Clinical Trial Reporting Biased; Full Disclosure, Transparency Needed, Speakers Say

A conference on clinical drug trials held today shed a harsh light on the availability and honesty of clinical trial reports. Many factors concur to possible distortion of results, speakers said, calling for more stringent obligations to provide all data for analysis. They also noted legislative efforts to tackle the issue. Speakers also pointed out a growing trend for pharmaceutical companies to conduct clinical trials in developing countries.

The conference was organised by Health Action International and Public Eye (formerly Bern Declaration), and gathered a number of speakers coming from international organisations, academics, public-private partnership, and public institutions. The organisers said they invited the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) but that they were unable to participate.

Clinical trials are at the heart of commercial interests, as approval of a drug could translate into “huge money,” Patrick Durisch from Public Eye said in introductory remarks. Data released on clinical trials suffer from manipulation and bias, putting participants at risk but also the public at large. Efficiency results are often overplayed and the harmful side effects downplayed.

“Full transparency should be the rule and not the exception,” he said.

Causes for Distortion in Published Results

Tom Jefferson, honorary research fellow at the Centre for Evidence Based Medicine & Cochrane Acute Respiratory Infections Group in the United Kingdom, said clinical drug trials are vital but a set of principles should be respected. These include a clear basis for participants recruitment, the follow-up of those trials, the measurement, the analysis, the documentation and the reporting.

However, there is a considerable number of possible causes for distortion in published results of clinical trials. These include: failure of randomisation, weak comparator to dampen possible harmful effects, difference in taste or look between the drug being tested and a placebo against which the drug is evaluated, the loss of participants for undisclosed reasons, and restrictions of analysis.

“Never lie,” he said sarcastically in summing up the situation, “but be economical with the truth when needed.”

Some sensible data are often lost in huge documents, making it difficult to find, “in particular if you are not looking for it.” He suggested including pictures of the drugs in clinical trial reports to help with the issue of differences between the drugs and placebos.

Jefferson also underlined the threat to systematic reviews of clinical trials. Many trials are unpublished, or reported in a distorted fashion, he said, adding there are numerous examples of misconducted trials published in journals. What appears in publications is misleading, he said, because there is not enough information for appraising trials.

Unpublished trials and misreporting of published trials are major threats to the validity of Cochrane Systematic Reviews, he said.

Offshoring of Clinical Trials in LMICs on the Rise

According to Durisch, there is an increasing trend of conducting clinical drug trials in low and middle-income countries, now about one-third of the global trials.

Reasons for companies to go to developing countries are multiple. The recruitment of participants is easier because a lot of people are looking to access free medicines, there is a large pool of participants who are “treatment naïve,” a weaker regulatory environment, less stringent ethical reviews, although efforts are being conducted in those countries to remedy the issue. There is also local demand for those trials, as they are perceived as being of interest to university hospitals and researchers, he said.

However, a number of ethical concerns have been pointed out by investigations, he said. In particular, clinical trials may not meet local health priorities, it is unclear if informed consent has been obtained from participants, there is a lack of compensation in case of adverse reaction to the drug, and there are systemic oversight weaknesses and loopholes, he said.

If the product is brought to market, there remains a problem of affordability for the local population, he added.

He mentioned the Ordinary Revision of the Therapeutic Products Swiss Act in March, including two articles on transparency, as a positive step.

According to a source, some pharmaceutical companies are interested in shortening the clinical trial process to bring patented products on the market sooner. In low and middle-income countries the recruitment of participants is easier, he told Intellectual Property Watch.

Egypt is one of the countries which host a large number of clinical drug trials, according to Ayman Sabae, Right to Health researcher for the Egyptian Initiative for Personal Rights. One of the reasons for this trend is that in Egypt, some 60 percent of total health care comes from personal expenses, as only about 8 percent of the population has access to private insurance.

Egypt has an attractive research infrastructure, he said, and a fast-growing treatment-naïve population. Clinical trials are much cheaper and the legislation protecting the rights of patients is weak.

Post-trial access and affordability of treatment is very limited, he said. A monthly treatment with some of the medicines surveyed cost more than 20 times the official monthly minimum wage of the public sector, he said, adding that only a small amount of medicines tested in Egypt were approved for marketing in the country.

He called for the Egyptian authorities to build a single robust legislative framework with a functional, independent control system that clearly establishes conditions of trials, regulates funding, monitoring, and promote transparency.

A participant in the audience remarked that sometimes developing countries make it a condition that if a drug is to be marketed in their countries, clinical trials should be conducted in the country also.

For Samia Hurst, director of the Institute for Ethics History and the Humanities at Geneva University, problems arise when you separate hope and risks. Much of research ethics is about weighing what is acceptable or unacceptable in the face of competing interests, she said.

Swiss Authorities Inspect Clinical Trials in Switzerland

Françoise Jaquet, head of Clinical Trials Divisions for Swissmedic, remarked on the changing landscape of clinical trials over the past 30 years. Since then, many guidelines and regulations have been issued, she said, in particular the need to register clinical trials in databases.

She said Swissmedics carries out inspections on clinical trials, but only in Switzerland, following the Good Clinical Practice of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), which she called a “gold standard.”

Clinical trials must comply with the Good Clinical Practice guidelines in order to be performed in Switzerland, she said, and to be accepted in market authorisation requests.

Legislative Efforts in EU, WHO Registry

Jan Stadler, legal officer and the Inquiry Coordination Unit at the European Ombudsman, said EU Ombudsman Emily O’Reilly, is asked to investigate maladministration within the EU administration, and was involved in the request for release of clinical trials data. However, her requests are not legally binding, he said.

He underlined the 2015 European Medicines Agency (EMA) policy on clinical data publication, and said it is now a question of knowing how it is put into practice.

Ancella Santos Quintano policy advisor for HAI, also underlined the lack of clinical trials data, the bias in publication and selective reporting results. Mandatory clinical trials data disclosure can help improve treatment decision-making, address publication and reporting bias, and prevent unnecessary clinical trial duplication.

Legislative efforts in the European Union and in the United States have been done in the last five years, she said, such as the EU clinical trial regulation in 2014.

She however warned against possible attempts by industry to use the concept of “commercial confidentiality” to retain some data. She also said that multiple layers of anonymization of participants could undermine the scientific usefulness of clinical trials data. A balance between ensuring a low risk of identification of participants and the availability of data has to be found, she said.

The World Health Organization International Clinical Trials Registry Platform (ICTRP) was established in 2006, said the ICTRP’s Ghassan Karam. A voluntary platform, the ICTRP now includes 17 countries, he said, with a big gap in Africa. The ICTRP supports the WHO Registry Network, and supports countries and regions wanting to join by establishing clinical trial registries. It provides a search portal.

The ICTRP website, provides “the minimum amount of trial information that must appear in a register in order for a given trial to be considered fully registered. There are currently 20 items in the WHO Trial Registration Data Set.”