Leading universities in Sweden and Finland pledge to tackle unreported clinical trials

Four of the five largest clinical trial sponsors in Sweden and Finland have pledged to make public the results of their investigative drug trials, dramatically accelerating the shift towards more transparency in the region.

Between them, Karolinska Institutet and Uppsala University & Hospital (Sweden) and Helsinki University and the University of Turku (Finland) are responsible for nearly 450 drug trials. They are now reviewing their portfolios and preparing to make public the results of their drug trials as required by European Union transparency rules.

UPDATE 09 November 2020: University of Gothenburg today also provided a statement, see below. This means that all five top clinical trial sponsors have now committed to improving their performance.

Karolinska Institutet’s Vice President, Professor Anders Gustafsson, said:

"Timely and accurate reporting of clinical trial results is a scientific and ethical imperative. Karolinska Institutet (KI) highly values these essential initiatives and is fully dedicated to the timely disclosure of clinical trial results. Through our commitment to enhance accessibility and transparency of clinical trial data, KI has developed an infrastructure to centralize and manage clinical trial registration and results reporting. KI is working proactively to ensure clinical trial registrations are up-to-date and accurate, and that results are posted for completed trials."

HIGH RISK OF RESEARCH WASTE

An analysis by TranspariMED shows that the results of hundreds of drug trials run by major universities, public bodies and pharmaceutical companies in the two countries are currently missing results on the European registry.

The twenty largest trial sponsors in Sweden and Finland have verifiably failed to upload the results of 112 drug trials onto the European registry. The true number of missing trial results is around 400. If these sponsors fail to take action, some results are likely to be lost forever, while others will only be made public in part or after considerable delays, slowing down the pace of medical progress and undermining public health.

A spokesperson for Swedish patient group Melanomföreningen (Melanoma Association) commented that:

"We are greatly concerned about the fact that the outcomes of a large proportion of clinical trials are not reported to the European Union Clinical Trials Register, and thus not made available to the public. This may cause an important bias in the reporting of drug trials and it is not ethical towards the patients who have agreed to participate in trials, if the outcomes are not publicly reported."

UNIVERSITIES CURRENTLY PERFORM WEAKLY

Major universities, hospitals, and public bodies in both countries currently all perform weakly. The data they provide on the registry is of such low quality that it is impossible to determine exactly how many of their trials have been completed and are due to report results.

Karolinska Institute in the past has failed to make an estimated 107 trial results public; 24 of those trials are verifiably in violation of European transparency rules. Helsinki University owes the public and its patients an estimated 54 trial results. Both universities are now working to fix the problem (details below).

Only two trial sponsors, the Finnish Orion Corporation (95% of due trial results made public) and the Swedish Orphan Biovitrum AB (78%), currently perform well. Both are for-profit pharmaceutical companies, the only ones in the study cohort.

WHAT ARE THE SWEDISH AND FINNISH REGULATORS DOING?

The national medicines regulators in Sweden and Finland have clearly failed to ensure that data on clinical trials run in their countries is accurate and up to date.

In addition, it appears that regulators Läkemedelsverkets (Sweden) and FIMEA (Finland) are not actively contacting trial sponsors to remind them of their obligation to upload missing results.

It is unclear whether and how these two regulators intend to impose fines once the EU Clinical Trial Regulation fully comes into force in late 2021. At that point, regulators will have a clear legal basis for imposing fines and other sanctions on companies and institutions that fail to make results public.

Regulators in other countries are far more proactive. For example, Denmark’s DKMA has improved trial reporting in the country by providing support to universities and making clear to trial sponsors that if they do not make their results public, they will face sanctions.

Data compiled by the European Medicines Agency using a different methodology show that 60 trials involving Swedish children and 24 trials involving Finnish children are currently missing results. In the past, hidden clinical trial results have led to thousands of patient deaths.

Till Bruckner, founder of TranspariMED, said:

“Clinical trials whose results remain invisible are a waste of money, a betrayal of the trust of the volunteers who participated in these trials, and a threat to public health. The pledges by leading universities to embrace transparency are good news for taxpayers and patients. FIMEA and Läkemedelsverkets should urgently reach out to trial sponsors and assist them in making their clinical trial results public as rapidly as possible, before results are lost forever and become research waste. At the same time, FIMEA and Läkemedelsverkets should publish detailed plans for imposing sanctions from 2021 onwards.”

Bettina Ryll of the Horizon Europe Cancer Mission Board and the Melanoma Patient Network Europe said:

“Withholding trial results – and we should never forget that these are experiments conducted on humans – prevents society from benefiting from the results from the research it enabled and financed. Especially now in times of increasing financial constraints, we should aim to avoid any unnecessary duplication of research efforts and ensure that learnings from clinical trials are used to improve outcomes for patients – none of which is possible if these results never see the light of day.”

WHAT ARE SCANDINAVIAN UNIVERSITIES DOING?

Four of the largest universities the region are now beginning to tackle the problem.

Karolinska Institutet’s efforts appear to be both the most ambitious and the furthest advanced.

The institution has already set up a team tasked with uploading missing trial results on three separate clinical trial registries, exceeding minimum regulatory transparency requirements. According to a Karolinska spokesperson:

“The University Director of Karolinska Institutet (KI) has issued a new initiative to centralize clinical trial registration and results reporting. This important task has been assigned to the Research Data Office (RDO) within the Grants Office (GO) at KI. RDO has developed strategies to centralize and manage clinical trials registered primarily in EudraCT, ISRCTN and ClinicalTrials.gov registries. Since this new initiative took effect three months ago, KI has produced positive results in several key areas. To date, out of a total of 851 trial registrations, we have identified 369 trial registrations that required immediate attention. Among those, 175 trial registrations have been updated in ClinicalTrials.gov. We will begin to implement similar strategies to update and report results for [the European] EudraCT [registry] shortly.”

Helsinki University has also already started addressing the issue. In a statement, the university explained that:

“Essentially all the clinical trials in Helsinki are run together with joint personnel from the University of Helsinki and the Helsinki University Hospital. After this issue of not reporting of the completion of the clinical trials was brought up, the Research Director, Professor Anne Pitkäranta and the Dean of the Medical Faculty, Professor Risto Renkonen set up together a process to guide and help the researchers to take care of this duty. In addition to that, a lot of information was given to the researchers to help them to correct the issue.

However, unfortunately we do not yet have an alert system, which would notify the leadership of this issue. We will go through the very large set of clinical trials to sort out the failures within the reporting of the completed trials.

We do see that during the next year 2021 we should be able to overcome this failure of reporting.”

University of Turku issued the following statement in July:

“In conducting clinical trials University of Turku collaborates with Turku University Hospital Clinical Research Centre, CRC. Our university researchers cannot conduct research which involves patients without partnering with the University Hospital to get access to hospital pharmacy and hospital patient insurances. CRC guides the researchers to apply the required permissions and to report the new trials to our national medicine regulator, FIMEA, Finnish Medicines Agency… We are now planning to arrange information session together with CRC for all those researchers working on clinical trials to remind them about the importance of reporting the final data.”

Uppsala University’s Vice-rector Professor Mats Larhed stated that:

“Uppsala University is committed to the promotion of good research practice and ethics, and we constantly strive to be better and to set a good example. We will, therefore, do better concerning the transparency rules governing the EU Clinical Trial Register.

Uppsala University shares a sponsor post with Uppsala Country Council on the EU Clinical Trial Register. We are, however, two separate entities, and Uppsala University can take no responsibility for studies sponsored by the Uppsala County Council. We have forwarded your letter to the appropriate officer, though.

Concerning the studies that Uppsala University has sponsored, we have asked the principal investigators to make sure that the data is uploaded as soon as possible.

Going forward, the Disciplinary domain of Medicine and Pharmacy will ensure that principal investigators are correctly informed about the rules concerning uploading trial data to the EU Clinical Trial Register.”

University of Gothenburg provided the following statement on 09 November 2020:

"University of Gothenburg works continually with quality improvements on all levels to strengthen research quality, and we regularly invite external evaluators to help us improve further. For ethical as well as scientific reasons. Securing that all researchers and external partners involved in clinical studies understand and follow correct procedures is part of that work.

We want to emphasize the importance of clinical trials conducted at, or in collaboration with, University of Gothenburg following applicable laws and regulations, including reporting end of trial to Swedish Medical Products Agency and results in applicable databases, such as EudraCT, ClinicalTrials.gov and ResearchWeb."

STRONG PROGRESS IN DENMARK - BUT NOT IN NORWAY OR ICELAND

Elsewhere in Scandinavia, the picture is mixed. Strong engagement by the Danish regulator has led to a rapid increase in the number of clinical trial results being made public in Denmark, but no positive momentum is yet visible in Norway or Iceland. At present, the University of Oslo’s performance is disappointing, with few signs of progress.

Over the coming months, TranspariMED will continue to track Scandinavian regulators’ and trial sponsors’ progress on this blog.

Scandinavian trial sponsors can access TranspariMED’s collection of transparency tools to learn how to report missing clinical trial results and ensure that in future, all trial outcomes are reported on time as required by EU transparency rules. Sponsors can also use the EU Trials Tracker to examine their trial portfolios.

Note on methodology:

The cohort consists of all trial sponsors located within Finland and Sweden that have sponsored 20 or more drug trials (so-called CTIMPs). Other trials, such as trials of medical devices and non-drug interventions, cannot be registered on the European trial registry and therefore fall outside the scope of this analysis.

The data above was extracted from the EU Trials Tracker created by the EBM Data Lab at the University of Oxford. Readers are encouraged to search the Tracker for their local university, hospital or public body and view the list of all their unreported trials.

In keeping with the standard approach used by the EU Trials Tracker and TranspariMED, only trials clearly identifiable as due and having results were counted as reported.

Hundreds of Swedish and Finnish trials that were completed long ago remain falsely listed as ‘ongoing’ on the EU registry and are therefore not visibly due to report results. The chart above displays the number of verifiably due trials per sponsor. In addition, the chart provides an estimate of the true number of missing clinical trial results. This estimate was calculated by dividing the total number of trials by two, based on the assumption that half of all listed trials ended more than a year ago and are thus due to report results, and then subtracting the number of due trials that already have results. (Exception: The data on Orion Corporation’s and Swedish Orphan Biovitrum’s overdue trials was taken at face value, because both of these companies clearly manage their trial portfolios.)

The Tracker lists Skane University and Skane University Hospital as separate trial sponsors; in the charts above, their trial portfolios are combined. The same applies to Uppsala University and Uppsala University Hospital.

TranspariMED would like to thank Nick Devito from EBM Data Lab, who provided the data that enabled the largest sponsors in each country to be identified. Neither Nick Devito nor the EBM Data Lab were involved in subsequent data analysis or in the writing of this blog. Any mistakes are the sole responsibility of TranspariMED.