Category Archives: oa.pharma

[Open letter to US FDA and NIH]

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“I write regarding concerns about the lack of compliance by medical product sponsors with requirements to report certain clinical trial results information to the ClinicalTrials.gov database. The law requires that certain clinical trial sponsors report results to ClinicalTrials.gov to expand the knowledge base, support additional research, and provide important safety and efficacy information to health care providers and researchers. These important goals depend on adequate compliance with applicable requirements and appropriate enforcement.”

US congress committee calls for tougher action on trial sponsors who fail to meet reporting deadlines | The BMJ

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“A US congress committee has criticised the Food and Drug Administration (FDA) and National Institutes of Health (NIH) for taking “only modest compliance action” against clinical trial sponsors who have not published results.1

Under US law, clinical trial sponsors are required to submit their results within one year of the completion date. Research looking at compliance in recent years found, however, that over 5000 trials were in “violation of applicable reporting requirements,”2 while over half (37 of 72) of reviewed trials that were funded by the NIH had failed to comply with applicable reporting requirements.3

The US Congressional Committee on Energy and Commerce has written to ask why the FDA and NIH have failed to sanction trial sponsors who break reporting rules….”

Patients at the Heart of the Scientific Dialogue: An Industry Perspective | SpringerLink

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“Pharmaceutical companies need to regularly communicate to patients all essential information about their medicines, especially data from the research studies that were conducted to evaluate the medicine’s benefits and risks. To do that, companies will need to make sure patients have access to and awareness of relevant information. This can be achieved by ensuring medical information is freely available to the reader, and working with publishers to facilitate open access (free) publications. Companies should also help improve patients’ understanding of medical terminology, offer simplified versions of scientific content, and deliver information through various formats (print versus digital, text versus audio versus video) to address different learning styles and literacy levels. This will empower patients with knowledge and improve shared decision-making. It will also be essential for pharmaceutical companies to involve patients in various stages of medicine development, such as getting their input on how the research studies for investigating these medicines are designed and reported to ensure relevant information to patients are well-captured and clear. This should also go in parallel with providing opportunities to elevate the patient voice through patient-partnered research and authorship on topics particularly relevant to them.”

 

Open and reusable annotated mass spectrometry dataset of a chemodiverse collection of 1,600 plant extracts | GigaScience | Oxford Academic

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Abstract:  As privileged structures, natural products often display potent biological activities. However, the discovery of novel bioactive scaffolds is often hampered by the chemical complexity of the biological matrices they are found in. Large natural extract collections are thus extremely valuable for their chemical novelty potential but also complicated to exploit in the frame of drug-discovery projects. In the end, it is the pure chemical substances that are desired for structural determination purposes and bioactivity evaluation. Researchers interested in the exploration of large and chemodiverse extract collections should thus establish strategies aiming to efficiently tackle such chemical complexity and access these structures. Establishing carefully crafted digital layers documenting the spectral and chemical complexity as well as bioactivity results of natural extracts collections can help prioritize time-consuming but mandatory isolation efforts. In this note, we report the results of our initial exploration of a collection of 1,600 plant extracts in the frame of a drug-discovery effort. After describing the taxonomic coverage of this collection, we present the results of its liquid chromatography high-resolution mass spectrometric profiling and the exploitation of these profiles using computational solutions. The resulting annotated mass spectral dataset and associated chemical and taxonomic metadata are made available to the community, and data reuse cases are proposed. We are currently continuing our exploration of this plant extract collection for drug-discovery purposes (notably looking for novel antitrypanosomatids, anti-infective and prometabolic compounds) and ecometabolomics insights. We believe that such a dataset can be exploited and reused by researchers interested in computational natural products exploration.

 

Mehr Transparenz in der klinischen Forschung: Wie werden die neuen Transparenzvorschriften aus Sicht der pharmazeutischen Industrie bewertet? | SpringerLink

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[English-language abstract, article in German.]

Abstract:  The year 2014 was a turning point for transparency in clinical research. Two regulatory innovations comprehensively changed the rules in the EU. For one thing, Regulation (EU) No. 536/2014 on clinical trials of medicinal products for human use (Clinical Trials Regulation – CTR) came into force, and for another thing, Policy 0070 of the European Medicines Agency (EMA) on the publication of and access to clinical data was published. While the policy has been occupying the pharmaceutical industry in practice since 2015, the requirements of the CTR came into effect at the end of January 2022.

The main innovation of the CTR is public access to the majority of documents and records that are created during the application process as well as during the course and after completion of a clinical trial. The special feature of Policy 0070 is the possibility for EU citizens to inspect the essential parts of a marketing authorisation application, such as the Clinical Study Report.

This contribution to the discussion describes the completely new challenges in the area of transparency that the pharmaceutical industry is facing as a result of the new requirements. In principle, transparency is to be welcomed in order to achieve the goals of the EU in the development and availability of medicines and vaccines. However, the protection of trade and business secrets of the pharmaceutical industry would be jeopardised. In the worst case, this could lead to a decline in investment in research and development within the scope of this regulation and to an international shift of clinical trials, including developing or emerging countries. Germany could lose more and more its leading role in conducting clinical trials in the EU.

Antibiotic discovery in the artificial intelligence era – Lluka – Annals of the New York Academy of Sciences – Wiley Online Library

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Abstract:  As the global burden of antibiotic resistance continues to grow, creative approaches to antibiotic discovery are needed to accelerate the development of novel medicines. A rapidly progressing computational revolution—artificial intelligence—offers an optimistic path forward due to its ability to alleviate bottlenecks in the antibiotic discovery pipeline. In this review, we discuss how advancements in artificial intelligence are reinvigorating the adoption of past antibiotic discovery models—namely natural product exploration and small molecule screening. We then explore the application of contemporary machine learning approaches to emerging areas of antibiotic discovery, including antibacterial systems biology, drug combination development, antimicrobial peptide discovery, and mechanism of action prediction. Lastly, we propose a call to action for open access of high-quality screening datasets and interdisciplinary collaboration to accelerate the rate at which machine learning models can be trained and new antibiotic drugs can be developed.

 

Clinical Trial Data-sharing Policies Among Journals, Funding Agencies, Foundations, and Other Professional Organizations: A Scoping Review – Journal of Clinical Epidemiology

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Abstract:  Objectives

To identify the similarities and differences in data-sharing policies for clinical trial data that are endorsed by biomedical journals, funding agencies, and other professional organizations. Additionally, to determine the beliefs, and opinions regarding data-sharing policies for clinical trials discussed in articles published in biomedical journals.

 

Study Design

Two searches were conducted, a bibliographic search for published articles that present beliefs, opinions, similarities, and differences regarding policies governing the sharing of clinical trial data. The second search analyzed the gray literature (non-peer-reviewed publications) to identify important data-sharing policies in selected biomedical journals, foundations, funding agencies, and other professional organizations.

 

Results

A total of 471 articles were included after database search and screening, with 45 from the bibliographic search and 426 from the gray literature search. A total of 424 data-sharing policies were included. Fourteen of the 45 published articles from the bibliographic search (31.1%) discussed only advantages specific to data-sharing policies, 27 (27/45; 60%) discussed both advantages and disadvantages, and 4 (4/45; 8.9%) discussed only disadvantages specific. A total of 216 journals (of 270; 80%) specified a data-sharing policy provided by the journal itself. One hundred industry data-sharing policies were included, and 32 (32%) referenced a data-sharing policy on their website. One hundred and thirty-six (42%) organizations (of 327) specified a data-sharing policy.

 

Conclusion

We found many similarities listed as advantages to data-sharing and fewer disadvantages were discussed within the literature. Additionally, we found a wide variety of commonalities and differences — such as the lack of standardization between policies, and inadequately addressed details regarding the accessibility of research data — that exist in data-sharing policies endorsed by biomedical journals, funding agencies, and other professional organizations. Our study may not include information on all data sharing policies and our data is limited to the entities’ descriptions of each policy.

Left in the dark: the importance of publicly available clinical trial protocols – Braat – 2022 – Medical Journal of Australia – Wiley Online Library

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“Prospective registration of a randomised controlled trial (RCT) based on a protocol with formal ethics approval is a benchmark for transparent medical research. The reporting of the primary results of the study should correspond to the design, analysis, and reporting specified in the protocol and trial registration. However, modifications to various aspects of the trial are often made after registration, ranging from administrative updates to substantial protocol amendments. To track the history of revisions, the protocol and registry entry should be updated, and the documentation trail should support an independent appraisal of whether any biases have been introduced that could affect interpretation of trial results.

In this issue of the MJA, Coskinas and colleagues report their investigation of changes to 181 phase 3 RCTs registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) during 1 September 2007 – 31 December 2013.1 The authors compared protocol documents (including ANZCTR registration information) with subsequent journal publications for any changes to the primary outcome, treatment comparisons, analysis set definition, eligibility criteria, sample size, or primary analysis method. They found that protocols were available for only 124 trials (69%); it could be determined that no major changes had been made to eleven of these trials (9%), while 78 had definitely been modified (63%). By comparing publications with trial registration information, it was found that no changes were made to five of the 57 trials without available protocols (9%), and it could not be determined whether changes had been made to a further ten (18%)….”

EZCancerTarget: an open-access drug repurposing and data-collection tool to enhance target validation and optimize international research efforts against highly progressive cancers | BioData Mining | Full Text

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Abstract:  The expanding body of potential therapeutic targets requires easily accessible, structured, and transparent real-time interpretation of molecular data. Open-access genomic, proteomic and drug-repurposing databases transformed the landscape of cancer research, but most of them are difficult and time-consuming for casual users. Furthermore, to conduct systematic searches and data retrieval on multiple targets, researchers need the help of an expert bioinformatician, who is not always readily available for smaller research teams. We invite research teams to join and aim to enhance the cooperative work of more experienced groups to harmonize international efforts to overcome devastating malignancies. Here, we integrate available fundamental data and present a novel, open access, data-aggregating, drug repurposing platform, deriving our searches from the entries of Clue.io. We show how we integrated our previous expertise in small-cell lung cancer (SCLC) to initiate a new platform to overcome highly progressive cancers such as triple-negative breast and pancreatic cancer with data-aggregating approaches. Through the front end, the current content of the platform can be further expanded or replaced and users can create their drug-target list to select the clinically most relevant targets for further functional validation assays or drug trials. EZCancerTarget integrates searches from publicly available databases, such as PubChem, DrugBank, PubMed, and EMA, citing up-to-date and relevant literature of every target. Moreover, information on compounds is complemented with biological background information on eligible targets using entities like UniProt, String, and GeneCards, presenting relevant pathways, molecular- and biological function and subcellular localizations of these molecules. Cancer drug discovery requires a convergence of complex, often disparate fields. We present a simple, transparent, and user-friendly drug repurposing software to facilitate the efforts of research groups in the field of cancer research.

 

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

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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

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“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

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“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

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“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

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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

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“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. …”