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  1. Article ; Online: The effectiveness of interventions to disseminate the results of non-commercial randomised clinical trials to healthcare professionals: a systematic review.

    South, Annabelle / Bailey, Julia V / Parmar, Mahesh K B / Vale, Claire L

    Implementation science : IS

    2024  Volume 19, Issue 1, Page(s) 8

    Abstract: Background: It is unclear how to disseminate the results of randomised controlled trials effectively to health professionals and policymakers to improve treatment, care or prevention through changing policy and practice. This systematic review examined ... ...

    Abstract Background: It is unclear how to disseminate the results of randomised controlled trials effectively to health professionals and policymakers to improve treatment, care or prevention through changing policy and practice. This systematic review examined the effectiveness of different methods of dissemination of clinical research results to professional audiences.
    Methods: We systematically reviewed the published and grey literature from 2000 to 2022 for studies assessing different approaches for disseminating clinical study results to professional audiences (health professionals, policymakers and guideline developers). Two reviewers assessed potentially relevant full texts for inclusion. We grouped studies by intervention type, synthesising findings using effect direction plots. Outcomes were grouped into out-takes (e.g. awareness, knowledge, understanding), outcomes (e.g. attitude changes) and impact (changes in policy/practice). The quality of evidence was assessed using GRADE.
    Results: Our search identified 13,264 unique records, of which 416 full texts were assessed for eligibility. Of 60 studies that were identified as eligible for inclusion, 20 evaluated the effectiveness of interventions to disseminate clinical research results (13 RCTs, 2 observational studies, 3 pre- and post-intervention surveys and 2 cross-sectional surveys). Studies were grouped by intervention: 7 studies that involved face-to-face meetings between the target audience and trained educators were classified as 'outreach interventions'; 5 studies that provided a summary format for systematic review findings (e.g. summary of findings tables) were grouped together. There was high certainty evidence of a small beneficial impact of outreach interventions on health and moderate certainty evidence of impact on practice (mostly prescribing). There was no evidence of impact on policy and very low certainty around benefits on outcomes and out-takes. We found no consistent benefits of summary formats for systematic review results on outcomes or out-takes (moderate quality evidence). Other interventions with less evidence are reported in the Additional Materials.
    Conclusions: Outreach interventions to disseminate clinical research results can lead to changes in practice and improvements in health. However, these interventions can be resource-intensive. Investment is vital to identify and implement effective and cost-effective ways to disseminate results, so that the potential benefits of trials to patients can be realised.
    Trial registration: International Prospective Register of Systematic Reviews (PROSPERO), CRD42019137364.
    MeSH term(s) Humans ; Cross-Sectional Studies ; Delivery of Health Care ; Health Personnel ; Randomized Controlled Trials as Topic
    Language English
    Publishing date 2024-02-01
    Publishing country England
    Document type Journal Article ; Review ; Systematic Review
    ZDB-ID 2225822-X
    ISSN 1748-5908 ; 1748-5908
    ISSN (online) 1748-5908
    ISSN 1748-5908
    DOI 10.1186/s13012-023-01332-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: When should factorial designs be used for late-phase randomised controlled trials?

    White, Ian R / Szubert, Alexander J / Choodari-Oskooei, Babak / Walker, A Sarah / Parmar, Mahesh Kb

    Clinical trials (London, England)

    2023  Volume 21, Issue 2, Page(s) 162–170

    Abstract: Background: A 2×2 factorial design evaluates two interventions (A versus control and B versus control) by randomising to control, A-only, B-only or both A and B together. Extended factorial designs are also possible (e.g. 3×3 or 2×2×2). Factorial ... ...

    Abstract Background: A 2×2 factorial design evaluates two interventions (A versus control and B versus control) by randomising to control, A-only, B-only or both A and B together. Extended factorial designs are also possible (e.g. 3×3 or 2×2×2). Factorial designs often require fewer resources and participants than alternative randomised controlled trials, but they are not widely used. We identified several issues that investigators considering this design need to address, before they use it in a late-phase setting.
    Methods: We surveyed journal articles published in 2000-2022 relating to designing factorial randomised controlled trials. We identified issues to consider based on these and our personal experiences.
    Results: We identified clinical, practical, statistical and external issues that make factorial randomised controlled trials more desirable. Clinical issues are (1) interventions can be easily co-administered; (2) risk of safety issues from co-administration above individual risks of the separate interventions is low; (3) safety or efficacy data are wanted on the combination intervention; (4) potential for interaction (e.g. effect of A differing when B administered) is low; (5) it is important to compare interventions with other interventions balanced, rather than allowing randomised interventions to affect the choice of other interventions; (6) eligibility criteria for different interventions are similar. Practical issues are (7) recruitment is not harmed by testing many interventions; (8) each intervention and associated toxicities is unlikely to reduce either adherence to the other intervention or overall follow-up; (9) blinding is easy to implement or not required. Statistical issues are (10) a suitable scale of analysis can be identified; (11) adjustment for multiplicity is not required; (12) early stopping for efficacy or lack of benefit can be done effectively. External issues are (13) adequate funding is available and (14) the trial is not intended for licensing purposes. An overarching issue (15) is that factorial design should give a lower sample size requirement than alternative designs. Across designs with varying non-adherence, retention, intervention effects and interaction effects, 2×2 factorial designs require lower sample size than a three-arm alternative when one intervention effect is reduced by no more than 24%-48% in the presence of the other intervention compared with in the absence of the other intervention.
    Conclusions: Factorial designs are not widely used and should be considered more often using our issues to consider. Low potential for at most small to modest interaction is key, for example, where the interventions have different mechanisms of action or target different aspects of the disease being studied.
    MeSH term(s) Humans ; Research Design ; Sample Size ; Randomized Controlled Trials as Topic
    Language English
    Publishing date 2023-10-31
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2138796-5
    ISSN 1740-7753 ; 1740-7745
    ISSN (online) 1740-7753
    ISSN 1740-7745
    DOI 10.1177/17407745231206261
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Treatment selection in multi-arm multi-stage designs: With application to a postpartum haemorrhage trial.

    Choodari-Oskooei, Babak / Thwin, Soe Soe / Blenkinsop, Alexandra / Widmer, Mariana / Althabe, Fernando / Parmar, Mahesh Kb

    Clinical trials (London, England)

    2023  Volume 20, Issue 1, Page(s) 71–80

    Abstract: Background: Multi-arm multi-stage trials are an efficient, adaptive approach for testing many treatments simultaneously within one protocol. In settings where numbers of patients available to be entered into trials and resources might be limited, such ... ...

    Abstract Background: Multi-arm multi-stage trials are an efficient, adaptive approach for testing many treatments simultaneously within one protocol. In settings where numbers of patients available to be entered into trials and resources might be limited, such as primary postpartum haemorrhage, it may be necessary to select a pre-specified subset of arms at interim stages even if they are all showing some promise against the control arm. This will put a limit on the maximum number of patients required and reduce the associated costs. Motivated by the World Health Organization Refractory HaEmorrhage Devices trial in postpartum haemorrhage, we explored the properties of such a selection design in a randomised phase III setting and compared it with other alternatives. The objectives are: (1) to investigate how the timing of treatment selection affects the operating characteristics; (2) to explore the use of an information-rich (continuous) intermediate outcome to select the best-performing arm, out of four treatment arms, compared with using the primary (binary) outcome for selection at the interim stage; and (3) to identify factors that can affect the efficiency of the design.
    Methods: We conducted simulations based on the refractory haemorrhage devices multi-arm multi-stage selection trial to investigate the impact of the timing of treatment selection and applying an adaptive allocation ratio on the probability of correct selection, overall power and familywise type I error rate. Simulations were also conducted to explore how other design parameters will affect both the maximum sample size and trial timelines.
    Results: The results indicate that the overall power of the trial is bounded by the probability of 'correct' selection at the selection stage. The results showed that good operating characteristics are achieved if the treatment selection is conducted at around 17% of information time. Our results also showed that although randomising more patients to research arms before selection will increase the probability of selecting correctly, this will not increase the overall efficiency of the (selection) design compared with the fixed allocation ratio of 1:1 to all arms throughout.
    Conclusions: Multi-arm multi-stage selection designs are efficient and flexible with desirable operating characteristics. We give guidance on many aspects of these designs including selecting the intermediate outcome measure, the timing of treatment selection, and choosing the operating characteristics.
    MeSH term(s) Female ; Humans ; Research Design ; Postpartum Hemorrhage/therapy ; Sample Size ; Patient Selection ; Outcome Assessment, Health Care
    Language English
    Publishing date 2023-01-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2138796-5
    ISSN 1740-7753 ; 1740-7745
    ISSN (online) 1740-7753
    ISSN 1740-7745
    DOI 10.1177/17407745221136527
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Book: Survival analysis

    Machin, David / Cheung, Yin Bun / Parmar, Mahesh K. B.

    a practical approach

    2006  

    Author's details David Machin ; Yin Bun Cheung ; Mahesh K. B. Parmar
    Keywords Survival Analysis ; Proportional Hazards Models ; Survival analysis (Biometry)
    Subject code 610.72
    Language English
    Size 266 S. : graph. Darst.
    Edition 2. ed.
    Publisher Wiley
    Publishing place Chichester
    Publishing country Great Britain
    Document type Book
    Old title 1. Aufl. u.d.T. Parmar, Mahesh K. B. : Survival analysis
    HBZ-ID HT014671052
    ISBN 0-470-87040-0 ; 978-0-470-87040-2
    Database Catalogue ZB MED Medicine, Health

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  5. Article ; Online: A simulation study comparing the power of nine tests of the treatment effect in randomized controlled trials with a time-to-event outcome.

    Royston, Patrick / B Parmar, Mahesh K

    Trials

    2020  Volume 21, Issue 1, Page(s) 315

    Abstract: Background: The logrank test is routinely applied to design and analyse randomized controlled trials (RCTs) with time-to-event outcomes. Sample size and power calculations assume the treatment effect follows proportional hazards (PH). If the PH ... ...

    Abstract Background: The logrank test is routinely applied to design and analyse randomized controlled trials (RCTs) with time-to-event outcomes. Sample size and power calculations assume the treatment effect follows proportional hazards (PH). If the PH assumption is false, power is reduced and interpretation of the hazard ratio (HR) as the estimated treatment effect is compromised. Using statistical simulation, we investigated the type 1 error and power of the logrank (LR)test and eight alternatives. We aimed to identify test(s) that improve power with three types of non-proportional hazards (non-PH): early, late or near-PH treatment effects.
    Methods: We investigated weighted logrank tests (early, LRE; late, LRL), the supremum logrank test (SupLR) and composite tests (joint, J; combined, C; weighted combined, WC; versatile and modified versatile weighted logrank, VWLR, VWLR2) with two or more components. Weighted logrank tests are intended to be sensitive to particular non-PH patterns. Composite tests attempt to improve power across a wider range of non-PH patterns. Using extensive simulations based on real trials, we studied test size and power under PH and under simple departures from PH comprising pointwise constant HRs with a single change point at various follow-up times. We systematically investigated the influence of high or low control-arm event rates on power.
    Results: With no preconceived type of treatment effect, the preferred test is VWLR2. Expecting an early effect, tests with acceptable power are SupLR, C, VWLR2, J, LRE and WC. Expecting a late effect, acceptable tests are LRL, VWLR, VWLR2, WC and J. Under near-PH, acceptable tests are LR, LRE, VWLR, C, VWLR2 and SupLR. Type 1 error was well controlled for all tests, showing only minor deviations from the nominal 5%. The location of the HR change point relative to the cumulative proportion of control-arm events considerably affected power.
    Conclusions: Assuming ignorance of the likely treatment effect, the best choice is VWLR2. Several non-standard tests performed well when the correct type of treatment effect was assumed. A low control-arm event rate reduced the power of weighted logrank tests targeting early effects. Test size was generally well controlled. Further investigation of test characteristics with different types of non-proportional hazards of the treatment effect is warranted.
    MeSH term(s) Computer Simulation ; Humans ; Proportional Hazards Models ; Randomized Controlled Trials as Topic ; Research Design ; Sample Size
    Language English
    Publishing date 2020-04-06
    Publishing country England
    Document type Comparative Study ; Journal Article
    ZDB-ID 2040523-6
    ISSN 1745-6215 ; 1468-6694 ; 1468-6708
    ISSN (online) 1745-6215 ; 1468-6694
    ISSN 1468-6708
    DOI 10.1186/s13063-020-4153-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Smarter adaptive platform clinical trials in neurology: a showcase for UK innovation.

    Mehta, Arpan R / Pal, Suvankar / Chataway, Jeremy / Carpenter, James R / Parmar, Mahesh K B / Chandran, Siddharthan

    Brain : a journal of neurology

    2022  Volume 145, Issue 8, Page(s) e64–e65

    MeSH term(s) Clinical Trials as Topic ; Diffusion of Innovation ; Humans ; Neurology ; Research Design ; United Kingdom
    Language English
    Publishing date 2022-05-10
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awac169
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Testing alternative schedules of adjuvant immune checkpoint blockers - The need for well-designed clinical trials.

    Bouche, Gauthier / Langley, Ruth / Rush, Hannah / Parmar, Mahesh / Gilbert, Duncan C

    European journal of cancer (Oxford, England : 1990)

    2022  Volume 178, Page(s) 88–90

    MeSH term(s) Humans ; Immune Checkpoint Inhibitors ; Immunotherapy ; Clinical Trials as Topic
    Chemical Substances Immune Checkpoint Inhibitors
    Language English
    Publishing date 2022-10-31
    Publishing country England
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 82061-1
    ISSN 1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
    ISSN (online) 1879-0852
    ISSN 0277-5379 ; 0959-8049 ; 0964-1947
    DOI 10.1016/j.ejca.2022.10.024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: A three protein signature fails to externally validate as a biomarker to predict surgical outcome in high-grade epithelial ovarian cancer.

    Hawarden, Amy / Price, Marcus / Russell, Bryn / Wilson, Godfrey / Farrelly, Laura / Embleton-Thirsk, Andrew / Parmar, Mahesh / Edmondson, Richard

    PloS one

    2023  Volume 18, Issue 3, Page(s) e0281798

    Abstract: Introduction: For patients with advanced epithelial ovarian cancer, complete surgical cytoreduction remains the strongest predictor of outcome. However, identifying patients who are likely to benefit from such surgery remains elusive and to date few ... ...

    Abstract Introduction: For patients with advanced epithelial ovarian cancer, complete surgical cytoreduction remains the strongest predictor of outcome. However, identifying patients who are likely to benefit from such surgery remains elusive and to date few surgical outcome prediction tools have been validated. Here we attempted to externally validate a promising three protein signature, which had previously shown strong association with suboptimal surgical debulking (AUC 0.89, accuracy 92.8%), (Riester, M., et al., (2014)).
    Methods: 238 high-grade epithelial ovarian cancer samples were collected from patients who participated in a large multicentre trial (ICON5). Samples were collected at the time of initial surgery and before randomisation. Surgical outcome data were collated from prospectively collected study records. Immunohistochemical scores were generated by two independent observers for the three proteins in the original signature (POSTN, CXCL14 and pSmad2/3). Predictive values were generated for individual and combination protein signatures.
    Results: When assessed individually, none of the proteins showed any evidence of predictive affinity for suboptimal surgical outcome in our cohort (AUC POSTN 0.55, pSmad 2/3 0.53, CXCL 14 0.62). The combined signature again showed poor predictive ability with an AUC 0.58.
    Conclusions: Despite showing original promise, when this protein signature is applied to a large external cohort, it is unable to accurately predict surgical outcomes. This could be attributed to overfitting of the original model, or differences in surgical practice between cohorts.
    MeSH term(s) Humans ; Female ; Carcinoma, Ovarian Epithelial/surgery ; Ovarian Neoplasms/surgery ; Biomarkers ; Prognosis ; Proteins ; Cytoreduction Surgical Procedures ; Treatment Outcome
    Chemical Substances Biomarkers ; Proteins
    Language English
    Publishing date 2023-03-23
    Publishing country United States
    Document type Multicenter Study ; Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0281798
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: artbin: Extended sample size for randomized trials with binary outcomes.

    Marley-Zagar, Ella / White, Ian R / Royston, Patrick / Barthel, Friederike M-S / Parmar, Mahesh K B / Babiker, Abdel G

    The Stata journal

    2023  Volume 23, Issue 1, Page(s) 24–52

    Abstract: We describe the command artbin, which offers various new facilities for the calculation of sample size for binary outcome variables that are not otherwise available in Stata. While artbin has been available since 2004, it has not been previously ... ...

    Abstract We describe the command artbin, which offers various new facilities for the calculation of sample size for binary outcome variables that are not otherwise available in Stata. While artbin has been available since 2004, it has not been previously described in the
    Language English
    Publishing date 2023-04-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2209308-4
    ISSN 1536-8734 ; 1536-867X
    ISSN (online) 1536-8734
    ISSN 1536-867X
    DOI 10.1177/1536867X231161971
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: The role of placebo control in clinical trials for neurodegenerative diseases.

    Mehta, Arpan R / Carpenter, James R / Nicholas, Jennifer M / Chataway, Jeremy / Virgo, Bruce / Parmar, Mahesh K B / Chandran, Siddharthan / Pal, Suvankar

    Nature medicine

    2023  Volume 29, Issue 11, Page(s) 2682–2683

    Language English
    Publishing date 2023-09-13
    Publishing country United States
    Document type News
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/d41591-023-00080-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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