Data-sharing and re-analysis for main studies assessed by the European Medicines Agency—a cross-sectional study on European Public Assessment Reports | BMC Medicine | Full Text

Abstract:  Background

Transparency and reproducibility are expected to be normative practices in clinical trials used for decision-making on marketing authorisations for new medicines. This registered report introduces a cross-sectional study aiming to assess inferential reproducibility for main trials assessed by the European Medicines Agency.

Methods

Two researchers independently identified all studies on new medicines, biosimilars and orphan medicines given approval by the European Commission between January 2017 and December 2019, categorised as ‘main studies’ in the European Public Assessment Reports (EPARs). Sixty-two of these studies were randomly sampled. One researcher retrieved the individual patient data (IPD) for these studies and prepared a dossier for each study, containing the IPD, the protocol and information on the conduct of the study. A second researcher who had no access to study reports used the dossier to run an independent re-analysis of each trial. All results of these re-analyses were reported in terms of each study’s conclusions, p-values, effect sizes and changes from the initial protocol. A team of two researchers not involved in the re-analysis compared results of the re-analyses with published results of the trial.

Results

Two hundred ninety-two main studies in 173 EPARs were identified. Among the 62 studies randomly sampled, we received IPD for 10 trials. The median number of days between data request and data receipt was 253 [interquartile range 182–469]. For these ten trials, we identified 23 distinct primary outcomes for which the conclusions were reproduced in all re-analyses. Therefore, 10/62 trials (16% [95% confidence interval 8% to 28%]) were reproduced, as the 52 studies without available data were considered non-reproducible. There was no change from the original study protocol regarding the primary outcome in any of these ten studies. Spin was observed in the report of one study.

Conclusions

Despite their results supporting decisions that affect millions of people’s health across the European Union, most main studies used in EPARs lack transparency and their results are not reproducible for external researchers. Re-analyses of the few trials with available data showed very good inferential reproducibility.

Accelerating pooled licensing of medicines to enhance global production and equitable access – The Lancet

“From October to November, 2021, the pharmaceutical firms Merck and Pfizer licensed their new COVID-19 oral antiviral medications to the Medicines Patent Pool (MPP). In both cases, the drugs were licensed quickly, before they were launched, and the MPP then reached agreements with pharmaceutical firms across the globe (27 firms for Merck’s molnupiravir and 36 firms for Pfizer’s nirmatrelvir) to provide generic versions of these to roughly 100 low-income and middle-income countries. This Viewpoint examines the importance of these licences for the global production of, and access to, new medicines, during the pandemic and beyond. It would be a welcome development for these arrangements, which can generate sufficient volumes of production to avoid the supply shortages that encumbered the global vaccination response, to be an indication of a future in which new drugs have multiple suppliers in most low-income and middle-income countries. To explore that possibility, the Viewpoint highlights the political conditions that could make originator firms more inclined to license their products quickly to the MPP, and discusses how public policy can build on the opportunity created by these conditions to promote such licensing further….”

 

Accelerating pooled licensing of medicines to enhance global production and equitable access – The Lancet

“From October to November, 2021, the pharmaceutical firms Merck and Pfizer licensed their new COVID-19 oral antiviral medications to the Medicines Patent Pool (MPP). In both cases, the drugs were licensed quickly, before they were launched, and the MPP then reached agreements with pharmaceutical firms across the globe (27 firms for Merck’s molnupiravir and 36 firms for Pfizer’s nirmatrelvir) to provide generic versions of these to roughly 100 low-income and middle-income countries. This Viewpoint examines the importance of these licences for the global production of, and access to, new medicines, during the pandemic and beyond. It would be a welcome development for these arrangements, which can generate sufficient volumes of production to avoid the supply shortages that encumbered the global vaccination response, to be an indication of a future in which new drugs have multiple suppliers in most low-income and middle-income countries. To explore that possibility, the Viewpoint highlights the political conditions that could make originator firms more inclined to license their products quickly to the MPP, and discusses how public policy can build on the opportunity created by these conditions to promote such licensing further….”

 

Clinical trial results for $3.2 billion Covid drug are missing in action

“The results of most clinical trials of the Covid drug molnupiravir (Lagrevio) have not been made public and remain completely unknown, a new study has found.

 

 

 

The drug is currently being administered to Covid patients in the United States, the UK, and India. The World Health Organisation has issued a “conditional recommendation” for its use in some patient groups. Global sales so far stand at $3.2 billion….”

Evaluation of publication bias for 12 clinical trials of molnupiravir to treat SARS-CoV-2 infection in 13,694 patients | Research Square

Abstract:  Introduction:

During the COVID-19 pandemic, Merck Sharp and Dohme (MSD) acquired the global licensing rights for molnupiravir. MSD allowed Indian manufacturers to produce the drug under voluntary license. Indian companies conducted local clinical trials to evaluate the efficacy and safety of molnupiravir.

Methods

Searches of the Clinical Trials Registry-India (CTRI) were conducted to find registered trials of molnupiravir in India. Subsequent investigations were performed to assess which clinical trials had been presented or published.

Results

According to the CTRI, 12 randomised trials of molnupiravir were conducted in India, in 13,694 patients, starting in late May 2021. By July 2022, none of the 12 trials has been published, one was presented at a medical conference, and two were announced in press releases suggesting failure of treatment. Results from three trials were shared with the World Health Organisation. One of these three trials had many unexplained results, with effects of treatment significantly different from the MSD MOVE-OUT trial in a similar population.

Discussion

The lack of results runs counter to established practices and leaves a situation where approximately 90% of the global data on molnupiravir has not been published in any form. Access to patient-level databases is required to investigate risks of bias or medical fraud.

EU Clinical Trials Register – Update

“Following the issuing of the Joint Letter by the European Commission, EMA and HMA, National Competent Authorities and European Medicines Agency have sent reminders to sponsors who were not compliant with the European Commission guideline on results posting. Thanks to these reminders, the percentage of posted results substantially increased. However, for some trials the reminders were not successful: detailed lists of these trials can be found here. …”

Clinical Trial Registry Errors Undermine Transparency | The Scientist Magazine®

“Confusion about terminology on the world’s largest clinical trials registry may be delaying the release of drug trial results and undermining rules designed to promote transparency, an investigation by The Scientist has found. 

Key study dates and other information are entered into the ClinicalTrials.gov database by trial researchers or sponsors, and are used by US science and regulatory agencies to determine legal deadlines by which results must be reported. The rules are supposed to ensure timely public access to findings about a potential therapy’s harms and benefits, as well as provide the scientific community with an up-to-date picture of the status of clinical research.

But neither the agencies nor staff overseeing the database routinely monitor individual trial records for veracity, instead relying on the person in charge of a given record to correctly declare information such as when a study ends and how many people were enrolled. …”

Adoption of World Health Organization Best Practices in Clinical Trial Transparency Among European Medical Research Funder Policies | Global Health | JAMA Network Open | JAMA Network

Abstract:  Importance  Research funders can reduce research waste and publication bias by requiring their grantees to register and report clinical trials.

Objective  To determine the extent to which 21 major European research funders’ efforts to reduce research waste and publication bias in clinical trials meet World Health Organization (WHO) best practice benchmarks and to investigate areas for improvement.

Design, Setting, and Participants  This cross-sectional study was based on 2 to 3 independent assessments of each funder’s publicly available documentation and validation of results with funders during 2021. Included funders were the 21 largest nonmultilateral public and philanthropic medical research funders in Europe, with a combined budget of more than US $22 billion.

Exposures  Scoring of funders using an 11-item assessment tool based on WHO best practice benchmarks, grouped into 4 broad categories: trial registries, academic publication, monitoring, and sanctions. Funder references to reporting standards were captured.

Main Outcomes and Measures  The primary outcome was funder adoption or nonadoption of 11 policy and monitoring measures to reduce research waste and publication bias as set out by WHO best practices. The secondary outcomes were whether and how funder policies referred to reporting standards. Outcomes were preregistered after a pilot phase that used the same outcome measures.

Results  Among 21 of the largest nonmultilateral public and philanthropic funders in Europe, some best practices were more widely adopted than others, with 14 funders (66.7%) mandating prospective trial registration and 6 funders (28.6%) requiring that trial results be made public on trial registries within 12 months of trial completion. Less than half of funders actively monitored whether trials were registered (9 funders [42.9%]) or whether results were made public (8 funders [38.1%]). Funders implemented a mean of 4 of 11 best practices in clinical trial transparency (36.4%) set out by WHO. The extent to which funders adopted WHO best practice items varied widely, ranging from 0 practices for the French Centre National de la Recherche Scientifique and the ministries of health of Germany and Italy to 10 practices (90.9%) for the UK National Institute of Health Research. Overall, 9 funders referred to reporting standards in their policies.

Conclusions and Relevance  This study found that many European medical research funder policy and monitoring measures fell short of WHO best practices. These findings suggest that funders worldwide may need to identify and address gaps in policies and processes.

Medical research funders across Europe tighten rules on clinical trial reporting

“Eight of the 21 largest public and philanthropic medical research funders in Europe are stepping up their efforts to improve clinical reporting, following an assessment that found widespread gaps in existing research waste safeguards.

 

 

 

At present, many academic clinical trials in Europe fail to make their results public, wasting taxpayers’ money and leaving large gaps in the medical evidence base.

 

 

 

The public institutions that hand out money to medical researchers can prevent such waste by putting into place eleven safeguards recommended by the World Health Organisation. …”

Early firm engagement, government research funding, and the privatization of public knowledge | SpringerLink

Abstract:  Early firm engagement in the scientific discovery process in public institutions is an important form of science-based innovation. However, early firm engagement may negatively affect the academic value of public papers due to firms’ impulse to privatize public knowledge. In this paper, we crawl all patent and paper text data of the Distinguished Young Scholars of the National Science Foundation of China (NSFC) in the chemical and pharmaceutical field. We use semantic recognition techniques to establish the link between scientific discovery papers and patented technologies to explore the relationship between the quality of public knowledge production, government research funding, and early firm engagement in the science-based innovation process. The empirical results show that, first, there is a relatively smooth inverted U-shaped relationship between government research funding for scholars and the quality of their publications. An initial increase in government research funding positively drives the quality of public knowledge production, but the effect turns negative when research funding is excessive. Second, government research funding for scholars can act as a value signal, triggering the firm’s impulse to privatize high-value scientific discoveries. Hence, early firm engagement moderates the inverted U-shaped relationship such that at low levels of research funding, early firm engagement can improve the quality of public knowledge production, and at high levels of research funding, early firm engagement can further reduce the quality of public knowledge production.

 

Comparative Analyses of Medicinal Chemistry and Cheminformatics Filters with Accessible Implementation in Konstanz Information Miner (KNIME)

Abstract:  High-throughput virtual screening (HTVS) is, in conjunction with rapid advances in computer hardware, becoming a staple in drug design research campaigns and cheminformatics. In this context, virtual compound library design becomes crucial as it generally constitutes the first step where quality filtered databases are essential for the efficient downstream research. Therefore, multiple filters for compound library design were devised and reported in the scientific literature. We collected the most common filters in medicinal chemistry (PAINS, REOS, Aggregators, van de Waterbeemd, Oprea, Fichert, Ghose, Mozzicconacci, Muegge, Egan, Murcko, Veber, Ro3, Ro4, and Ro5) to facilitate their open access use and compared them. Then, we implemented these filters in the open platform Konstanz Information Miner (KNIME) as a freely accessible and simple workflow compatible with small or large compound databases for the benefit of the readers and for the help in the early drug design steps. View Full-Text

 

Identifying novel drugs with new modes of action for neglected tropical fungal skin diseases (fungal skinNTDs) using an Open Source Drug discovery approach: Expert Opinion on Drug Discovery: Vol 0, No ja

Article highlights

 

Antifungal drug discovery for the three fungal skinNTDs chromoblastomycosis, mycetoma and sporotrichosis have been fragmented and there are only a few drugs which were evaluated for causative agents of all three skinNTDs.

Except for the azoles and iodoquinol, there were no antifungal classes active against all the causative agents of all three fungal skinNTDs.

Since all causative agents form melanin and inhibiting melanin enhances the antifungal activity of different antifungal agents, combining melanin inhibition with antifungal therapy should be further explored for fungal skinNTDs.

Of the azoles, ravuconazole and posaconazole showed the strongest activity against the causative agents of all three fungal skinNTDs, clinical evaluation of fosravuconazole for mycetoma treatment is underway, however currently no evaluation for chromoblastomycosis and sporotrichosis are reported.

Studies on combination treatment, treatment intensity and duration of treatment in fungal skinNTDs are lacking and should be performed….”

The LOTUS initiative for open knowledge management in natural products research | eLife

Abstract:  Contemporary bioinformatic and chemoinformatic capabilities hold promise to reshape knowledge management, analysis and interpretation of data in natural products research. Currently, reliance on a disparate set of non-standardized, insular, and specialized databases presents a series of challenges for data access, both within the discipline and for integration and interoperability between related fields. The fundamental elements of exchange are referenced structure-organism pairs that establish relationships between distinct molecular structures and the living organisms from which they were identified. Consolidating and sharing such information via an open platform has strong transformative potential for natural products research and beyond. This is the ultimate goal of the newly established LOTUS initiative, which has now completed the first steps toward the harmonization, curation, validation and open dissemination of 750,000+ referenced structure-organism pairs. LOTUS data is hosted on Wikidata and regularly mirrored on https://lotus.naturalproducts.net. Data sharing within the Wikidata framework broadens data access and interoperability, opening new possibilities for community curation and evolving publication models. Furthermore, embedding LOTUS data into the vast Wikidata knowledge graph will facilitate new biological and chemical insights. The LOTUS initiative represents an important advancement in the design and deployment of a comprehensive and collaborative natural products knowledge base.

 

WHA clinical trial resolution: draft text now public

“The World Health Organization today published the draft text of the clinical trial resolution being debated at the ongoing World Health Assembly.

 

 

The resolution’s overall aim is to improve the coordination, design, conduct and reporting of clinical trials worldwide. It was partly spurred by the realisation that hundreds – maybe thousands – of Covid clinical trials have ended up as costly research waste….

 

Promoting, as appropriate, measures to facilitate the timely reporting of both positive and negative interpretable clinical trial results in alignment with the WHO joint statement on public disclosure of results from clinical trials and the WHO joint statement on transparency and data integrity, including through registering the results on a publicly available clinical trial registry within the [global trial registry network] ICTRP, and encouraging timely publication of the trial results preferably in an open-access publication.

Exploring measures during public health emergencies of international concern to encourage researchers to rapidly and responsibly share interpretable results of clinical trials, including negative results, with national regulatory bodies or other appropriate authorities, including WHO for clinical guideline development and emergency use listing (EUL), to support rapid regulatory decision-making and emergency adaptation of clinical and public health guidelines as appropriate, including through pre-print publication. …”