Numerous clinical trials involving children are missing results from the European trial registry, data released by the European Medicines Agency (EMA) shows.
UPDATE 26 June: The European Medicines Agency today got in touch to challenge the figures reported in the original version of this blog. The blog below has been amended to take this new information into account. Please see the end of this blog for details and a discussion.
According to an email from EMA dated 26 June 2020, "the total number of trials with due results is now below 5900, of which less than 380 are trials involving paediatric subjects."
While EMA has not provided precise up-to-date figures, the data highlight national regulatory agencies’ failure to ensure sponsors’ compliance with long-standing European transparency rules.
(TranspariMED has filed a new Freedom of Information request with EMA to obtain precise figures on the number of clinical trials currently missing results across Europe.)
Non-reporting and incomplete reporting of clinical trial results harms patients and undermines public health, and has in the past led to numerous patient deaths. It also affects the integrity of the marketing approval process of medical technologies by regulatory authorities.
The figures given below are based on November 2019 data on Clinical Trial Applications that were released by EMA in response to a Freedom of Information request submitted by TranspariMED and Health Action International.
In total, across the European Union, trials linked to 1,345 Clinical Trial Applications involving children were missing results as of November 2019.
Some trials take place in multiple countries at the same time. The figure of 1,345 Clinical Trial Applications is larger than the total number of trials because trials that are run in more than one country are counted multiple times. For example, a single cancer trial with study sites in Germany, France and Spain would be counted as three separate national Clinical Trial Applications, one for each of those countries.
German regulators BfArM and Paul Ehrlich Institute between them approved 178 paediatric trials in their country whose results were overdue. This means that 178 clinical trials involving German children were missing results on the European registry, in violation of European transparency requirements. (Some of these trials might also have involved children in other countries.)
Lax oversight by the Italian medicines agency contributed to 146 paediatric trial results going unreported. The French regulator ANSM and the Spanish AEMPS were responsible for over a hundred paediatric Clinical Trial Applications each for whose trials results are now missing.
The data is equally disappointing for trials involving adult patients. Adult trials linked to 13,534 national Clinical Trial Applications were missing results as of late 2019.
The results for trials linked to 2,474 Clinical Trial Applications filed in Germany alone were overdue, followed by Spain (1,014 applications), Italy (952 applications), Belgium (877), Denmark (781) and the Netherlands (699).
The data above suggest that national regulators have a weak track record in protecting the interests of patients and taxpayers.
Trial sponsors in Europe have since 2014 been obliged to upload results onto the European registry EudraCT within six months (paediatric trials) or twelve months (adult trials) of study completion.
However, enforcement of these rules lies with national regulators in individual member states. Denmark is so far the only European country that has introduced sanctions for failures to report the results of drug trials.
In reaction to the data, patient and health groups around Europe today call on EU Member States and their national medicines regulators to take decisive action.
Ward Rommel, Chair of the Access to Medicines Task Force at the European Cancer Leagues, said:
"Open access to clinical trials' results is crucial. This lack of transparency prevents further research and hampers the development of up-to date clinical guidelines, patient safety as well as reimbursement decisions of public health authorities."
"We call on EU Member States to guarantee that both public and private research entities follow their obligations and publish full data sets of clinical studies’ results."
NETHERLANDS. Jaume Vidal, Senior Policy Advisor at European Projects at Health Action International, said:
"The release, upon demand, of this data shows the need for effective enforcement of existing reporting rules on clinical trials and lays bare the challenges faced by national authorities. Their incapacity to adequately respond has harmful consequences for researchers, patients and societies at large. Action must be taken by relevant executive and legislative bodies."
GERMANY. Joerg Meerpohl, Director of the Institute for Evidence in Medicine, said:
“The non-availability of data from clinical trials poses a massive problem for evidence synthesis and guideline development."
"Timely reporting of results is therefore of paramount importance to ensure a complete and unbiased evidence base for health care decision making. Non-reporting of findings is also unfair towards children and parents who participated in trials to advance medical knowledge.”
GERMANY. Jörg Schaaber, Executive Director of BUKO Pharma-Kampagne, said:
“It is totally inacceptable to hide data from trials with the most vulnerable patients - children. It is appalling to see German authorities still lacking oversight and being last in the ranking of clinical trial transparency.”
FRANCE. Pauline Londeix, co-founder of Observatoire Transparence Médicaments, said:
"There is no excuse for such data to be missing. It is the role of Member States, including national regulators, to take concrete actions to compel companies to provide the missing results."
"This situation clearly shows that a voluntary mechanism is not enough. Therefore, we call on the [French regulator] ANSM to take concrete actions and to sanction companies that have failed to provide this critical information."
FRANCE. Pierre Chirac, Publication Manager of Prescrire, said:
“Access to clinical trial results is of vital interest for patients and healthcare professionals for enlightened treatment decisions. It is high time that national authorities take action to ensure compliance with European transparency rules. Patients - including young patients - deserve this respect.”
SPAIN. Vanessa López, Executive Director of Salud por Derecho, said:
"Transparency and accountability are essential conditions for the access of researchers, clinicians, patients, and political decision-makers to quality and ethical scientific evidence that provides the basis for decisions and that, ultimately, protects and ensures patient benefit and good governance of science."
"In the case of Spain, the AEMPS should establish the necessary internal mechanisms of monitoring, surveillance, and auditing to ensure that results are adequately reported and completed."
ITALY. Daniele Dionisio, member of the European Parliament Working Group on Innovation, Access to Medicines and Poverty-Related Diseases, and Head of Policies for Equitable Access to Health, said:
“Non-fulfilment of transparency obligations regarding the reporting of clinical trial results across the European Union, including in Italy, runs contrary to the human right to equitable access to health and puts financial resources invested in research at risk. Clinical trial results allow doctors, patients and policy leaders to make informed choices about the safety and appropriateness of therapeutic interventions. Sharing the methods and results of all clinical investigations is a scientific and moral duty."
"National regulatory agencies must be proactive and impose sanctions when needed, so that all involved parties comply with their duty to make trials data fully accessible to citizens, health professionals and researchers.”
BELGIUM. Martine Van Hecke, Health Expert at Test Aankoop/Test Achats, said:
“Patients who participate in clinical trials do so to contribute to scientific progress, therefore the results of the trials belong to them and to society at large. Transparency is a key ingredient of scientific progress. Governments have the responsibility to protect and defend the interests of citizens and patients. Regulators should monitor compliance with transparency rules and take strong measures when transparency obligations are not followed. As compliance remains weak, sanctions are needed. We are happy that the principle of sanctions has been enshrined in the Belgian legislation that transposed the Clinical Trial Regulation into national law."
"Belgian authorities must now put into place detailed rules and processes that ensure that sanctions are routinely and consistently imposed on trial sponsors that break the law."
REGIONAL. Till Bruckner, founder of TranspariMED, said:
“The data clearly show that voluntary compliance has failed to protect patient interests. No university or company running a clinical trial should be allowed to ignore basic transparency rules. Parents who enrol their sick children in medical research should not have to worry about the results later disappearing into a dusty drawer.”
"The forthcoming incorporation of the Clinical Trial Regulation into national law across Europe offers a unique window of opportunity for other EU Member States to follow Denmark’s positive example and introduce sanctions with teeth.
REGIONAL. Solveig Kemna of the European Coordinating Committee of Universities Allied for Essential Medicines (UAEM) Europe said:
"The data presented here clearly show that there are still huge steps to be made in improving the reporting of pediatric clinical trial results. This lack of transparency has negative repercussions on patient safety and health systems in general, and is particularly concerning as these clinical trials concern children. Universities have a special responsibility and should be setting a good example."
Germany is unusual in Europe in that it has two regulators, with each regulator responsible for different types of trials. The data released by the European Medicines Agency show that BfArM was responsible for 2,135 adult trials and 141 paediatric trials that were missing results. The second regulator, Paul Ehrlich Institute, was responsible for 339 adult trials and 37 paediatric trials that were missing results.
Clinical trial sponsors can use TranspariMED's collection of Transparency Tools to improve their trial reporting performance.
Note: The data released by the EMA represents the status quo as of 21 November 2019. More recent data are not available. Due to Brexit, trials overseen by the UK regulator MHRA are not discussed in the narrative of the blog above.
IMPORTANT UPDATE, 26 June 2020
The European Medicines Agency today got in touch to challenge the figures reported in the original version of this blog.
The blog originally stated that results were missing for 1,345 paediatric trials and 13,534 adult trials. In fact, according to EMA, these figures did not relate to trials per se, but to Clinical Trial Applications, resulting in an overcounting of overdue trials.
TranspariMED is committed transparency and accuracy. Therefore, please find an explanation below.
According to EMA, the data it released in response to a Freedom of Information request:
"refer to the number of Clinical Trial Applications.... single trials are calculated per EudraCT number, and not per CTAs. If results are missing for a multi country trial, they should be counted as missing once and not for each CTA submitted in the various countries where the clinical trial took place... the current published information is misleading. We are about to publish the following in our website, feel free to report the same numbers in yours as well. 'The total number of trials with due results is now below 5900, of which less than 380 are trials involving paediatric subjects.' For your information, at the end of 2019 the total number of trials with due results was just above 6000 trials, of which around 415 were trials including paediatric subjects."
Background: Many trials take place in multiple countries at the same time. The data originally presented in the TranspariMED blog counted each such multi-country trials more than once, for each country in which the trial is run. EMA had released the data in PDF format (sic) without accompanying contextual information, so this distinction was not apparent from the information EMA had originally provided.
TranspariMED welcomes EMA's planned publication of data on drug trials missing results in Europe.
TranspariMED hopes that going forward, EMA will regularly and routinely proactively make such data public, rather than only releasing it in response to Freedom of Information requests. This would allow European citizens to track their national regulatory agencies' progress in ensuring that all drug trials involving European patients make their results public as required by existing transparency rules.