KEY TAKEAWAYS

• Pharmaceutical companies that sponsor clinical trials are required to balance the need for transparency with protecting confidential information. This is achieved by redacting confidential details from documents before they are made public.
• The redaction process is often hindered by inefficient systems, which can lead to delays. Implementation of a range of practical tips can streamline and simplify the process.

Health authorities, including the European Medicines Agency and Health Canada, require detailed information to be made public as part of clinical trial registration and reporting. This is critical for transparency, but can present practical challenges for pharmaceutical companies as they seek to meet these criteria while protecting intellectual property. Redacting confidential information from documents before public release is an accepted solution, but it can be an onerous and inefficient process. In a recent article for the European Medical Writers Association’s journal, Medical Writing, Elliot Zimmerman outlined the challenges involved, along with a series of practical solutions.

Pitfalls and challenges

As detailed by Zimmerman, the redaction processes followed by pharmaceutical companies can be fraught with inefficiencies, including:

• Decisions on which details are confidential are often made across multiple teams.
• Changes to the classification of confidential information across the research cycle, as information is released into the public domain, make it difficult for teams to keep up to date with changes to confidential status.

These factors contribute to high rates of redaction rejection by health authorities: 60% of sponsor-requested redactions are rejected by the EMA and 65% by Health Canada.

These factors contribute to high rates of redaction rejection by health authorities: 60% of sponsor-requested redactions are rejected by the EMA and 65% by Health Canada.

Practical solutions

Zimmerman proposed a number of practical solutions to ease the burden of redaction:

• ensure processes, roles, and responsibilities are clearly defined, including between teams
• implement a centralised ‘library’ to track confidential information
• ensure a common understanding of what constitutes confidential information across teams
• only include necessary information in documents from the outset and cross-reference within a document, rather than duplicating information
• use integrated management and tracking systems.

Through implementation of these approaches, sponsors could streamline and simplify the redaction process and, thus, reduce delays in clinical trial registration and reporting.

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KEY TAKEAWAYS

• Stakeholders at biomedical research institutions agreed on 19 key open science practices that should be monitored to help institutions track their progress.
• Selected open science practices include prospective registration and timely reporting of clinical trials, specifying information to be shared, publishing open access, and disclosing author and funder information.

Open science aims to improve the quality and reproducibility of research through increasing transparency and accessibility. Following the 2021 adoption of the United Nations Educational, Scientific and Cultural Organization (UNESCO) Recommendation on Open Science, the US National Institutes of Health (NIH) and World Health Organization (WHO) have also introduced data sharing policies. ‘Success’ in open science generates effective research outcomes, reduces costs, and improves reputation. However, questions remain on which practices are the most important and how they should be monitored.

A recent publication in PLoS Biology shared results from a 3-round Delphi study asking which open science practices should be monitored at biomedical research institutions globally. 80 participants, including researchers, open science specialists, and librarians, contributed to the study. They reached consensus on 12 traditional and 7 broader transparency practices that should be monitored, including several also assessed in PLOS’ Open Science Indicators initiative.

The key open science practices were related to:

• registration and timely reporting for clinical trials and systematic reviews
• information sharing, eg, stating whether data, study materials, or code were shared openly at the time of publication, and the use of clear licences for any shared information
• use of persistent identifiers, including ORCID identifiers for researchers and digital object identifiers (DOIs) for shared data, study materials, or code
• use of open access publication (including whether open access is immediate or delayed)
• disclosure of author contributions, conflicts of interest, and funding.

Dr Kelly D. Cobey and co-authors now plan to develop a fully automated open science dashboard interface, incorporating the agreed core open science practices where these can be measured accurately and reliably. Dr Cobey and co-authors believe the tool will allow institutions to track their progress adopting open science practices and adhering to mandates, and that it will facilitate open science meta-research, without evoking competition or indicating prestige at the institutional level.

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KEY TAKEAWAYS

• Prospective registration of clinical trials and subsequent comprehensive publication of the trial results can support the full and accurate evaluation of drugs, but occurs too infrequently despite the efforts of regulators.
• Wider access to clinical trial data sets could help validate findings and facilitate secondary analyses, but concerns surrounding copyright and licensing, patient confidentiality, and potential erroneous analysis of the data by third parties are a barrier to the wider adoption of open data sharing policies.

An article published in Science and Public Policy highlights the ongoing disconnect between the number of clinical trials conducted and the number fully published in the medical literature. The article, by Habeeb Razack et al, outlines the four key components to clinical trial transparency:

• trial registration
• data documentation
• data sharing
• publishing trial outcomes.

The authors describe how journals have made progress towards supporting and encouraging greater transparency. International Committee of Medical Journal Editors (ICMJE) Guidelines require authors of clinical trial publications to provide trial registration details and many publishers also request data sharing statements. Some journals follow the Transparency and Openness Promotion Guidelines (TOP) from the Center for Open Science (which also publishes the related TOP Factor that ranks academic journals based on their commitment to research transparency and reproducibility).

Elsewhere, there are various mandates in place to encourage transparent reporting of trial data. These include the US Food and Drug Administration Amendments Act (FDAAA) Final Rule, which sets a deadline of within one year of trial completion for applicable trials to have their results posted to the ClinicalTrials.gov registry. However, compliance with the FDAAA mandate is reported to be low, as highlighted in a recent analysis. The All Trials campaign, which calls for the mandatory registration and reporting of results from all clinical trials, provides ongoing monitoring of FDAAA compliance via the FDAAA Trials Tracker website. Razack et al underline the importance of reporting data from all trials, as the evaluation of a drug should be based on all available data for that drug and not just data that has been selected for publication.

The latest Good Publication Practice Guidelines (GPP 2022) encourage the publication of all clinical trial data (and at a minimum, trials reporting Phase II and Phase III data) in a peer-reviewed journal  —a policy supported by the authors, who point out that posting results on clinical trial registries does not directly contribute to the medical literature. The authors direct researchers to guidelines such as CONSORT (Consolidated Standards of Reporting Trials) for clinical trials, and those available on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) website for other study types, to improve the rigour and consistency of health research reporting.

“The finish line of a clinical trial is when it gets published.”

The authors make some suggestions to encourage increased data sharing, including a common data sharing repository and data reporting policy that would make the process less onerous for clinical trial sponsors. They suggest that complementary sharing of data could improve the accuracy of meta-analyses and reduce the need for additional trials. Interestingly, the authors highlight a study that found a positive correlation between articles that include a link to a data repository and citation counts. The authors note a high number (>10,000) of clinical trials related to COVID-19 listed in the WHO International Clinical Trials Registry Platform (ICTRP), for which open research practices could be transformative in expediting research validation, particularly given the need for rapid research dissemination and treatment uptake.

“Maintaining data transparency is a [part] of the obligation that the pharmaceutical industry has towards the public.”

The authors also highlight potential barriers to adopting transparent data sharing practices, of which the most commonly cited appears to be uncertainty surrounding copyright and licensing. There is also the issue of patient privacy and confidentiality. To fully understand how a clinical trial was conducted may require access to study materials, including the raw data, which may include patient-level data. One suggestion to allow patients to opt in to a data sharing clause during the informed consent process is countered by the risk of creating bias in secondary analyses due to patients choosing to opt out. Furthermore, there is a risk that third parties accessing trial data may use inappropriate analyses and reach erroneous conclusions that undermine trust in the original trial findings. Finally, the authors question whether increased availability of data and study materials, including complete clinical study reports, may undermine the availability of novel findings for publication.

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A New York judge has ruled that hundreds of the clinical trials registered on ClinicalTrials.gov are in breach of the law due to unreported results. As noted on the AllTrials website, the case was brought against the US Department of Health and Human Services and concerns trials of unapproved drugs that were registered on ClinicalTrials.gov between 2007 and 2017, which failed to report results. Researchers and institutions have often interpreted the requirement to disclose clinical trial outcomes, as laid down in the 2007 FDA Amendments Act, as only applying to approved drugs.

The ruling establishes that reporting requirements apply regardless of approval status, including for studies registered prior to 2017 when the Amendments Act was clarified and expanded to cover a broader range of studies.

Organisations must now report missing results or risk being in breach of the law.

This may present a particular challenge for academic institutions and researchers, as compliance with reporting requirements by these organisations has been found to be significantly lower compared with industry. A 2019 study reported mean disclosure rates of 74% for trials sponsored by pharmaceutical companies compared with 46% for those with non-industry sponsors.

While the ruling may have clarified that applying reporting requirements to approved drugs only is a misinterpretation of the law, much uncertainty remains. As yet, it is not clear whether the ruling will be appealed and the FDA has not indicated what action it may take. Even prior to the ruling, many organisations were found to be falling short in reporting clinical trial results and the effectiveness and transparency of enforcement has been questioned. What is not in doubt is the time and resources required to report missing data from a decade’s worth of clinical trials. We wait with interest to see just how many of these undisclosed results will be made available and whether this ruling results in fewer future breaches of the law.

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Summary by Ian Faulkner PhD from Aspire Scientific

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In 2007, the US Food and Drug Administration Amendments Act (FDAAA) Final Rule mandated that results of clinical trials are reported on ClinicalTrials.gov within one year of trial completion. A study into Trials Transparency from the Ben Goldacre EBM DataLab at the University of Oxford has found that less than half of sponsors are meeting this deadline.

In an article published in The Lancet, the authors present reporting timelines for applicable studies, based on data collected from ClinicalTrials.gov between March 2018 and September 2019. Of the 4209 trials due to report results (excluding those with a certificate of extension), 40.9% did so within the one-year time-frame. This rose to 63.8% when results reported after one year were included, leaving over a third of studies unreported. The median time from study completion to data reporting was 424 days, representing a delay of 59 days beyond the mandated requirement of one year.

Encouragingly for pharmaceutical companies, industry sponsors were significantly more likely to report results on time than non-industry sponsors (50% vs 34%; odds ratio 3.08 [2.52–3.77]). Of note, results were reported within one year for just 31% of trials sponsored by the US Government. Sponsors who had registered a large number of trials, were more likely to report results, and more likely to report results on time, compared with sponsors who had few trials registered. Of the 13 biggest sponsors, each with more than 30 due trials, six were pharmaceutical companies, who all achieved more than 92% compliance. Similarly, there was high compliance among pharmaceutical companies sponsoring 10 or more due trials, with many reporting 100% compliance.

Non-reporting of clinical trial data is a public concern as it erodes the evidence base for medical decision-making, as highlighted by the AllTrials campaign. This study shows that while some industry sponsors are leading the way, the timely release of all clinical trial data is still yet to be attained. The study authors suggest that the overall lack of compliance is likely to reflect a lack of enforcement by regulators: to their knowledge no fines have been imposed by the FDA to date.

Given the lack of effective enforcement by regulators, the study authors are maintaining a public registry of compliance data for individual sponsors at fdaaa.trialstracker.net/rankings, relying on public accountability to put pressure on those who continue to fall short on clinical trial results reporting.

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Summary by Julianna Solomons PhD, CMPP from Aspire Scientific

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European Union (EU) regulations mandate that sponsors of interventional clinical trials registered on the European Clinical Trials Database (EudraCT) should publish their results on EudraCT within 12 months of trial completion (6 months for paediatric trials). Certain details, including trial protocols and data subsets, are then made accessible to the public via the EU Clinical Trials Register (EUCTR). Despite these regulations, a recent joint report on clinical trial transparency by TranspariMED, BUKO Pharma-Kampagne, Test Aankoop and Health Action International identified that 83% of eligible clinical trials run by 30 European universities were missing results on the EUCTR. The results and implications of the report are discussed in detail by Nic Fleming in a news article published in Nature.

Fleming highlights that in the worst case an institution reported data from only 7% of the 188 trials they were due to have reported on. Furthermore, universities running eligible trials in four European countries (France, Italy, Sweden and Norway) had not posted any results. The author of the full report, Dr Till Bruckner (TranspariMED), also notes that the situation has likely been underestimated, as many of the old trials listed on EUCTR as ‘ongoing’ may have completed, but their status and results have not been updated.

Fleming has observed a similar situation in the US with regards to trial reporting. A recent study identified 25 US universities that were in violation of US trial disclosure law, which requires sponsors of certain applicable clinical trials of FDA-regulated products to post clinical trial data within 12 months of trial completion.

However, it’s not all doom and gloom – Fleming highlights that three UK universities (University of Oxford, King’s College London, and University College London) performed significantly better than the rest of Europe with regards to trial reporting, publishing 81–93% of results due.

As a reminder to us all, he warns of the implications of failing to report clinical trial data by noting that “Campaigners say the resulting lack of transparency harms patients by undermining the efforts of doctors and health authorities to provide the best treatments, slows medical progress and wastes public funds”.

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Summary by Emma Evans PhD, CMPP from Aspire Scientific

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Guidance from the EQUATOR network and the ICMJE stipulates that clinical trials must be publicly registered at inception in order for results to be considered for publication. This practice was intended to reduce selective reporting of trial outcomes; however, discrepancies between pre-specified and published outcomes of clinical trials persist. A recent article published in Trials by Dr Ben Goldacre (AllTrials-founder) and colleagues reported high levels of outcome misreporting in journals listed as endorsing the CONSORT statement on the correct reporting of clinical trials. What’s more, the group reported that most correction letters they sent to address such misreporting were rejected.

This prospective study (COMPare) tracked outcome switching in 67 randomised controlled trials (RCTs) published over a six-week period (19 Oct–30 Nov 2015) in the five top CONSORT-endorsing medical journals (The New Engl J Med, The Lancet, JAMA, The BMJ and Annals of Internal Medicine). Overall, outcome reporting was deemed to be poor; 58/67 (87%) manuscripts analysed contained CONSORT-breaching discrepancies judged to require a correction letter. Of these letters, only 40% were published, with a median delay of 99 days. Qualitative analysis was thought to suggest misunderstanding among journal editors surrounding correct outcome reporting and CONSORT, a finding that may explain why some journals did not cooperate when presented with evidence of misreporting.

The authors warn that readers of a journal with a CONSORT-supporting stance may assume that trial results are reported in line with pre-specified outcomes. To ensure this is the case, Goldacre and his colleagues suggest a number of strategies: 1) Changes to journals’ correspondence processes; 2) Indexed post-publication peer review; 3) Changes to CONSORT’s enforcement mechanisms; 4) Changes to practices in methodology research to increase sharing of misreporting with the broader academic community.

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Summary by Emma Prest PhD from Aspire Scientific

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A recent study published in BMC Central evaluated the eligibility of independent researchers to request participant-level data from industry-sponsored clinical trials.

Researchers identified primary publications (in 2015, in the top 10 medical journals by impact factor) for trials of medicines registered on ClinicalTrials.gov. Fifty-six publications reporting 61 clinical trials were identified. A publicly available policy for data sharing was identified for over half (52%) of the trials, and 9 trials (15%) were confirmed as being eligible for data sharing. Industry sponsors within the top 25 by global sales were more likely to have a publicly available data sharing policy than those below the top 25 (93% vs 10%), and there was a trend towards increased data sharing eligibility (23% vs 4%). Industry sponsors that were members of the Pharmaceutical Research and Manufacturers of America (PhRMA) or the European Federation of Pharmaceutical Industries and Associations (EFPIA) were significantly more likely to have a data sharing policy (94% vs 5%) and confirm trial data sharing eligibility (30% vs 0%) than non-members.

For those trials where data sharing was not available (43%), the most common reasons were that the sponsor does not share individual patient data, the study has ongoing follow-up, or the medicine is not approved by both the European Medicines Agency (EMA) and FDA. The study authors suggest that follow-up for secondary endpoints should not prevent the sharing of data supporting published primary outcomes. Further to this, they state that once a medicine “is in widespread use in one jurisdiction, data sharing of the pivotal trials supporting the registration decision is in the public interest irrespective of the registration status in another jurisdiction”. As of 1 July 2018, manuscripts reporting the outcomes of clinical trials published in International Committee of Medical Journal Editors (ICMJE) member journals are required to include a data sharing statement. Further to this, for clinical trials enrolling participants on or after 1 January 2019, a data sharing plan must be included in the trial’s registration. With these requirements, and as more journals encourage open data, it will be interesting to see whether study sponsors will relax their conditions for data sharing in the future.

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Summary by Louise Niven DPhil, CMPP from Aspire Scientific

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• Study publication bias: The results of half of the trials examined were considered positive by the FDA and 98% of these were published, while the other half were considered negative or questionable and only 48% of these were published.
• Outcome reporting bias: The authors considered that 10 of the published negative trials were reported as ‘positive’ within the publication, by switching the status of the primary and secondary outcomes or failing to include less favourable data.
• Spin: Eleven of the remaining published negative trials were written using language the authors felt made the negative results appear positive, such as ‘a trend for efficacy’.
• Citation bias: Positive trials and those including spin in the abstract were cited more frequently than negative trials.

Interestingly, the authors noted that all of the negative trials that remained unpublished were completed before 2004. Therefore, the more recent requirement for trials to be prospectively registered and to report results following completion may be helping to prevent study publication bias. However, a review conducted by Aaron Carroll in The New York Times delved further into the issue, highlighting the serious effects of various cumulative biases, including how they can skew the results of meta-analyses, a tool critical for evidence-based decision-making. Carrol calls for the scientific community to encourage journals to publish negative results and asks us to ”celebrate and elevate negative results, in both our arguments and reporting, as we do positive ones”.

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Summary by Louise Niven, DPhil from Aspire Scientific

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