Unpublished results from clinical trials distort medical research

By Lilian Nassi-Calò

Photo: Jason Rogers.

The ClinicalTrials.gov initiative was created in 1997 as a joint action of the US Food and Drug Administration and the Department of Health and Human Services (HSS) of the United States through the National Institutes of Health (NIH). Its purpose was to establish a platform for recording information on clinical trials conducted by public (research institutes and government agencies) and private initiatives (pharmaceutical companies). The Food and Drug Administration Modernization Act (FDAMA) made compulsory the registration of clinical trials that year, as well as its wide disclosure to the medical community, researchers and the general public. The website and domain are administered by the National Library of Science (NLM/NIH) and in it one can find all information about the drug or medical procedure under study, the main investigator, sponsor and mainly the results on treatment effectiveness and observed side effects. The main objective of the initiative is to prevent stakeholders to conceal negative results or unwanted side effects.

Since then, organizations, governments and scientific societies worldwide corroborated, adopted and created similar initiatives in order to regulate the mandatory registration and increase reliability and transparency of the studies. In Brazil, the development of the Brazilian Clinical Trials Registry Platform (ReBEC) began in 2006 as a joint action of the Ministry of Health of Brazil, Fundação Oswaldo Cruz, Agência Nacional de Vigilância Sanitária (Anvisa) and BIREME/PAHO/WHO, being inaugurated in 2010 and approved in 2011 by the World Health Organization through the International Clinical Trials Registry Platform.

In spite of that, a post previously published in this blog¹ showed that the reproducibility of studies on potential new drugs and innovative therapies is very low, which compromises clinical trials. As a result, pharmaceutical companies are repeating the experiments in their laboratories before recruiting volunteers for the testing phase, preventing financial and human resources to be used on unpromising drugs and therapies.

A recent study published in the New England Journal of Medicine², however, shows a worrisome scenario. The survey performed with over 13,000 clinical trials conducted between 2008 and 2013 registered in ClinicalTrials.gov, and thus, subject to regulation by the Food and Drug Administration Amendments Act (FDAAA), a US Federal Law passed in 2007. The study shows that, despite the requirement to register clinical trials in a publicly accessible database, only a small fraction are published in scientific journals, compromising the transparency and applicability of the outcomes. It is worth mentioning that the US is where most of the new drugs developed in the world receive their first approval.

Within a year, researchers at Duke University found that only 17% of the trials ordered by the pharmaceutical industry were published. The NIH has a worst rate, with only 8.1% of papers published in the same period, and other government research institutions have a 5.7% publication rate. In five years, the rate of published clinical trials rose to 41.5% for industry, 38.9% for the NIH, and 27.7% for other public academic institutions. There are, in theory, sanctions for those who do not. The FDA has the power to fine companies and report on ClinicalTrials.gov portal on non-publication and the NIH can cancel funding, but this practice is uncommon.

The researchers assume that unpublished trials are those that do not show the new drugs as its designers would like to. Pharmaceutical companies have obvious reasons for hiding them and researchers, on the other hand, prefer to publish positive results on promising drugs, which boosts their academic careers. Journals also contribute to this scenario, by favoring articles that show positive results. As a result of that, many drugs being studied seem more promising than they actually are.

The article by Duke University researchers was reported in the July 25^th issue of The Economist³. The weekly magazine highlights the international initiative AllTrials, created by the British agency Sense About Science to force researchers to publish all clinical trials they conduct. The charitable initiative works to bring scientific research closer to civil society and publishes guidelines on best practices in research and scientific communication in all areas of knowledge. AllTrials is supported by the Cochrane Collaboration, BMJ and PLoS, among others, and aims to encourage the registration and publication of all clinical trials. A petition⁴ that calls on governments, regulatory agencies and research institutions to implement measures to promote the wide dissemination of clinical trial results was signed, up to now, by more than 85,000 people and almost 600 organizations worldwide.

One of the creators of AllTrials, the physician and British researcher Ben Goldacre, illustrates through examples how relevant results from clinical trials would have changed the course of the use of certain drugs such as antidepressant Prozac and antiviral Tamiflu, if they would have been disclosed on due time.

If not for ethical and scientific reasons, pharmaceutical companies may henceforth consider the opinion of their shareholders to comply with the obligation to report all clinical trials results. It may seem contradictory that shareholders would prefer to disclose the whole truth about a new drug, as this can translate into lower profits. Long-term investors prefer the truth right away in order to reduce the level of risk of their portfolios. Data indicates that 30% of a company’s value is linked to the results of their trials. Moreover, in recent years pharmaceutical companies have been heavily fined for failing to comply with the reporting policy. In this regard, Sense About Science is developing a system to rank companies according to their commitment to publish clinical trial results, which will certainly be of interest to shareholders and investors.

The future imagined in 1997, when the ClinicalTrials.gov initiative was created, might be different from the present. However, the initiatives that have been created lately point to greater transparency of clinical trials from now on. Some companies have even considered publishing results so far undisclosed – except for the authors of the studies – but were hindered by the lack of proper consent from the participants at the time.

It is expected that the attitude of the pharmaceutical industry, the NIH and other public academic institutions subject to FDAAA legislation changes regarding the publication of clinical trial results. As stated Dr. Monique Anderson, the corresponding author of the NEJM² study, “Reporting clinical trials results in order to contribute to scientific and medical knowledge is as much an ethical obligation for researchers as a legal one: It’s something we really promise to every patient when they enroll on a trial”.

Notes

1. SCIENTIFIC ELECTRONIC LIBRARY ONLINE. Reproducibility of research results: the tip of the iceberg. SciELO in Perspective. [viewed 02 August 2015]. Available from: http://blog.scielo.org/en/2014/02/27/reproducibility-of-research-results-the-tip-of-the-iceberg/

2. ANDERSON, M.L., et al. Compliance with results reporting at ClinicalTrials.gov. N Engl J Med. 2015, vol. 372, pp. 1031-1039. DOI: 10.1056/NEJMsa1409364 Available from: http://www.nejm.org/doi/full/10.1056/NEJMsa1409364

3. Clinical trials: Spilling the beans. Failure to publish the results of all clinical trials is skewing medical science. The Economist. 2015. Available from: http://www.economist.com/news/science-and-technology/21659703-failure-publish-results-all-clinical-trials-skewing-medical

4. Petição: “Todos os resultados de testes clinicos devem ser publicados”. AllTrials. Available from http://www.alltrials.net/petition/

References

ANDERSON, M.L., et al. Compliance with results reporting at ClinicalTrials.gov. N Engl J Med. 2015, vol. 372, pp. 1031-1039. DOI: 10.1056/NEJMsa1409364 Available from: http://www.nejm.org/doi/full/10.1056/NEJMsa1409364

Clinical trials: Spilling the beans. Failure to publish the results of all clinical trials is skewing medical science. The Economist. 2015. Available from: http://www.economist.com/news/science-and-technology/21659703-failure-publish-results-all-clinical-trials-skewing-medical

Food and Drug Administration Amendment Act of 2007. U.S. Government Publishing Office (GPO). 2007. Available from: http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110.pdf#page=82

Petição: “Todos os resultados de testes clinicos devem ser publicados”. AllTrials. Available from http://www.alltrials.net/petition/

SCIENTIFIC ELECTRONIC LIBRARY ONLINE. Reproducibility of research results: the tip of the iceberg. SciELO in Perspective. [viewed 02 August 2015]. Available from: http://blog.scielo.org/en/2014/02/27/reproducibility-of-research-results-the-tip-of-the-iceberg/

SCIENTIFIC ELECTRONIC LIBRARY ONLINE. The EU will centralize the registry of clinical trials. SciELO in Perspective. [viewed 02 August 2015]. Available from: http://blog.scielo.org/en/2014/05/05/the-eu-will-centralize-the-registry-of-clinical-trials/

External Links

AllTrials –- <http://www.alltrials.net/>

ICTRP – <http://www.who.int/ictrp/en/>

Rebec – <http://ensaiosclinicos.gov.br/>

Sense About Science – <http://www.senseaboutscience.org/>

About Lilian Nassi-Calò

Lilian Nassi-Calò studied chemistry at Instituto de Química – USP, holds a doctorate in Biochemistry by the same institution and a post-doctorate as an Alexander von Humboldt fellow in Wuerzburg, Germany. After her studies, she was a professor and researcher at IQ-USP. She also worked as an industrial chemist and presently she is Coordinator of Scientific Communication at BIREME/PAHO/WHO and a collaborator of SciELO.

Translated from the original in portuguese by Lilian Nassi-Calò.