Why did clinical trial registries fail to prevent Covid research chaos?

“There is a long-standing global ethical obligation to register all trials before they start, shored up by regulatory requirements in some jurisdictions. Data from 18 registries worldwide feed into the WHO-managed International Clinical Trials Registry Platform (ICTRP), providing a continuously updated overview of who is researching what, when, where and how – at least in theory.

 

 

If the registry infrastructure had worked and been used as intended, much of the COVID-19 research chaos would have been avoided.

 

 

For example, researchers considering launching a hydroxychloroquine trial could have searched ICTRP and discovered that the drug was already being investigated by numerous other trials. Those researchers could accordingly have focused on investigating other treatment options instead, or aligned their outcome measures with existing trials. …

The global registry infrastructure has long been inadequately supported by legislators and regulators, and is woefully underfunded.

 

 

 

This persistent neglect of the world’s only comprehensive directory of medical research led to costly research waste on an incredible scale during the pandemic.

 

 

The WHO recommends that member states should by law require every interventional trial to be registered and reported. In addition, WHO recommends that all trial results should be made public specifically on a registry within 12 months, and that registry data should be kept up to date.

 

 

 

By enforcing these three simple rules, regulators would ensure that there is a comprehensive, up-to-date global database of all trials and their results.

 

In reality, existing laws in the EU and the US only cover a small minority of trials and are not being effectively enforced, while many other jurisdictions have no relevant laws at all. …”

 

 

Why preprints are good for patients | Nature Medicine

“Rapid communication of clinical trial results has likely saved lives during the COVID-19 pandemic and should become the new norm….

But during health emergencies, there are many tensions, one of which is the mismatch between the urgent need for information and evidence and the much longer time frames of scientific peer review and publication. The COVID-19 pandemic is the first global health emergency of the new information age, with data and results widely shared via social media. This has resulted in very real difficulties in distinguishing important information from noise, and real news from fake news. How should the research and medical community best manage this new reality?…

Some may argue that the speed advantage of preprints does not outweigh the risks of poor-quality, misleading or even fraudulent research being published and acted upon. I would counter that clinicians should not rely solely on peer review to assess the validity and meaningfulness of research findings. This is because dubious, perhaps fraudulent data can still get through peer review, as was seen with early COVID papers published and then retracted from two of the most prestigious medical journals. In addition, even valid data can be misleading. There has been an avalanche of observational data that passed peer review and was then used to justify treatments, most notably with hydroxychloroquine, but the susceptibility of observational methodology to moderate biases means that such data should not be the basis of patient care.

I take two lessons from our experience running the largest COVID-19 clinical trial over the last two years. The first is that that the preprint system has come of age, demonstrating huge value in rapidly communicating important research findings. Almost daily I am alerted through social media alerts from trusted sources and colleagues of important new findings published as preprints. A degree of immediate peer review is also available by means of the preprint comments section and from colleagues via social media. The full peer-reviewed manuscripts usually appear many weeks or even months later. I cannot envisage a future without such rapid dissemination of new evidence.

 

Given this new reality, the second lesson is that we must ensure that the medical community and policy makers are sufficiently skilled in critical thinking and scientific methods that they can make sensible decisions, regardless of whether an article is peer reviewed or not.”

‘The EMA is withholding too much information”, 1 May 2022

“Transparency is a requirement for better and safer patient care. There is no valid reason to hide information about clinical trials, their methodology or their results, or evaluation data obtained on drugs after their market introduction, particularly data on adverse effects.

The creation of the European Medicines Agency (EMA) in 1995 constituted a step forward, compared with the practices of France’s drug regulatory agency at the time. For example, the EMA’s online publication of information on drug evaluations, such as European Public Assessment Reports, was a major advance in transparency as to the data in its possession….

It is one thing for pharmaceutical companies to consider that data showing the limitations of their drugs are commercially sensitive. But it is quite another – and utterly unacceptable – for the EMA to actually orchestrate the concealment of these data by pharmaceutical companies.

Transparency is not a fad or an end in itself. In the pharmaceutical field, it is a requirement for better and safer patient care. There is no valid reason to hide information about clinical trials, their methodology or their results, or evaluation data obtained on drugs after their market introduction, particularly data on adverse effects.

 

Perhaps there are certain individuals within the EMA who are dissatisfied with this situation? Or who are simply resigned to the power relations at play? Or who feel that the way the EMA operates is a necessary compromise, given the varying legislation? If so, these individuals are not speaking up and their opinions are not reflected in the EMA’s practices. Whatever the case may be, Prescrire’s negative assessment of the level of transparency at the EMA is intended as a wake-up call for policy makers and for legal bodies (such as the Ombudsman) who are in a position to improve the EMA’s operational practices….”

 

Discrepancies between FDA documents and ClinicalTrials.gov for Orphan Drug-related clinical trial data

Abstract:  Clinical trial registries such as ClinicalTrials.gov (CTG) hold large amounts of data regarding trials. Drugs for rare diseases are known as orphan drugs (ODs), and it is particularly important that trials for ODs are registered, and the data in the trial record are accurate. However, there may be discrepancies between trial-related data that were the basis for the approval of a drug, as available from Food and Drug Administration (FDA) documents such as the Medical Review, and the data in CTG. We performed an audit of FDA-approved ODs, comparing trial-related data on phase, enrollment, and enrollment attribute (anticipated or actual) in such FDA documents and in CTG. The Medical Reviews of 63 ODs listed 422 trials. We used study identifiers in the Medical Reviews to find matches with the trial ID number, ‘Other ID’ or ‘Acronyms’ in CTG, and identified 202 trials that were registered with CTG. In comparing the phase data from the ‘Table of Clinical Studies’ of the Medical Review, with the data in CTG, there were exact matches in only 75% of the cases. The enrollment matched only in 70% of the cases, and the enrollment attribute in 91% of the cases. A similar trend was found for the sub-set of pivotal trials. Going forward, for all trials listed in a registry, it is important to provide the trial ID in the Medical Review. This will ensure that all trials that are the basis of a drug approval can be swiftly and unambiguously identified in CTG. Also, there continue to be discrepancies in trial data between FDA documents and CTG. Data in the trial records in CTG need to be updated when relevant.

 

 

No records found for 220 clinical trials of orphan drugs approved by the FDA

“A new study has found widespread gaps and inconsistencies in clinical trials of orphan drugs, suggesting suboptimal data management by the FDA and failures by some pharma companies to consistently register clinical trials and keep public registry records up to date.

 

 

The study team compared publicly available FDA documents and ClinicalTrials.gov registry data for 63 orphan drugs approved between 2009-2019.

 

 

FDA documents identified 422 clinical trials linked to these drug approvals, but the team was only able to find 202 related trials in the ClinicalTrials.gov registry. 220 trials could not be located on the registry.\

 

 

For those trials with data available in both types of sources, the number of trial participants recruited did not match in over 30% of cases….”
 

Publication of clinical trials on medicinal products: follow-up on trials authorized in Hungary | Trials | Full Text

Abstract:  Background

Clinical research should provide reliable evidence to clinicians, health policy makers, and researchers. The reliability of evidence will be assured once study planning, conducting, and reporting of results are transparent. The present research investigates publication rates, time until publication, and characteristics of clinical trials on medicinal products associated with timely publication of results, measures of scientific impact, authorship, and open access publication.

Methods

Clinical trials authorized in Hungary in 2012 were followed until publication and/or June 2020. Corresponding scientific publications were searched via clinical trial registries, PubMed (MEDLINE), and Google.

Results

Overall, 330 clinical trials were authorized in 2012 of which 232 trials were completed for more than 1?year in June 2020. The proportion of industry initiation was high (97%).

Time to publication was 21 (22) months [median (IQR)]. Time to publication was significantly shorter when trials involved both European and non-European countries (26 vs 69?months [median]; hazard ratio = 0.38, 95% CI 0.22–0.66, p<?0.001), and were registered in both EU CTR and clinicaltrials.gov (27 vs 88?months; hazard ratio = 0.24, 95% CI 0.11–0.54; p<?0.001) based on survival analyses.

A significant amount (24.1%) of unpublished clinical trial results were accessible in a trial register. The majority of available publications were published “open access” (70.93%). A minority of identified publications had a Hungarian author (21.5%).

Conclusions

We encourage academic researchers to plan, register and conduct trials on medicinal products. Registries should be considered as an important source of information of clinical trial results. Publications with domestic co-authors contribute to the research output of a country. Measurable domestic scientific impact of trials on medicinal products needs further improvement.

WHA 75: UK draft resolution on Strengthening Clinical Trials to Improve Public Health – Knowledge Ecology International

“On 30 March 2022, Knowledge Ecology International (KEI) published the text of the draft resolution on social media. The text of the UK draft resolution on Strengthening Clinical Trials to Improve Public Health can be found here: Strengthening Clinical Trials to Improve Public Health – zero draft …”

European parliamentarians urge action on missing clinical trial results

“A cross-party group of members of the European parliament has sent an open letter to regulators urging them to not drop the ball on over 3,400 clinical trial results that are still missing on the EudraCT trial registry, in violation of long-standing transparency rules.

 

 

Under European rules, institutions running investigative drug trials must make their results public within 12 months of trial completion. While the rules are set at the European level, responsibility for encouraging and enforcing compliance lies with the national medicines regulators in each country….”

Substantial delays in clinical data published by the European Medicines Agency – a cross sectional study – Journal of Clinical Epidemiology

Abstract:  

Background

Reporting bias poses a fundamental threat to the transparency and validity of interpretations of clinical trials, which may, in part, be mitigated through access Clinical Study Reports (CSRs). The European Medicines Agency (EMA), under their Policy 0070, prospectively publishes clinical data, including CSRs, submitted as part of marketing authorization applications or post-authorization procedures, although this practice is currently suspended for non-COVID-19 medicines, and have set out planned timelines for publication.

 

Methods

We conducted a cross-sectional study assessing the content and characteristics of all clinical data packages released by the EMA under Policy 0070 and the time to their publication. We extracted the number and characteristics of trials included in the clinical packages, assessed the delay to publication relative to the EMAs planned timeline and whether it differed between the EMAs various transparency measures and types of application procedures.

 

Results

We identified 148 clinical data packages that contained data on a total of 1,005 clinical trials, of which 261 (26%) were labelled as phase 3 trials. Full CSRs were available for 913 (90•8%) of the trials. The median time to publication was 511 (IQR 411 to 574) days. Only 2 (1•4%) of the clinical data packages were published within the EMA’s planned timeline. The delay was shorter for clinical data packages released under the EMAs transparency measures for COVID.19 medicines compared with their standard transparency measure.

 

Conclusion

The clinical data packages released by the EMA under Policy 0070 contained CSRs on many trials but were published with considerable delays relative to the timeline set forth by the EMA, reducing their potential impact on reporting bias.

Where are the Clinical Study Reports we were promised?

“Years ago, the European Medicines Agency announced that it would proactively make CSRs accessible to independent researchers. It was the first regulator worldwide to do so. Medical researchers strongly applauded the move. (Health Canada has since launched a similar transparency effort.)

 

 

However, new research shows that the European Medicines Agency’s efforts have lagged far behind its own disclosure targets. …”

benefits of data sharing and ensuring open sources of systematic review data | Journal of Public Health | Oxford Academic

Abstract:  Aims

The benefits of increasing public access to data from clinical trials are widely accepted. Such benefits extend to the sharing of data from high-quality systematic reviews, given the time and cost involved with undertaking reviews. We describe the application of open sources of review data, outline potential challenges and highlight efforts made to address these challenges, with the intent of encouraging publishers, funders and authors to consider sharing review data more broadly.

Results

We describe the application of systematic review data in: (i) advancing understanding of clinical trials and systematic review methods, (ii) repurposing of data to answer public health policy and practice relevant questions, (iii) identification of research gaps and (iv) accelerating the conduct of rapid reviews to inform decision making. While access, logistical, motivational and legal challenges exist, there has been progress made by systematic review, academic and funding agencies to incentivise data sharing and create infrastructure to support greater access to systematic review data.

Conclusion

There is opportunity to maximize the benefits of research investment in undertaking systematic reviews by ensuring open sources of systematic review data. Efforts to create such systems should draw on learnings and principles outlined for sharing clinical trial data.

The Pandemic Response Box?Accelerating Drug Discovery Efforts after Disease Outbreaks | ACS Infectious Diseases

Abstract:  The current Covid-19 pandemic has underlined the need for a more coordinated and forward-looking investment in the search for new medicines targeting emerging health care threats. Repositioning currently approved drugs is a popular approach to any new emerging disease, but it represents a first wave of response. Behind this would be a second wave of more specifically designed therapies based on activities against specific molecular targets or in phenotypic assays. Following the successful deployment and uptake of previous open access compound collections, we assembled the Pandemic Response Box, a collection of 400 compounds to facilitate drug discovery in emerging infectious disease. These are based on public domain information on chemotypes currently in discovery and early development which have been shown to have useful activities and were prioritized by medicinal chemistry experts. They are freely available to the community as a pharmacological test set with the understanding that data will be shared rapidly in the public domain.

The doors of precision: Reenergizing psychiatric drug development with psychedelics and open access computational tools

“In a truly remarkable way, the study was performed at essentially no additional cost. Ballentine et al. (3) made use of existent, openly available resources: the Erowid psychedelic “experience vault,” the pharmacokinetic profiles of each psychedelic, the Allen Human Brain gene transcription profiles, and the Schafer-Yeo brain atlas that mapped gene transcript to brain structure. The computational tools—primarily python toolboxes—that Ballentine et al. deployed were also available at no cost. So in the same way that the psychedelics industry is repurposing old drugs, Ballentine et al. repurposed old data and tools to define a new framework….”