a. Extent of industry funding
Many authors document considerable reliance on industry funding for medical research. This also appears to be increasing. Massie and Rothenburg146 surveyed authors of papers on the medical treatment of angina. Sixty-nine per cent of the studies were funded by the pharmaceutical industry and 45% of the authors would have done the study without industry funding. Anderson et al.147 found that, over time, it has become increasingly common for clinical trials of secondline agents for rheumatoid arthritis to be supported by the pharmaceutical industry. In 1945-1969 they found no published studies that were fully funded by the industry, but by 1980-89, 61% of studies were. Kunin148 found 39% of his respondents (members of the Infectious Diseases Society of America) had obtained research funds from pharmaceutical companies. This sum accounted for 34% of the funding reported. About half the researchers felt that they needed industry support for their work. Dorman et al.149 found that the proportion of published trials on acute stroke that were apparently supported by the industry increased substantially from 1955 to 1995, from 0 to 54%. They also concluded that descriptions of the nature and extent of industry involvement were poor, and consequently 54% could underestimate the real level of industry involvement.
Blumenthal and colleagues have documented extensive relationships between industry and university life sciences faculty in the US. They have also shown that such links lead to more secrecy around research findings. In 1986 they surveyed faculty members involved in biotechnology in 40 major universities in the USA150. Those who had received industry funding for their work were found to publish more, patent more, participate in administration and professional activities more, and to earn more. They were also four times as likely to report that their work had resulted in trade secrets, and four times as likely to say that commercial considerations had influenced their choice of research projects, as biotech faculty members without industrial support. Most faculty, with or without industry support, agreed that relationships between industry and universities led to a risk of shifting too much emphasis towards applied research150.
Similarly, Krimsky et al.151 describe extensive relationships between academic scientists and biotechnology companies. They developed a database of 889 US and Canadian biotechnology companies, and 832 scientists with whom they had formal ties. They found that at least 37% of members of the National Academy of Sciences (a group that provides advice to Congress and other government bodies) had formal ties with biotechnology companies.
In 1994 the Blumenthal group surveyed both faculty about relationships with industry, and industry about their relationships with universities. In their work ‘industry’ refers not only to the pharmaceutical industry, but to other life-science related sectors, such as agriculture. In one study152 the group describe the survey of agricultural, chemical and pharmaceutical companies in the US about their links with academic institutions. More than 90% of the 210 companies they surveyed had some relationship with academia. The most common was the use of faculty members as consultants. From these results the authors estimated that these industries as a whole supported 6000 research projects at a cost of US$1.5 billion. Of the respondents, 34% of companies reported disputes with their academic partners over intellectual property, 82% sometimes required academics to keep information secret until a patent application was filed, and 47% occasionally required secrecy longer. The Blumenthal group also reported results of their survey of over 2000 faculty members from the 50 US universities that received the most National Institutes of Health funding in 1993153-155. The group found that nearly 20% of the scientists reported having delayed publication of their results for more than six months for a commercial reason, and 8.9% had refused to share results with other university scientists153. Those who had received industry funding were more likely to report having delayed publication for commercial reasons, but those who relied more on industry (i.e. obtained a higher proportion of their funding from industry) were less likely to report having refused to share results. The group also reported that 28% of the faculty surveyed had received research funding from industry, that the receipt of industry support was more common in clinical than non-clinical departments, and that industry had supplied 8.9% of all research funds (excluding overheads)154. Those who had received industry funding for their research published more, participated more in administrative activities and were more commercially active than others. But those receiving more than two-thirds of their research support from industry were less academically productive than those receiving lower levels of support.
In 1998, Campbell and colleagues from the Blumenthal group155 described the extent of research-related gifts given to academic life scientists by companies. Twenty-four per cent of respondents had been given biomaterials, 15% discretionary funds, 11% equipment, and 11% travel to professional meetings. Thirty-two per cent of respondents thought that the donors expected to review reports and articles before publication, as a consequence of the gift.
Choudhry et al.156 investigated relationships between authors of clinical practice guidelines and the pharmaceutical industry. They looked at 44 guidelines endorsed by European or North American professional societies. Eighty-seven per cent of the authors they contacted had some relationship with industry, 59% had relationships with companies whose products were considered or included in guidelines, and almost all of these pre-dated the guidelines. In 42 of the 44 guidelines no declarations were made about potential conflicts of interest.
CONCLUSION: The percentage of research studies funded by pharmaceutical companies has increased over the past 50 years. Funding of research by these companies is associated with influence over choice of topic, secrecy, delayed publication for commercial reasons and conflict of interest problems for authors of guidelines.
b. The effect of industry funding on published results
Several studies explore this area. Some suggest different mechanisms by which the published evidence on drugs is likely to over-estimate their benefits157-162. One of these157 also suggests that company funded research is less likely to be published than non-company funded research. Many studies show that funded studies are more likely to present positive results about the study drug163-176. One study177 examines the effect of company research sponsorship on what kind of research is done.
c. Is there an association between funding source and publication status?
Several studies have looked at whether the source of funding for studies affects their publication status. If company-funded studies with negative results are less likely to be published this could lead to an over-estimate of treatment effects or risk-factor associations in published work, and in meta-analyses that rely only on published work.
Easterbrook et al.157 attempted to follow up studies that had been approved by the Oxford Regional Ethics Committee, in the UK. They found that drug company-sponsored clinical trials were significantly less likely to be published or presented than unfunded studies. Stern and Simes158 successfully followed up 520 studies out of 748 submitted to a Sydney hospital ethics committee in 1979-1988. In their study, pharmaceutical industry funding was not a statistically significant predictor of time to publication. Ioannidis159 looked at Phase 2 and Phase 3 trials related to HIV treatments and did not find that the source of funding affected the time it took the results to appear in peer reviewed literature. Dickersin et al.160 followed up studies approved by institutional review boards at two centres. The publication rate at one of the two was considerably higher for studies funded by the National Institutes of Health than for pharmaceutical industry-funded studies, but there was no evidence that the tendency to publish important results differed.
d. Multiple publication
Huston and Moher161 report that trials can be published in different forms, with different authors, which can make it seem that there is more evidence favouring a treatment than there actually is. They recount trying to untangle the genealogy of a risperidone trial funded by its manufacturer. Similarly, Johansen and Gotzsche162 describe the difficulties they encountered trying to carry out a metaanalysis on trials of anti-fungal agents. It was often unclear whether data in multi-centre trials were also published separately, and when contacted, many authors did not respond, or said they no longer had access to the data because it was with the manufacturing company or their previous employer. Tramer et al.178 reviewed 84 trials investigating the use of ondansetron for post-operative emesis to quantify the impact of duplicate data on estimates of efficacy. They found that 17% of published full reports and 28% of patient data were duplicated, concluding that trials reporting greater treatment effect were significantly more likely to be duplicated, and that inclusion of duplicated data in meta-analysis led to a 23% overestimation of ondansetron's antiemetic efficacy.
CONCLUSION: The evidence that trials sponsored by a drug company are less likely to be published is contradictory. Some major company-funded trials have been published in multiple papers that make them appear to be separate studies, and this can distort the findings of systematic reviews or meta-analyses.
e. Is there an association between industry funding and published results?
Stelfox et al.163 examined links between financial relationships with pharmaceutical manufacturers and doctors’ published positions on calcium channel antagonists. They found 70 articles about calcium channel antagonists, and classified them, and their authors as either ‘supportive’, ‘neutral’ or ‘critical’ about the use of these medicines. They then contacted the authors and asked them about their financial relationships with manufacturers of calcium channel antagonists and/or competing products. They found that authors who supported the use of calcium channel antagonists were more likely than others to have financial relationships with manufacturers of these products. Unexpectedly they found that authors who criticised the use of calcium channel antagonists were less likely than other authors to have financial relationships with manufacturers of competing products. The timing of the authors’ position on calcium channel antagonists and their financial relationships were not explored. It is possible that authors supportive of calcium channel antagonists were sought out by companies, rather than company sponsorship leading to more positive positions on calcium channel antagonists. The authors note that only two of the 70 articles disclosed potential conflicts of interest.
In their meta-analysis of third generation oral contraceptives and the risk of venous thromboembolism, Kemmeren et al.164 found odds ratios of 1.3 (1.0-1.7) in industry funded studies, and 2.3 (1.7-3.2) in other studies. On the same topic, in a letter to the editor of the British Medical Journal, Vandenbroucke et al.165 report that of nine unsponsored studies, eight found relative risks of 1.5 to 4.0, while four sponsored studies found relative risks of 0.8 to 1.5. Similarly, Mandelkern wrote to the Journal of Clinical Psychiatry166 that in 1997 all 16 industry-supported studies in the journal were favourable to the manufacturer’s drug, while all six unsupported studies were not favourable to the study drug.
Wahlbeck and Adams, in a letter to the editor of the British Medical Journal outline their findings that industry-funded trials on clozapine reported more positive results than non-industry sponsored trials167. Similarly, Cho and Bero found that articles that acknowledged support from the industry were more likely to present results which favoured the drug of interest168. Rochon et al.169 analysed 56 published trials of NSAIDs that they defined as ‘manufacturer associated’, including studies where the manufacturer had only provided study drugs. They found that the manufacturer’s drug was always reported as comparable to (71%) or superior to (29%) the comparison drug. This was usually justified by the results. In 22 trials one drug was claimed to be less toxic, and in 19 of these this was the manufacturer-associated drug. This claim was justified by a test of statistical significance only 54% of the time. Liebeskind et al.170, in a poster presentation, outlined a study of controlled clinical trials in acute ischaemic stroke from 1957 to 1997. They suggest there is under-reporting of trials showing adverse effects of experimental agents, and that the time from the start of enrolment to publication is longer for trials with negative outcomes than positive outcomes, and that this difference is greater for trials with corporate sponsorship.
Azimi and Welch171 looked at cost-effectiveness analyses in journals most visible to clinicians and found that funding source significantly affected the authors’ conclusions about whether therapies requiring additional expenditure were justified, regardless of the quantitative conclusions of the study. Nine out of 10 articles that acknowledged industry funding supported additional expenditure, while 15 of the 34 with no industry funding did. Authors of articles supported by the industry supported the use of new technologies at higher costs than other authors.
Friedberg et al.172 looked at studies on the cost or cost-effectiveness of new oncology drugs. They found that industry sponsored studies were less likely to report unfavourable qualitative conclusions than studies funded by non-profit organizations. Eighty-nine per cent of the studies they looked at used a retrospective design, which Friedberg et al. say allows the sponsor to look at the results of clinical trials and fund economic studies based on those most likely to give favourable economic results. Knox et al.179 used the same trials as Friedberg et al., and concluded that industry-funded studies provided less information about the generalizability of their findings. They tended to highlight specific settings where the drug was most likely to be cost-effective.
Davidson173 analysed all trials with concurrent or cross-over control groups published in 1984 in five major medical journals. He classified them according to whether they favoured a new therapy or intervention, or favoured traditional management. He also recorded whether the authors acknowledged industry funding or not. Provision of the study drugs or placebos was not counted as industry support. Davidson found a statistically significant association between industry support and whether studies favoured new therapies. Only four industry supported studies favoured traditional therapies. In two of these the manufacturer who supported the study did not make either medicine, and in one they made both medicines. Davidson speculates on the mechanism for the relationship between funding and published results. He suggests that industry funding may allow researchers to include large sample sizes which increases their ability to detect statistically significant differences and therefore to publish in a major journal. He also suggests companies may select drugs for study that have already been shown to be efficacious, that they may discontinue studies if the results are appearing to be negative, and that they may pressure investigators not to submit negative results.
Jadad et al.174 looked at meta-analyses and systematic reviews of treatments for asthma. The six industry-funded reviews were of low quality and the conclusions of all but one favoured the intervention associated with the sponsoring company. The one exception examined the effect of Vitamin C, which was not a new proprietary compound.
Djulbegovic et al.175,176 argue that randomised controlled trials should only be done if there is substantial uncertainty about which treatment is best. Therefore over time, roughly half of the trials should favour standard treatments, and half should favour experimental treatments. However, when looking at 126 published randomised trials on one disease, those supported by commercial organizations mostly (74%) supported new treatments over standard treatments. This was not due to low quality of commercially-supported trials. Kjaergard et al.180 also found industry-funded trials to be higher quality than some others (those not receiving external funding).
Freemantle et al.181 found that sponsored trials were likely to show greater efficacy of the sponsors’ drugs, but this result was not statistically significant.
CONCLUSION: Pharmaceutical company funded research is more likely to show results favourable to the product being studied than research funded from other sources. There is an association between the opinions of investigators about products and their source of funding but causality has not been established.