Jump to Section 1. Introduction 2. Methods 2.1. Bibliographic search and inclusion study criteria 2.1.1. Data extraction 2.2. Statistical analysis 3. Results 3.1. Characteristics of included trials 3.2. Funding source 3.3. Trial characteristics by funding source 3.4. Association of industry funding, sample size, and design with “positive” results 4. Discussion Supplementary data References

Our empirical evaluation assessed 319 recent head-to-head randomized trials across a wide spectrum of treatments and conditions. Most head-to-head comparative evidence is procured by industry-sponsored trials. Typically, only one industry sponsor is involved, apparently with an objective to obtain evidence on its product that could be used for promotion. Noteworthy, the vast majority of industry trials were funded exclusively by companies, as only 2.8% were cosponsored by nonprofit institutions.

Industry-sponsored trials tend to be larger, they are more frequently registered, and they tend to have higher citation impact and “favorable” results for the experimental treatment. Industry-sponsored trials also use noninferiority/equivalence designs more frequently than other trials. Industry funding and noninferiority/equivalence designs are strongly associated with “favorable” findings, and when they coexist, almost all trials get desirable “favorable” results.

It has been speculated whether industry tends to avoid head-to-head comparisons to avoid jeopardizing its market share by unfavorable results [9x[9]Lathyris, D.N., Patsopoulos, N.A., Salanti, G., and Ioannidis, J.P. Industry sponsorship and selection of comparators in randomized clinical trials. Eur J Clin Invest. ; 40: 172–182

Crossref | PubMed | Scopus (57) | Google ScholarSee all References, 28x[28]Dunn, A.G., Bourgeois, F.T., Murthy, S., Mandl, K.D., Day, R.O., and Coiera, E. The role and impact of research agendas on the comparative-effectiveness research among antihyperlipidemics. Clin Pharmacol Ther. ; 91: 685–691

Crossref | PubMed | Scopus (8) | Google ScholarSee all References, 29x[29]Dunn, A.G., Mandl, K.D., Coiera, E., and Bourgeois, F.T. The effects of industry sponsorship on comparator selection in trial registrations for neuropsychiatric conditions in children. PLoS One. ; 8: e84951

Crossref | PubMed | Scopus (10) | Google ScholarSee all References]. However, we documented that among the head-to-head RCTs that are eventually performed, the industry still has the lion's share of this research agenda, which can be highly influential for informing guidelines and evidence-based practice. A preponderance of industry sponsorship in head-to-head trials has also been demonstrated in previous smaller evaluations of trials in specific areas of cardiovascular and psychiatric disorders [5x[5]Ridker, P.M. and Torres, J. Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000-2005. JAMA. ; 295: 2270–2274

Crossref | PubMed | Scopus (198) | Google ScholarSee all References, 6x[6]Bero, L., Oostvogel, F., Bacchetti, P., and Lee, K. Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. PLoS Med. ; 4: e184

Crossref | PubMed | Scopus (189) | Google ScholarSee all References, 7x[7]Heres, S., Davis, J., Maino, K., Jetzinger, E., Kissling, W., and Leucht, S. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry. ; 163: 185–194

Crossref | PubMed | Scopus (316) | Google ScholarSee all References, 8x[8]Gartlehner, G., Morgan, L., Thieda, P., and Fleg, A. The effect of study sponsorship on a systematically evaluated body of evidence of head-to-head trials was modest: secondary analysis of a systematic review. J Clin Epidemiol. ; 63: 117–125

Abstract | Full Text | Full Text PDF | PubMed | Scopus (12) | Google ScholarSee all References] and H1N1 influenza vaccines [27x[27]Alsheikh-Ali, A.A., Qureshi, W., Al-Mallah, M.H., and Ioannidis, J.P. Public availability of published research data in high-impact journals. PLoS One. ; 6: e24357

Crossref | PubMed | Scopus (156) | Google ScholarSee all References, 30x[30]Manzoli, L., De Vito, C., Salanti, G., D'Addario, M., Villari, P., and Ioannidis, J.P. Meta-analysis of the immunogenicity and tolerability of pandemic influenza A 2009 (H1N1) vaccines. PLoS One. ; 6: e24384

Crossref | PubMed | Scopus (62) | Google ScholarSee all References].

We found that more than three-quarters of the head-to-head trials compared products owned by different companies, with no significant difference between industry and nonindustry-funded trials. However, we observed that cosponsorship of antagonistic trials was infrequent. Twenty-three RCTs were supported by two (or more) different companies; however, only in three of these (0.9% of the total sample) two sponsors, each owning an active treatment, were truly compared against each other. In the other RCTs, the cosponsoring companies shared the ownership of the same intervention(s), or one of the sponsors was the owner of the common backbone treatment given to all patients, or owned both the interventions—the standard of care and the new drug. In this way, sponsoring companies have to gain from the trial regardless of the outcome, unless a company owns and compares a new drug against an older one, which is about to go off patent. In this peculiar case, the company would not gain if the old drug proves to be as good, or even better, than the new one. Overall, each company tended to support almost exclusively trials focused on its own products, trying to prove its new agent superior or noninferior to some established comparator.

As for randomized trials in general [31x[31]Okike, K., Kocher, M.S., Mehlman, C.T., and Bhandari, M. Industry-sponsored research. Injury. ; 39: 666–680

Abstract | Full Text | Full Text PDF | PubMed | Scopus (35) | Google ScholarSee all References][31], the profile and characteristics of head-to-head trials appear to be influenced by their sponsorship. Compared with nonindustry RCTs, industry trials had higher rates of registration, larger sample size, were published on journals with higher impact factors, and were more cited. All these findings tend to suggest that industry-sponsored head-to-head RCTs are outperforming other head-to-head trials. This is not surprising because supporting companies see these trials as an investment that is important for their marketing efforts, and thus, they want to optimize the compliance with requested policies (such as registration) and the impact of this research. Moreover, companies are expected to meet standard quality criteria during the planning and conducting of clinical trials and are subject to intense scrutiny by regulatory agencies [32x[32]Bhatt, A. Quality of clinical trials: a moving target. Perspect Clin Res. ; 2: 124–128

Crossref | PubMed | Google ScholarSee all References][32].

Also, as previously hypothesized [7x[7]Heres, S., Davis, J., Maino, K., Jetzinger, E., Kissling, W., and Leucht, S. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry. ; 163: 185–194

Crossref | PubMed | Scopus (316) | Google ScholarSee all References, 33x[33]Garattini, S. and Bertele, V. Ethics in clinical research. J Hepatol. ; 51: 792–797

Abstract | Full Text | Full Text PDF | PubMed | Scopus (18) | Google ScholarSee all References, 34x[34]Apolone, G., Joppi, R., Bertele, V., and Garattini, S. Ten years of marketing approvals of anticancer drugs in Europe: regulatory policy and guidance documents need to find a balance between different pressures. Br J Cancer. ; 93: 504–509

Crossref | PubMed | Scopus (70) | Google ScholarSee all References], we found that industry trials were more likely than other trials to adopt a noninferiority/equivalence design. There are two potential motivations for using noninferiority designs. First, often there can be advantages in terms of sample size (and, in turn, costs) [7x[7]Heres, S., Davis, J., Maino, K., Jetzinger, E., Kissling, W., and Leucht, S. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry. ; 163: 185–194

Crossref | PubMed | Scopus (316) | Google ScholarSee all References, 21x[21]Powers, J.H., Cooper, C.K., Lin, D., and Ross, D.B. Sample size and the ethics of non-inferiority trials. Lancet. ; 366: 24–25

Abstract | Full Text | Full Text PDF | PubMed | Scopus (8) | Google ScholarSee all References]. Moreover, proving noninferiority of a new product may be sometimes less risky than aiming to establish its superiority because a finding of noninferiority will require less of a treatment effect yet still may be enough to support product approval [33x[33]Garattini, S. and Bertele, V. Ethics in clinical research. J Hepatol. ; 51: 792–797

Abstract | Full Text | Full Text PDF | PubMed | Scopus (18) | Google ScholarSee all References, 35x[35]FDA. Guidance for industry—non-inferiority clinical trials. U.S. Food and Drug Administration, Silver Spring, MD, USA;

Google ScholarSee all References]. Along with this increasing trend, however, growing concerns occur: some argue that noninferiority RCTs mainly benefit companies, as they allow drugs without additional clinical efficacy to enter the market [20x[20]Garattini, S. and Bertele, V. Non-inferiority trials are unethical because they disregard patients' interests. Lancet. ; 370: 1875–1877

Abstract | Full Text | Full Text PDF | PubMed | Scopus (134) | Google ScholarSee all References, 36x[36]Gotzsche, P.C. Lessons from and cautions about noninferiority and equivalence randomized trials. JAMA. ; 295: 1172–1174

Crossref | PubMed | Scopus (83) | Google ScholarSee all References, 37x[37]Djulbegovic, B. and Clarke, M. Scientific and ethical issues in equivalence trials. JAMA. ; 285: 1206–1208

Crossref | PubMed | Scopus (57) | Google ScholarSee all References]. However, admittedly, these drugs may still be useful if they are safer and less expensive [38x[38]Chuang-Stein, C., Beltangady, M., Dunne, M., and Morrison, B. The ethics of non-inferiority trials. Lancet. ; 371: 895–896 ( )

Abstract | Full Text | Full Text PDF | PubMed | Scopus (4) | Google ScholarSee all References, 39x[39]Gandjour, A. The ethics of non-inferiority trials. Lancet. ; 371: 895 ( )

Abstract | Full Text | Full Text PDF | PubMed | Scopus (1) | Google ScholarSee all References, 40x[40]Soliman, E.Z. The ethics of non-inferiority trials. Lancet. ; 371: 895 ( )

Abstract | Full Text | Full Text PDF | PubMed | Scopus (11) | Google ScholarSee all References]. We found that published industry-sponsored trials with noninferiority/equivalence designs were practically almost always successful to get a favorable, “positive” result, that is, claim (at least) noninferiority. Unfortunately, no information is available to evaluate whether such a high success rate occurs among all trials including those that remain unpublished or whether pharmaceutical companies selectively fund trials on drugs that they consider to be superior to the competition. In any case, by focusing on noninferiority, companies shift the traditional concept of equipoise where typically only about half of the trials manage to show superiority of the new treatment against a standard comparator [41x[41]Djulbegovic, B., Lacevic, M., Cantor, A., Fields, K.K., Bennett, C.L., Adams, J.R. et al. The uncertainty principle and industry-sponsored research. Lancet. ; 356: 635–638

Abstract | Full Text | Full Text PDF | PubMed | Scopus (353) | Google ScholarSee all References, 42x[42]Mann, H. and Djulbegovic, B. Choosing a control intervention for a randomised clinical trial. BMC Med Res Methodol. ; 3: 7

Crossref | PubMed | Scopus (38) | Google ScholarSee all References, 43x[43]Djulbegovic, B. Acknowledgment of uncertainty: a fundamental means to ensure scientific and ethical validity in clinical research. Curr Oncol Rep. ; 3: 389–395

Crossref | PubMed | Scopus (42) | Google ScholarSee all References, 44x[44]Mann, H., Djulbegovic, B., and Gold, P. Failure of equipoise to resolve the ethical tension in a randomized clinical trial. J Law Med Ethics. ; 31: 5–6

Crossref | PubMed | Google ScholarSee all References, 45x[45]Djulbegovic, B. The paradox of equipoise: the principle that drives and limits therapeutic discoveries in clinical research. Cancer Control. ; 16: 342–347

Crossref | PubMed | Scopus (24) | Google ScholarSee all References] and select a design and inferential framework that is more likely to give them favorable results [46x[46]Gerlinger, C. and Schmelter, T. Determining the non-inferiority margin for patient reported outcomes. Pharm Stat. ; 10: 410–413

Crossref | PubMed | Scopus (13) | Google ScholarSee all References][46].

Although we found an independent, significant relationship between reporting positive findings and being sponsored by industry or having a noninferiority/equivalence design, trial results were not related to sample size. An association between industry sponsorship and positive findings has been documented by several surveys of clinical trials [5x[5]Ridker, P.M. and Torres, J. Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000-2005. JAMA. ; 295: 2270–2274

Crossref | PubMed | Scopus (198) | Google ScholarSee all References, 6x[6]Bero, L., Oostvogel, F., Bacchetti, P., and Lee, K. Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. PLoS Med. ; 4: e184

Crossref | PubMed | Scopus (189) | Google ScholarSee all References, 7x[7]Heres, S., Davis, J., Maino, K., Jetzinger, E., Kissling, W., and Leucht, S. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry. ; 163: 185–194

Crossref | PubMed | Scopus (316) | Google ScholarSee all References, 8x[8]Gartlehner, G., Morgan, L., Thieda, P., and Fleg, A. The effect of study sponsorship on a systematically evaluated body of evidence of head-to-head trials was modest: secondary analysis of a systematic review. J Clin Epidemiol. ; 63: 117–125

Abstract | Full Text | Full Text PDF | PubMed | Scopus (12) | Google ScholarSee all References, 19x[19]Lexchin, J., Bero, L.A., Djulbegovic, B., and Clark, O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ. ; 326: 1167–1170

Crossref | PubMed | Google ScholarSee all References, 26x[26]Lundh, A., Sismondo, S., Lexchin, J., Busuioc, O.A., and Bero, L. Industry sponsorship and research outcome. Cochrane Database Syst Rev. ; : MR000033

PubMed | Google ScholarSee all References, 47x[47]Bekelman, J.E., Li, Y., and Gross, C.P. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. ; 289: 454–465

Crossref | PubMed | Scopus (1220) | Google ScholarSee all References, 48x[48]Als-Nielsen, B., Chen, W., Gluud, C., and Kjaergard, L.L. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events?. JAMA. ; 290: 921–928

Crossref | PubMed | Scopus (527) | Google ScholarSee all References, 49x[49]Manzoli, L., Flacco, M.E., D'Addario, M., Capasso, L., De Vito, C., Marzuillo, C. et al. Non-publication and delayed publication of randomized trials on vaccines: survey. BMJ. ; 348: g3058

Crossref | PubMed | Scopus (34) | Google ScholarSee all References]. Sample size was previously found to be associated with favorable findings in few empirical surveys [6x[6]Bero, L., Oostvogel, F., Bacchetti, P., and Lee, K. Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. PLoS Med. ; 4: e184

Crossref | PubMed | Scopus (189) | Google ScholarSee all References, 50x[50]Rasmussen, N., Lee, K., and Bero, L. Association of trial registration with the results and conclusions of published trials of new oncology drugs. Trials. ; 10: 116

Crossref | PubMed | Scopus (49) | Google ScholarSee all References], only one of which focused on head-to-head trials [6x[6]Bero, L., Oostvogel, F., Bacchetti, P., and Lee, K. Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. PLoS Med. ; 4: e184

Crossref | PubMed | Scopus (189) | Google ScholarSee all References][6] and the association was seen for favorable trial conclusions rather than favorable trial results per se. Our analysis might also be partially affected by the exclusion of smaller RCTs.

Previous literature has showed an association between the presence of author's conflict of interest and favorable findings in randomized trials [51x[51]Friedman, L.S. and Richter, E.D. Relationship between conflicts of interest and research results. J Gen Intern Med. ; 19: 51–56

Crossref | PubMed | Scopus (152) | Google ScholarSee all References, 52x[52]Kjaergard, L.L. and Als-Nielsen, B. Association between competing interests and authors' conclusions: epidemiological study of randomised clinical trials published in the BMJ. BMJ. ; 325: 249

Crossref | PubMed | Google ScholarSee all References, 53x[53]Jagsi, R., Sheets, N., Jankovic, A., Motomura, A.R., Amarnath, S., and Ubel, P.A. Frequency, nature, effects, and correlates of conflicts of interest in published clinical cancer research. Cancer. ; 115: 2783–2791

Crossref | PubMed | Scopus (60) | Google ScholarSee all References]. Because of the strong correlation between funding source and conflict of interest (Spearman rho 0.77), the variable “conflict of interest” was not significant in multivariate analysis in our survey. However, if funding source was removed from the model, the presence of a conflict of interest would have been significantly associated with favorable findings (not shown).

Some limitations should be acknowledged. First, it is possible that we failed to identify funding sources and financial ties in some of the included trials. We classified trials as industry funded or not based on each article's disclosure of its funding source(s), and only if no funding source was listed in the article, we checked the corresponding trial registration record, if available. Krimsky et al. [54x[54]Krimsky, S. and Rothenberg, L.S. Financial interest and its disclosure in scientific publications. JAMA. ; 280: 225–226

Crossref | PubMed | Scopus (60) | Google ScholarSee all References, 55x[55]Krimsky, S. and Rothenberg, L.S. Conflict of interest policies in science and medical journals: editorial practices and author disclosures. Sci Eng Ethics. ; 7: 205–218

Crossref | PubMed | Scopus (145) | Google ScholarSee all References] showed, however, that there is a lack of disclosure of industry research support and personal financial ties across a wide variety of journals. Thus, we may have underestimated the number of industry-sponsored trials and personal financial ties of investigators. Second, we tried to ascertain all potential relationships between companies, but sometimes financial arrangements remain undetected in internet searches, especially those between small companies with larger ones [9x[9]Lathyris, D.N., Patsopoulos, N.A., Salanti, G., and Ioannidis, J.P. Industry sponsorship and selection of comparators in randomized clinical trials. Eur J Clin Invest. ; 40: 172–182

Crossref | PubMed | Scopus (57) | Google ScholarSee all References][9]. Third, because industry-funded trials and drug trials are more likely to have large samples [6x[6]Bero, L., Oostvogel, F., Bacchetti, P., and Lee, K. Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. PLoS Med. ; 4: e184

Crossref | PubMed | Scopus (189) | Google ScholarSee all References, 56x[56]Smoak, C.G. Regulatory submissions for medical devices and diagnostics: the basics. CDISC J. ; : 1–5

Google ScholarSee all References], the exclusion from our analyses of RCTs with <100 patients may have led to underrepresentation of nonindustry-funded trials and device trials in our sample.

Finally and most importantly, we only examined a (large) sample of RCTs published in 2011, and thus, we cannot map whether any changes in these patterns of head-to-head trials might have occurred over the years. However, our survey offers evidence on the profile of trials that were published in the recent literature.

In conclusion, there is strong dominance of the industry in the influential agenda of head-to-head comparisons, confirming the unbalance between profit and nonprofit sponsored sources of data of current literature. We observed a high prevalence of results that were favorable for the sponsoring companies, which may have several explanations including: (1) industry trials may be conducted more rigorously than nonprofit trials and are thus genuinely more successful; (2) pharmaceutical companies may selectively fund trials that are more likely to yield favorable results (possibly due to the many preliminary phase 1 and phase 2 studies that are conducted before embarking on phase 3); (3) industry trials choose suboptimal outcomes, comparators, and other design features that can secure a favorable result; or (4) trials with unfavorable findings may be less likely to be published by companies. It is currently impossible to determine the relative weight of each of the above, but given the importance of head-to-head comparisons in informing guideline recommendations and practice, consideration should be given to allowing the conduct of more large trials of comparative effectiveness and safety under the control of nonprofit entities [57x[57]Ioannidis, J.P. Mega-trials for blockbusters. JAMA. ; 309: 239–240

Crossref | PubMed | Scopus (33) | Google ScholarSee all References][57]. The design of such trials should be such as to inform important questions rather than pre-emptively ensure that results would be favorable for a tested intervention.