The randomized clinical trial trustworthiness crisis

Background

The rising number of retracted randomised clinical trials (RCTs) is a concern over their trustworthiness. In today's digital landscape electronic observational data is easily accessible for research purposes. This emerging perspective, in tandem with the growing scrutiny of RCT credibility, may steer some researchers towards favouring non-randomized studies. It is crucial to emphasize the ongoing need for robust RCTs, shedding light on the areas within trial design that require enhancements and addressing existing gaps in trial execution.

Main body

Evidence-based medicine pivots on the nexus between empirical medical research and the theoretical and applied facets of clinical care. Healthcare systems regularly amass patient data, creating a vast reservoir of information. This facilitates large-scale observational studies, which may appear as potential substitutes for RCTs. These large-scale studies inherently possess biases that place them a notch below randomized evidence. Honest errors, data manipulation, lapses in professionalism, and methodological shortcomings tarnish the integrity of RCTs, compromising trust in trials. Research institutions, funding agencies, journal editors and other stakeholders have the responsibility to establish robust frameworks to prevent both deliberate and inadvertent mishandling of RCT design, conduct and analysis. Systematic reviews that collate robust RCTs are invaluable. They amalgamate superior evidence instrumental in improving patient outcomes via informed health policy decisions. For systematic reviews to continue to retain trust, validated integrity assessment tools must be developed and routinely applied. This way it will be possible to prevent false or untrustworthy research from becoming part of the recommendations based on the evidence.

Conclusion

High-quality RCTs and their systematic reviews play a crucial role in acquiring valid and reliable evidence that is instrumental in improving patient outcomes. They provide vital information on healthcare effectiveness, and their trustworthiness is key to evidence-based medicine.

The term evidence-based medicine or EBM, the approach of using medical evidence to inform clinical decision-making [8], emphasizes the need to evaluate all relevant evidence thoroughly, rather than selectively choosing data that support a particular argument. EBM operates on the premise that not all evidence carries equal weight in the decision-making [48]. Medical decisions should rely on the best available evidence, while taking into account patients' values and preferences.

The trustworthiness of the evidence, i.e., the extent to which we can be confident that the research findings are firm, is central to EBM. EBM classifies controlled clinical observations as more reliable evidence than uncontrolled clinical observations, biological experiments, or individual clinician experiences [8]. Among controlled clinical studies, randomised controlled trials (RCTs) are at the top of the evidence hierarchy. However, some academicians, lobbyists, professional associations, funding organizations, and even regulators are now considering observational data, even for licensure purposes [49]. This is largely due to the ready availability of data in a digital world where every clinical episode is electronically captured in the health system [49]. This type of data, often referred to as real-world data, is different from randomised data.

This real-world data has inherent limitations of the observational design, which cannot be resolved solely by increasing the amount of data used. The size of the data merely serves to increase the statistical power; it does not necessarily enhance study validity. Therefore, abandoning RCTs will revert to the pre-EBM research era. This proposed reliance on observational data can result in false statistical inferences, downgrading the credibility of research findings and risking spurious statistical significance [1, 14, 23]. This commentary seeks to compare the value of clinical trials with observational studies, highlighting the importance of the former. We discuss the potential advantages of rigorously conducted observational research. Given the increasing concerns about RCT trustworthiness, we explore the current gaps and areas for improvement.

Importance of RCTs

A robust RCT determines efficacy for regulatory approval and identifies effective treatment options for practice. It provides insights into causal linkages, reducing the risk of bias and confounding. The specification of sample characteristics in RCT may adversely impact its generalizability to real-world situations, as the effects of treatment on people who are not part of the RCT become a matter of judgment [11]. Surrogate endpoints may not accurately reflect the desired patient-oriented outcomes. RCTs may not be practical in rare diseases. Emergency situations may also be considered a barrier. However, the response to COVID-19 pandemic has shown that RCTs a key to global health challenges.

Conducting RCTs that are reliable, unbiased, and transparent is crucial to improving healthcare. To achieve this, researchers should ask relevant questions that are important to patients and the public. They should conduct systematic reviews of prior evidence to design new trials that use the best possible comparators [33] to evaluate the effects on core clinical outcomes [25]. Patient and public involvement is a key feature of relevant clinical trials [34]. It is important to pre-register the RCT protocol and make it publicly accessible before recruiting participants. RCTs should be conducted as planned without protocol deviation along the course of the work. Proper randomization and allocation concealment are essential for high-quality trials, yet many RCTs have shortcomings [51]. Their analysis strategy should be pre-determined before the outcomes within the trial dataset are revealed to investigators. There should be detailed reporting of funding and conflicts of interest. Recently an international multistakeholder group has issued an integrity statement specifically covering RCTs [27].

Systematic reviews to compile RCT evidence

Systematic reviews assist medical professionals in collating and evaluating evidence, offering direction for future action. Some reviews have resulted in unintended consequences such as the production of unreliable guidelines, lapses in regulation, and tardiness in removing hazardous drugs [20]. These deficiencies have resulted in elevated treatment expenses, and superfluous medical procedures, including overdiagnosis, and overtreatment. However, there has been continued progress in the methodology of systematic review to push boundaries seeking significant advancement in this area [3, 20]. Over 50,000 systematic reviews were published in 2022 [38], coming closer to the vision of organising living collations of accumulating evidence for addressing the shortcomings of scientific research and for EBM [8]. The failure in the past to do so has led to unnecessary suffering, loss of life, and the misuse of healthcare resources. The mission now is to review existing research in a methodical way to prevent studies with integrity flaws from entering the evidence syntheses [38]. While RCTs are generally considered to be the gold standard, there are still some problematic RCTs that contribute to the current evidence base for patient management. Finding a solution to this issue will require efforts in the integrity test validation [28, 38].

Hidden aspects around RCT registration

Every day, 75 RCTs are published. Given that 60% of randomized controlled trials are eventually published [42], it is estimated that around 125 trials are initiated every day. This number is 2.5 times more than the number of trial protocols that are registered on clinicaltrials.gov [21]. Out of all the registered trials, approximately 5% were never started [44]. Many trials are terminated early, which accounts for 12% of those posted on clinicaltrials.gov and 28% of those approved by research ethics committees [53]. There is a notable amount of secondary literature [9], so it is necessary to evaluate 150 to 200 trials every day [21]. When accounting for rejections and resubmissions, the total number of submissions may exceed this range. Irrelevance can be a cause of waste in RCTs, but it is difficult to measure in part because the issue is subjective.

The ongoing tolerance of wastefulness in clinical research can be traced back to the existing incentive structure, which heavily prioritizes the number of publications as a gauge of academic achievement [22]. The way of ranking researchers needs reconsideration considering the effects of the academic incentive structure. This is essential for understanding the tremendous pressure that researchers face to publish as well as for raising the standard of scientific research. There is a need for a balance as a solution and for maintaining public confidence in science [16]. Researchers may actively cheat or purposefully remove data in order to generate publications more quickly due to academic competitiveness. Journals typically publish positive findings, which adds to publication bias. Preventing instances of cheating is necessary for achieving a reduction in academic misconduct [12].

The perspectives of patients are not always considered when formulating research questions and selecting outcomes [35]. Replication of a study's findings using the same methodology is a validation process. This notion needs to be valued in RCTs, where if a new RCT found similar conclusions to similar ones before it, all should earn credibility. It is unfortunate that null results and replications, which are scientifically sound, are not valued by clinical journals. Researchers should be incentivized to submit such findings or to conduct replication RCTs to correct the scientific record. Journals considering only positive results as a modus operandi to accept research for publication unintentionally incentivize the generation of spurious findings and false positives [20]. RCTs, if they lack transparency and independent scrutiny including instances of failure to follow their protocol, stopping early or including ghost authorship, will lead to publication with reporting biases, overinterpretation or misinterpretation of results, uncorrected errors, and undetected fraud [20].

The importance of replication

The issue of reproducibility is a generic concern across science. It has been said that 70% of researchers have attempted to duplicate another scientist's findings but failed [5]. This important validation research concept needs to be the norm in RCTs by encouraging trialists to do replication research instead of opining against RCT findings with which they disagree. This concept of replication research was established in the early days of the Royal Society (in 1660), where experimenters would duplicate whatever assertions, they made in front of their peers. Nowadays, replication has lost its interest, partly because journals constantly look for new findings to publish in the interest of seeking more citations. The lack of publicly available data, protocols, and statistical codes has made it unfeasible to re-analyze published data. It is commonly, but perhaps erroneously, accepted that a published study's findings or results are reliable [32]. This approach encourages the acceptance of published findings blindly. If the measures used in the original study are indirect and imprecise, and examining the raw data is arduous or time-intensive, it might be more feasible to utilize the outcomes from extension or replication studies as a fresh foundation [13].

In scientific research, replication studies will likely require a re-examination of all potentially controversial research practices. This is because the size of an effect can be impacted not only by questionable practices but also by sampling errors [43]. Replication studies serve multiple purposes, including correcting for sampling errors (false-positive detection), controlling for artefacts, addressing researcher fraud, testing generalizations to non-identical study samples, and examining the same hypothesis of a prior study with a different methodology. One single replication study cannot fulfil all five purposes simultaneously [54]. The RCT replication approach needs to be developed on the logical lines outlined above.

Intentional and unintentional misuse of statistics

Statistical analyses, regardless of methodology, are susceptible to misuse. Researchers possess various freedoms when conducting data analysis and interpretation, which can lead to variations in findings [17]. Multiple conclusions can be drawn from the same research question and data, e.g., findings from identical studies may even yield contradictory results. Statistical manipulation, whether intentionally as a kind of fraud or unintentionally as a kind of illusion, may be used to produce certain results from a dataset [17]. RCTs make claims from subgroup analysis while failing to consider multiple testing and lack appropriate interaction testing [17]. Making datasets publicly available emphasizes the need for openness in scientific publishing. The International Committee of Medical Journal Editors (ICMJE) has stated, “it is an ethical obligation to responsibly share data obtained from interventional clinical trials because participants have put themselves at risk” [46]. The ICMJE has recommended making the deidentified individual patient data (IPD) available to the public within six months of publication. This proposal sparked a discussion [19, 24, 39, 40, 50], resulting in withdrawal of the proposal followed by a reissue of recommendation requiring a data-sharing plan defined during study registration [47]. This limitation on openness in science ought to be reconsidered in the near future. This call for reconsideration is important as the current RCT integrity tests lack validation. Therefore, a triad of data sharing, integrity test validation and stop the blame game needs to run simultaneously. Irresponsible use of integrity tests can damage the reputation and career of honest researchers.

Artificial intelligence

Certain artificial intelligence (AI) solutions which include automated or semi-automated tools will likely be used as a solution towards improving RCT integrity testing. Areas where RCT validity may include concerns such as insufficient sample size, inadequate randomization with residual confounders, and poor patient selection [36]. Take as an example RCTs which need a large sample size when the effect of the treatment in question is small [45]. In conducting such RCTs, AI can be used to potentially select those patients who are more likely to meet the eligibility criteria based on the AI’s predicted algorithm. Utilizing AI also has the potential for more coherent implementation of the selection of patient subgroups with more advanced disease and greater control event rates. This approach has the potential to increase the expected effect size thus reducing the sample size, maximizing the statistical power and minimizing the time duration of the RCT compared to conventional recruitment approaches in RCTs [29]. AI may also be deployed in peer review or critical appraisal for integrity testing [52]. However, this approach depends on development of accurate tests for detecting flaws in integrity first [28].

Research integrity testing

There have been attempts to investigate published research for data integrity [7, 15, 30, 31]. Integrity tests are yet to be validated. An attempt to verify three post-publication tests failed to recommend any of them as valid [18]. Investing in the comprehensive validation of RCT integrity tests is a priority to improve the trustworthiness of the literature [28]. A meta-research process is needed to address issues in RCTs, including identifying, analyzing, proposing, and assessing solutions [17]. Meta-research by definition is a systematic study of the research itself as the object of investigation, i.e., research on research methodology and types, aiming to improve on the process of conducting research. This framework's objective is to enhance the efficiency, credibility and quality standards of the scientific ecosystem. It is a tool that researchers can use to identify potential flaws in the scientific environment, such as publication bias and poor research design, at an early stage [17]. This process involves: conceptual development and theoretical argumentation, performing empirical studies to assess the presence and acuteness of the identified issues: developing and implementing likely solutions which may include new infrastructure, policy changes or instructional program development [17]; and, assessing the effectiveness of proposed solutions, either through controlled experiments or field implementation. In theory, feedback from later phases can inform earlier stages [17]. Meta-research on RCTs should evaluate the impact of including methodologists with experience in the statistical team, as well as on the data and safety monitoring boards. These can serve in the protection of large-scale multicentre clinical trials [2]. Going ahead with research on research in this arena within RCTs is a timely scientific challenge.

The value of rigorous observational studies

In EBM, questions may be answered by different study designs. If randomisation is not feasible, observational studies can be used. This is particularly valuable when there is no link between the intervention and the outcome that can confound the effect [6]. The main limitation of observational studies is that as the intervention is not randomised, confounding becomes a probable explanation for the observed differences between the exposed and unexposed groups [37]. However, if randomisation is not ethical or feasible, observational studies become the only viable design option to help answer important clinical questions. Adjusting for the connection between the allocation of the intervention and the patient prognosis requires advanced statistical methods that make adjustments for potential confounding. A review found “no significant difference in point estimates across heterogeneity, pharmacological intervention, or propensity score adjustment subgroups” between observational studies and RCTs [4]. The propensity score is used in the statistical analysis of observational data to estimate the effect considering the covariates available in the dataset [10]. These adjustments may be adequate to disconnect the covariates from the effect estimated [41]. Mindful interpretation of the results from rigorous observational studies will help EBM. Evidence grading systems permit the upgrading of observational results when generating recommendations [26].

EBM is grounded in high-quality research evidence, primarily from RCTs, to generate trustworthy recommendations. However, EBM's credibility may be jeopardized if the focus shifts away from RCTs toward observational data without sound justification. While observational studies have utility, RCTs remain the gold standard for robust inference in clinical effectiveness research. Rather than abandoning RCTs, efforts must enhance their relevance, improve their reproducibility, and promote the transparency of their publications through design-specific research integrity frameworks. RCTs remain the cornerstone of progress when executed ethically and rigorously. Renewed commitment to their evidentiary value, paired with quality control enhancements and improved relevance, will enable RCTs to provide the robust evidence required for clinical practice and health policy decision-making.

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

RCT:

Randomized Control Trials

EBM:

Evidence-Based Medicine

AI:

Artificial Intelligence

KSK is a distinguished investigator at the University of Granada funded by the Beatriz Galindo (senior modality) programme of the Spanish Ministry of Education.

Data availability statement

Not applicable.

None.

Authors and Affiliations

1. Department of Preventative Medicine and Public Health, University of Granada, Granada, Spain

   Furqan A. Butt, Aurora Bueno-Cavanillas & Khalid S. Khan

2. IbnSina, Banon Amshaj and Qena IVF Centres, Sohag, Egypt

   Mohammad Fawzy

3. Beginnings Assisted Conception Unit, Epsom and St Helier University Hospitals, London, UK

   Bassel H. Al Wattar

4. Institute for Clinical Trials and Methodology, University College London, London, UK

   Bassel H. Al Wattar

5. Guy’s & St Thomas’ Hospital Foundation Trust, London, UK

   Yacoub Khalaf

Contributions

Writing original draft: M.F,K.S.K; Review and editing: F.A.B, M.F,K.S.K; Supervision: Y.K, BW, K.S.K and A.B.C.

Corresponding author

Correspondence to Khalid S. Khan.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests. ICMJE forms are attached as supplementary material.

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