Debate on missing trial results heats up in Europe
Regulators, institutions and experts across Europe are weighing in on how to tackle the dismal results reporting of drug trial results and address widespread data inaccuracies.
The renewed debate comes in the wake of a report released on Monday showing that both clinical trial registrations and trial results are frequently missing from the European trial registry, and that data on trials is often inaccurate or out of date.
Below an overview of media coverage and initial reactions from Germany, France, Belgium the Netherlands and Italy.
CORRECTION 06 July 2021: This blog post originally stated that German regulator BfArM had never directly contacted trial sponsors about their missing clinical trial results. BfArM has now revealed that it did directly contact over 1,100 sponsors in 2020. This blog has been corrected and expanded accordingly.
GERMANY: A cancer patient's story
Germany’s regulators BfArM and Paul Ehrlich Institut performed better than their counterparts in Italy and Belgium, but even so, at least 554 trials authorised by the twin regulators are currently missing results.
German patients harmed. An in-depth story by national broadcaster Tagesschau illustrated the harms that unreported trials can cause to patients. It discussed the case of Michael Zehnbauer, a terminally ill German cancer patient who desperately waited for the results of a clinical trial to be made public, but who eventually died before the results saw the light of day.
Photo: Michael Zehnbauer
Impunity for rule-breaking pharma companies. The company Celgene – since acquired by Bristol Myers Squibb – had failed to meet European transparency regulations in reporting the results of the trial that Michael Zehnbauer had seen as his last hope. Even today, both Celgene and BMS still have gaps in their trial reporting. With the exception of Denmark, no national regulator in Europe currently imposes sanctions on companies that violate the rules.
What are German medicines regulators doing?
Germany is unusual in having two responsible regulators. Depending on the type of trial, drug trials run in Germany are approved by either by Paul Ehrlich Institut or by BfArM, with the latter managing the majority of trial records.
Paul Ehrlich Institut completely dodged the issue by failing to respond to enquiries from three different media outlets, Sueddeutsche Zeitung reported.
BfArM. Following strong media coverage of the report in Germany, BfArM pushed back on Twitter, arguing that it has already publicly called on sponsors to publish their trial results, that it has currently has no legal powers to enforce the rules, and that it has opened a dialogue with trial sponsors on the issue.
TranspariMED subsequently contacted the BfArM press office for clarification. BfArM shared a piece of information that, to the best of TranspariMED's knowledge, has never before been made public:
"[L]ast year the BfArM reminded more than 1100 sponsors by letter of their obligation to publish the results in the European database EudraCT (i.e. not solely via a call on the Internet)".
The regulator did not share further details on its 2020 outreach to trial sponsors. However, BfArM did share its detailed responses to an earlier enquiry by German media, which provides more details on the legal and regulatory context in Germany:
FRANCE: One year of prison for not reporting trial results?
According to Research Professional:
"A spokesperson for the French national regulator ANSM said that it informs sponsors of their obligations on its website, and that in 2019 it provided a targeted reminder for sponsors. They said a forthcoming law will introduce a €15,000 fine and potential imprisonment for up to a year for non-compliance with EU trials reporting requirements."
BELGIUM: Lack of trial data "very serious"
The Belgian medicines regulator also performs weakly, with three quarters of older trials still missing results, and widespread data quality problems related to Belgian trials.
Concerns about evidence gaps. Professor of pharmacology Thierry Christiaens from the University of Gent told newspaper De Morgen that “The clinical studies are our basis, the raw material with which we do medicine. That publication bias and the lack of data is very serious.”
NETHERLANDS: Regulator CCMO unsuccessful
According to Research Professional:
Joop van Gerven, chairman of the Netherlands’ Central Committee on Research Involving Human Subjects, said that the committee considers the publication of trial results “of vital importance”.
He said the committee has “asked, on several occasions” for sponsors to meet their obligations, including through a joint appeal with the European Medicines Agency in 2019, but that “regretfully, this has not led to an increase in the publication of trial results in the public trial registers”.
At present the Netherlands has no legal way of enforcing the requirement such as through fines, but this will change with the entry into force of a new European Clinical Trial Regulation expected in early 2022, he said.
ITALY: Regulator must take action
The report showed that the Italian regulator AIFA has one of the weakest performances in Europe. Over 1,000 trials authorised by AIFA up to 2015 are still missing results today.
An AIFA spokesperson told Research Professional that its clinical trials office was undertaking “continuous” activity to catch up with reporting requirements “in order to recover [from an] accumulated delay due to technical problems”.
Calls for regulatory action. Marco Bregni, who directs the centre for clinical trials at the San Raffaele hospital in Milan – one of the largest trial sponsors in the country – told newspaper La Verita that “we have never received, neither on a formal level nor a informal level, any solicitation to publish the results” from the Italian regulator AIFA. Rita Banzi from Instituto Mario Negri added that "as a regulatory agency, AIFA could at least recall the attention of defaulting promoters” to the gaps in their trial reporting.
Results hidden deliberately? Maria Grazia Celani from Cochrane Italy told the newspaper that when she was involved in a trial sponsored by an American pharma company, “at the moment that they realized that the results were not what they hoped for, the company preferred to make the collected evidence disappear.” She too called on national regulators to urge trial sponsors “to respect the rules on transparency”.
Spotlight on mixed sponsor performance. Ospedale San Raffaele is currently uploading its missing trial results at a rapid pace, and Mario Negri already has a strong reporting performance. However, as the newspaper points out, other Italian trial sponsors have a terrible track record. Agostino Gemelli Polyclinic alone has run 157 clinical trials, but has not made a single result fully public. Similarly, Italian pharma company Lofarma has not yet made fully public any results of its trials.
EUROPEAN UNION: Joint actions to improve trial reporting
In a response to media enquiries (file linked above), BfArM provided details about ongoing discussions at the European level:
"All members of the [Heads of Medicines Agencies] Management Group agree that the obligation of sponsors to to make study results public on the EudraCT database is highly important. The network of European Heads of Medicines Agencies will turn to the European Commission and the European Medicines Agency to initiate joint actions to improve sponsors' compliance with results reporting requirements."
(Professor Karl Broich, who heads German regulator BfArM, also chairs the European Heads of Medicines Agencies group.)
BfArM's response further argued that medicines agencies themselves are currently unable to put into place legal sanction mechanisms, and suggested that additional national legislation within individual European Union member states would be required to impose sanctions.
According to Article 94 of the the EU Clinical Trial Regulation, which fully comes into force in all member states on 31 January 2022,
"Member States shall lay down rules on penalties applicable to infringements of this Regulation and shall take all measures necessary to ensure that they are implemented. The penalties provided for shall be effective, proportionate and dissuasive."
Media coverage to date
Tausende Studien nicht veröffentlicht
Tagesschau, 04 July 2021
Ergebnisse Tausender Studien nicht veröffentlicht
Sueddeutsche Zeitung, 04 July 2021
French language summary of German media coverage here:
Slechts een op de vier medicijnstudies openbaar in België
De Morgen, 05 July 2021
Clinical trials: regulators’ inaction has left EU registry “riddled with inaccurate and missing data”
BMJ, 05 July 2021
Regulators in many European countries fail to ensure clinical trial data are available
STAT News, 04 July 2021
Widespread failings in clinical trial reporting in Europe 'slowing medical progress'
APM Health Europe, 05 July 2021
Clinical trial (non) transparency
Politico, 05 July 2021
Poca trasparenza nella nostra agenzia che si occupa delle medicine
La Verita, 05 July 2021
European medicines regulators accused of failing patients on data
Research Professional, 07 July 2021
Note: Reporting by APM, La Verita and Politico’ is not available online.