretary General of INTERPOL presented the findings to the Chinese government, which then carried out a criminal investigation and arrested individuals alleged to have produced and distributed the counterfeit artesunate.
The collaboration between police, public health workers and scientists on combating fake artesunate is unique, and provides a model for others to follow. However, the authors note that substantial capacity in forensic analysis and the infrastructure to support collaborations between these different disciplines are needed.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050032.
The World Health Organization in 2006 created IMPACT—International Medical Products Anti-Counterfeiting Taskforce—with the aim of forging international collaboration to seek global solutions to this global challenge and in raising awareness of the dangers of counterfeit medical products. The task force membership includes international organizations, nongovernmental organizations, enforcement agencies, pharmaceutical manufacturers' associations, and drug and regulatory authorities. IMPACT's Web site notes that trade in counterfeit medicines is widespread and affects both developed and developing countries but is more prevalent in countries that have weak drug regulatory systems, poor supply of basic medicines, unregulated markets, high drug prices and/or significant price differentials. IMPACT holds international conferences and maintains a rapid alert system for counterfeit drugs.
The drug industry's anticounterfeit organization, Pharmaceutical Security Institute, works to develop improved systems to identify the extent of the counterfeiting problem and to assist in coordinating international inquiries. Its membership includes 21 large pharmaceutical companies.
The Web site of David Pizzanelli, a world expert on security holography, contains a PowerPoint presentation co-authored by Paul Newton that illustrates the different types of fake holograms found on fake artesunate packages, and their implications for artemisinin resistance (http://www.pizzanelli.co.uk/content/artesunate.html).
doi:10.1371/journal.pmed.0050032
PMCID: PMC2235893  PMID: 18271620
24.  Diet and Physical Activity for the Prevention of Noncommunicable Diseases in Low- and Middle-Income Countries: A Systematic Policy Review 
PLoS Medicine  2013;10(6):e1001465.
Carl Lachat and colleagues evaluate policies in low- and middle-income countries addressing salt and fat consumption, fruit and vegetable intake, and physical activity, key risk factors for non-communicable diseases.
Please see later in the article for the Editors' Summary
Background
Diet-related noncommunicable diseases (NCDs) are increasing rapidly in low- and middle-income countries (LMICs) and constitute a leading cause of mortality. Although a call for global action has been resonating for years, the progress in national policy development in LMICs has not been assessed. This review of strategies to prevent NCDs in LMICs provides a benchmark against which policy response can be tracked over time.
Methods and Findings
We reviewed how government policies in LMICs outline actions that address salt consumption, fat consumption, fruit and vegetable intake, or physical activity. A structured content analysis of national nutrition, NCDs, and health policies published between 1 January 2004 and 1 January 2013 by 140 LMIC members of the World Health Organization (WHO) was carried out. We assessed availability of policies in 83% (116/140) of the countries. NCD strategies were found in 47% (54/116) of LMICs reviewed, but only a minority proposed actions to promote healthier diets and physical activity. The coverage of policies that specifically targeted at least one of the risk factors reviewed was lower in Africa, Europe, the Americas, and the Eastern Mediterranean compared to the other two World Health Organization regions, South-East Asia and Western Pacific. Of the countries reviewed, only 12% (14/116) proposed a policy that addressed all four risk factors, and 25% (29/116) addressed only one of the risk factors reviewed. Strategies targeting the private sector were less frequently encountered than strategies targeting the general public or policy makers.
Conclusions
This review indicates the disconnection between the burden of NCDs and national policy responses in LMICs. Policy makers urgently need to develop comprehensive and multi-stakeholder policies to improve dietary quality and physical activity.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Noncommunicable diseases (NCDs)—chronic medical conditions including cardiovascular diseases (heart disease and stroke), diabetes, cancer, and chronic respiratory diseases (chronic obstructive pulmonary disease and asthma)—are responsible for two-thirds of the world's deaths. Nearly 80% of NCD deaths, close to 30 million per year, occur in low- and middle-income countries (LMICs), where they are also rising most rapidly. Diet and lifestyle (including smoking, lack of exercise, and harmful alcohol consumption) influence a person's risk of developing an NCD and of dying from it. Because they can be modified, these risk factors have been at the center of strategies to combat NCDs. In 2004, the World Health Organization (WHO) adopted the Global Strategy on Diet, Physical Activity and Health. For diet, it recommended that individuals achieve energy balance and a healthy weight; limit energy intake from total fats and shift fat consumption away from saturated fats to unsaturated fats and towards the elimination of trans-fatty acids; increase consumption of fruits, vegetables, legumes, whole grains, and nuts; limit the intake of free sugars; and limit salt consumption from all sources and ensure that salt is iodized. For physical activity, it recommended at least 30 minutes of regular, moderate-intensity physical activity on most days throughout a person's life.
Why Was This Study Done?
By signing onto the Global Strategy in 2004, WHO member countries agreed to implement it with high priority. A first step of implementation is usually the development of local policies. Consequently, one of the four objectives of the WHO Global Strategy is “to encourage the development, strengthening and implementation of global, regional, national and community policies and action plans to improve diets and increase physical activity.” Along the same lines, in 2011 the United Nations held a high-level meeting in which the need to accelerate the policy response to the NCD epidemic was emphasized. This study was done to assess the existing national policies on NCD prevention in LMICs. Specifically, the researchers examined how well those policies matched the WHO recommendations for intake of salt, fat, and fruits and vegetables, as well as the recommendations for physical activity.
What Did the Researchers Do and Find?
The researchers searched the Internet (including websites of relevant ministries and departments) for all publicly available national policies related to diet, nutrition, NCDs, and health from all 140 WHO member countries classified as LMICs by the World Bank in 2011. For countries for which the search did not turn up policies, the researchers sent e-mail requests to the relevant national authorities, to the regional WHO offices, and to personal contacts. All documents dated from 1 January 2004 to 1 January 2013 that included national objectives and guidelines for action regarding diet, physical exercise, NCD prevention, or a combination of the three, were analyzed in detail.
Most of the policies obtained were not easy to find and access. For 24 countries, particularly in the Eastern Mediterranean, the researchers eventually gave up, unable to establish whether relevant national policies existed. Of the remaining 116 countries, 29 countries had no relevant policies, and another 30 had policies that failed to mention specifically any of the diet-related risk factors included in the analysis. Fifty-four of the 116 countries had NCD policies that addressed at least one of the risk factors. Thirty-six national policy documents contained strategies to increase fruit and vegetable intake, 20 addressed dietary fat consumption, 23 aimed to limit salt intake, and 35 had specific actions to promote physical activity. Only 14 countries, including Jamaica, the Philippines, Iran, and Mongolia, had policies that addressed all four risk factors. The policies of 27 countries mentioned only one of the four risk factors.
Policies primarily targeted consumers and government agencies and failed to address the roles of the business community or civil society. Consistent with this, most were missing plans, mechanisms, and incentives to drive collaborations between the different stakeholders.
What Do These Findings Mean?
More than eight years after the WHO Global Strategy was agreed upon, only a minority of the LMICs included in this analysis have comprehensive policies in place. Developing policies and making them widely accessible is a likely early step toward specific implementation and actions to prevent NCDs. These results therefore suggest that not enough emphasis is placed on NCD prevention in these countries through actions that have been proven to reduce known risk factors. That said, the more important question is what countries are actually doing to combat NCDs, something not directly addressed by this analysis.
In richer countries, NCDs have for decades been the leading cause of sickness and death, and the fact that public health strategies need to emphasize NCD prevention is now widely recognized. LMICs not only have more limited resources, they also continue to carry a large burden from infectious diseases. It is therefore not surprising that shifting resources towards NCD prevention is a difficult process, even if the human cost of these diseases is massive and increasing. That only about 3% of global health aid is aimed at NCD prevention does not help the situation.
The authors argue that one step toward improving the situation is better sharing of best practices and what works and what doesn't in policy development. They suggest that an open-access repository like one that exists for Europe could improve the situation. They offer to organize, host, and curate such a resource under the auspices of WHO, starting with the policies retrieved for this study, and they invite submission of additional policies and updates.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001465.
This study is further discussed in a PLOS Medicine Perspective by Stuckler and Basu
The WHO website on diet and physical activity contains links to various documents, including a diet and physical activity implementation toolbox that contains links to the 2004 Global Strategy document and a Framework to Monitor and Evaluate Implementation
There is a 2011 WHO primer on NCDs entitled Prioritizing a Preventable Epidemic
A recent PLOS Medicine editorial and call for papers addressing the global disparities in the burden from NCDs
A PLOS Blogs post entitled Politics and Global HealthAre We Missing the Obvious? and associated comments discuss the state of the fight against NCDs in early 2013
The NCD Alliance was founded by the Union for International Cancer Control, the International Diabetes Federation, the World Heart Federation, and the International Union Against Tuberculosis and Lung Disease; its mission is to combat the NCD epidemic by putting health at the center of all policies
The WHO European Database on Nutrition, Obesity and Physical Activity (NOPA) contains national and subnational surveillance data, policy documents, actions to implement policy, and examples of good practice in programs and interventions for the WHO European member states
doi:10.1371/journal.pmed.1001465
PMCID: PMC3679005  PMID: 23776415
25.  Ayurveda and Panchakarma: Measuring the Effects of a Holistic Health Intervention 
TheScientificWorldJournal  2009;9:272-280.
Ayurveda, the traditional medical system of India, is understudied in western contexts. Using data gathered from an Ayurvedic treatment program, this study examined the role of psychosocial factors in the process of behavior change and the salutogenic process. This observational study examined associations with participation in the 5-day Ayurvedic cleansing retreat program, Panchakarma. Quality of life, psychosocial, and behavior change measurements were measured longitudinally on 20 female participants. Measurements were taken before the start of the program, immediately after the program, and 3 months postprogram. The program did not significantly improve quality of life. Significant improvements were found in self-efficacy towards using Ayurveda to improve health and reported positive health behaviors. In addition, perceived social support and depression showed significant improvements 3 months postprogram after the subjects had returned to their home context. As a program of behavior change, our preliminary results suggest that the complex intervention Panchakarma may be effective in assisting one’s expected and reported adherence to new and healthier behavior patterns.
doi:10.1100/tsw.2009.35
PMCID: PMC2699273  PMID: 19412555
Ayurveda; health behavior change; complex medical system

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