Barriers to the conduct of randomised clinical trials within all disease areas

Djurisic, Snezana; Rath, Ana; Gaber, Sabrina; Garattini, Silvio; Ngwabyt, Sandra; Hivert, Virginie; Neugebauer, Edmund; Laville, Martine; Hiesmayr, Michael; Demotes-Mainard, Jacques; Kubiak, Christine; Jakobsen, Janus Christian; Gluud, Christian

doi:10.1186/s13063-017-2099-9

Cited by 121 publications

(105 citation statements)

References 58 publications

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“…We feel that the chance to introduce the required amendments into all fields of medicine would be greatly enhanced by forming national and regional infrastructures that could support clinical research 75,103 . We will in four connected papers discuss the common and special bottlenecks for conducting clinical research on medical devices, nutrition, and rare diseases [7][8][9][10] . Through identifying the threats to internal validity and through providing solutions for these problems, it is our hope that more and better quality clinical research may be achieved and used.…”

Section: Discussionmentioning

confidence: 99%

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Klinička praksa temeljena na dokazima: pregled prijetnji valjanosti dokaza i kako ih spriječiti

et al. 2017

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Abstract.Using the best quality of clinical research evidence is essential for choosing the right treatment for patients. How to identify the best research evidence is, however, difficult. In this narrative review we summarise these threats and describe how to minimise them. Pertinent literature was considered through literature searches combined with personal files. Treatments should generally not be chosen based only on evidence from observational studies or single randomised clinical trials. Systematic reviews with meta-analysis of all identifiable randomised clinical trials with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment represent the highest level of evidence. Even though systematic reviews are trust worthier than other types of evidence, all levels of the evidence hierarchy are under threats from systematic errors (bias); design errors (abuse of surrogate outcomes, composite outcomes, etc.); and random errors (play of chance). Clinical research infrastructures may help in providing larger and better conducted trials. Trial Sequential Analysis may help in deciding when there is sufficient evidence in meta-analyses. If threats to the validity of clinical research are carefully considered and minimised, research results will be more valid and this will benefit patients and heath care systems. Sažetak. Primjena najkvalitetnijih dokaza kliničkih istraživanja ključna je u odabiru ispravnog liječenja pacijenata. No, način na koji će se odabrati najbolji dokazi predstavlja često poteškoću. Ovim preglednim člankom prikazujemo opasnosti navedenog odabira, kao i načine kako ih umanjiti. Relevantni izvori razmatrani su pretragom literature u kombinaciji s osobnim datotekama. Izbor liječenja uglavnom se ne bi smio temeljiti isključivo na opservacijskim ili pojedinačnim randomiziranim kliničkim studijama. Sustavni pregledi s metaanalizom svih identificiranih randomiziranih kliničkih studija procijenjenih sustavom stupnjevanja procjene, razvoja i evalua cije preporuka (engl. Grading of Recommendations Assessment, Development and Evaluation; GRADE) predstavljaju najvišu razinu dokaza. Iako su sustavni pregledi pouzdaniji od drugih vrsta dokaza, sve razine hijerarhije dokaza ugrožene su sustavnim pogreškama (engl. bias); pogreškama dizajna studije (zloupotreba surogatnih ishoda, složenih ishoda itd.) i slučajnim pogreškama (igra slučaja). Kliničke istraživačke infrastrukture mogu pomoći u pružanju većih i adekvatnije provedenih ispitivanja. Sekvencijska analiza studija može pomoći pri odlučivanju kada postoji dovoljna razina dokaza u metaanalizama. Ako se prijetnje valjanosti kliničkih istraživanja pažljivo razmatraju i minimiziraju, rezultati istraživanja bit će vrjedniji i korisniji pacientima i zdravstvenim sustavima.Ključne riječi: klinička praksa temeljena na dokazima; medicina temeljena na dokazima; meta-analiza; randomizirana klinička studija; sekvencijska analiza studija; sustavni pregled

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Section: Discussionmentioning

confidence: 99%

“…53, No. 4, p. 424-438 these fields and how these barriers could be broken down in order to improve their evidencebased clinical practice [7][8][9][10] .…”

Section: Phase II Patients With Disease In Question -Randomised Clinimentioning

confidence: 99%

Klinička praksa temeljena na dokazima: pregled prijetnji valjanosti dokaza i kako ih spriječiti

et al. 2017

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“…Rare diseases affect few patients -and this by definition only allows rare clinical observation and therapeutic evaluation, let alone controlled treatment trials. [49][50][51][52][53] Conducting large randomised double-blinded trials, which have become the standard for common liver diseases, such as hepatitis B or C infections, represents a real challenge in answering the therapeutic questions we have in patients with rare diseases, in a timely fashion. Where the conventional approach to evidence generation has been attempted in rare liver disease, for example in the development of novel therapies in primary biliary cholangitis (PBC), heroic attempts to generate high-quality trials across multiple centres have still been followed by criticism of ''small" trial sizes.…”

Section: Lack Of Data Lack Of Experience: Therapeutic Problemsmentioning

confidence: 99%

Access to care in rare liver diseases: New challenges and new opportunities

Jones

Sturm

Lohse

2018

Journal of Hepatology

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Patients with rare diseases are often disadvantaged, particularly those with rare liver diseases. Reasons for disadvantage include delayed or overlooked diagnosis, lack of local expertise and high-quality care, poor scientific understanding of the disease process and limited therapeutic options. In adult liver disease this can be compounded by prejudices towards patients with liver disease in general, because of a perception (incorrect for all rare liver diseases) that liver disease is lifestyle related and thus "self-inflicted". In paediatric rare liver diseases, such as biliary atresia, optimising outcomes requires a particularly timely diagnosis. Irrespective of patient age, the scientific and medical community must rise to the challenge of advancing our understanding of rare liver disease, searching for more effective and specific therapies, and providing the infrastructure to provide the best care for all patients, infants, children, young and older adults. The European Reference Network for Rare Liver Diseases is an important step in this direction.

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“…The next step should be to con rm the results from exploratory trials in large con rmatory randomized controlled trials (RCTs) to avoid unproven off-label use of medicines based on low levels of clinical evidence (24). However, con rmatory RCTs are expensive, time-consuming and labour-intensive, and a lack of funding remains one of the most important barriers for initiating and completing these studies (25)(26)(27). The average cost of a phase III clinical trial is di cult to establish as it depends on many factors and varies across therapeutic areas.…”

Section: Introductionmentioning

confidence: 99%

New Mechanisms to Fund Independent Clinical Trials for Repurposing Off-Patent or Generic Medicines

Verbaanderd

Rooman

Huys

2020

Preprint

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Finding new therapeutic uses for approved, off-patent or generic medicines could lead to safe, affordable and timely new treatment options for patients with high medical needs. However, due to a lack of economic incentives, pharmaceutical developers are rarely interested to invest in this type of research. Consequently, potential new uses for off-patent or generic medicines are mainly studied in independent proof-of-concept clinical trials initiated and led by researchers from academia, research institutes or collaborative groups. Yet, these researchers need additional financial support to conduct expensive phase III clinical trials to confirm the results from exploratory research. In this study, scientific and grey literature was searched to identify and evaluate new mechanisms for funding clinical trials with repurposed medicines. Semi-structured interviews were conducted with 16 European stakeholders with expertise in clinical research, funding mechanisms and/or drug repurposing between November 2018 and February 2019 to consider the future perspectives of applying new funding mechanisms. Traditional grant funding awarded by government and philanthropic organisations or companies is well known and widely implemented in all research fields. In contrast, the application potential of newer mechanisms to fund independent clinical research, such as social impact bonds or crowdfunding, is not yet known. Interviewees stated that there is a substantial need for additional financial support in health research, especially in disease domains where there is limited commercial interest. However, the implementation of new funding mechanisms is facing several practical and financial challenges, such as a lack of expertise and guidelines, high transaction costs and difficulties to measure health outcomes. Furthermore, increased collaboration and centralisation at a European and international level is recommended to make clinical research more efficient and reduce the need for additional funding. New funding mechanisms to support clinical research may become more important in the future, but the unresolved issues warrant further exploration in pilot projects.

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Barriers to the conduct of randomised clinical trials within all disease areas

Cited by 121 publications

References 58 publications

Klinička praksa temeljena na dokazima: pregled prijetnji valjanosti dokaza i kako ih spriječiti

Klinička praksa temeljena na dokazima: pregled prijetnji valjanosti dokaza i kako ih spriječiti

Access to care in rare liver diseases: New challenges and new opportunities

New Mechanisms to Fund Independent Clinical Trials for Repurposing Off-Patent or Generic Medicines

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