text:
PLOS Medicine publishes research and commentary of general interest with clear implications for patient care, public policy or clinical research agendas.
Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease
Ben S. Cooper ,
* E-mail: ben@tropmedres.ac
Affiliations Mahidol Oxford Tropical Medicine Research Unit (MORU), Bangkok, Thailand, Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
Maciej F. Boni,
Affiliations Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam
Wirichada Pan-ngum,
Affiliation Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Nicholas P. J. Day,
Peter W. Horby,
Affiliation Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
Piero Olliaro,
Affiliations Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, UNICEF-UNDP-World Bank-WHO Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland
Trudie Lang,
Nicholas J. White,
Lisa J. White,
John Whitehead
Affiliation Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom
Ben S. Cooper,
https://doi.org/10.1371/journal.pmed.1001815
Ben S. Cooper Maciej F. Boni ... John Whitehead
Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic.
Methods and Findings
A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses.
Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group.
The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.
Editors' Summary
The current outbreak of Ebola virus disease (EVD)—a frequently fatal disease that first appeared in human populations in 1976 in remote villages in central Africa—has infected more than 24,000 people and killed more than 10,000 people in Guinea, Sierra Leone, and Liberia since early 2014. Ebola virus is transmitted to people from wild animals and spreads in human populations through direct contact with the bodily fluids (including blood, saliva, and urine) or with the organs of infected people or through contact with bedding and other materials contaminated with bodily fluids. The symptoms of EVD which start 2–21 days after infection, include fever, headache, vomiting, diarrhea, and internal and external bleeding. Infected individuals are not infectious until they develop symptoms but remain infectious as long as their bodily fluids contain virus. There is no proven treatment or vaccine for EVD, but supportive care—given under strict isolation conditions to prevent the spread of the disease to other patients or to healthcare workers—improves survival.
Why Was This Study Done?
Potential treatments for EVD include several antiviral drugs and injections of antibodies against Ebola virus from patients who have survived EVD. Before such therapies can be used clinically, their safety and effectiveness need to be evaluated, but experts disagree about how to undertake this evaluation. Drugs for clinical use are usually evaluated by undertaking a series of clinical trials. A phase I trial establishes the safety of the treatment and how the human body copes with it by giving several healthy volunteers the drug. Next, a phase II trial provides early indications of the drug's efficacy by giving a few patients the drug. Finally, a large-scale multi-arm phase III randomized controlled trial (RCT) confirms the drug's efficacy by comparing outcomes in patients randomly chosen to receive the investigational drug or standard care. This evaluation process is very lengthy. Moreover, it is hard to ethically justify undertaking an RCT in which only some patients receive a potentially life-saving drug during an Ebola epidemic. Here, the researchers evaluate a multi-stage approach (MSA) to EVD drug evaluation that comprises a single-arm phase II study followed by one or two phase III trials, one of which may be a sequential RCT (SRCT), a type of RCT that allows for multiple interim analyses, each of which may lead to study termination.
What Did the Researchers Do and Find?
The researchers used analytic methods and computer simulations to compare EVD drug evaluation using the MSA, an SRCT, and a conventional RCT without interim analyses. Specifically, they estimated the probabilities of rightly or wrongly recommending the experimental treatment and the consequences for epidemic outcomes over 100 days for the three approaches. Assuming 50% survival at 14 days after symptom development in patients treated with supportive care only, all three trial designs were equally likely to identify effective treatments, but the MSA was less likely than the other designs to incorrectly recommend an ineffective treatment. Notably, the MSA led to fewer patients receiving ineffective treatments and faster roll-out of highly effective treatments. In an epidemic where 100 new cases occurred per day, for highly effective treatments, the MSA led to between 6% and 15% larger reductions in epidemic mortality over the first 100 days of the epidemic than the SRCT did. Finally, both the MSA and the SRCT led to fewer deaths than the conventional RCT if the tested interventions were either highly effective or harmful.
What Do These Findings Mean?
These findings suggest that for experimental treatments that offer either no clinically significant benefit or large reductions in mortality the MSA can provide useful information about drug effectiveness faster than the other approaches tested. Thus, the MSA has the potential to reduce patient harm and the time to roll-out of an effective treatment for EVD. Although alternative evaluation designs are possible, the researchers suggest that including a non-randomized design in phase II is the quickest way to triage potential treatments and to decide how to test them further. For treatments that show strong evidence of benefit, it might even be possible to recommend the treatment without undertaking an RCT, they suggest. Moreover, for treatments that show only modest benefit in phase II, it should be easier (and more ethical) to set up RCTs to test the treatment further.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001815.
The World Health Organization (WHO) provides information about EVD, information about potential EVD therapies, and regular updates on the current EVD epidemic; a summary of the discussion of a WHO Ethics Working Group Meeting on the ethical issues related to study design for EVD drug trials is available; the WHO website also provides information about efforts to control Ebola in the field and personal stories from people who have survived EVD
The UK National Health Service Choices website provides detailed information on EVD
The US Centers for Disease Control and Prevention also provides information about EVD
Wikipedia provides information about adaptive clinical trial design; a Lancet Global Health blog argues why adaptive trial designs should be used to evaluate drugs for the treatment of EVD
Citation: Cooper BS, Boni MF, Pan-ngum W, Day NPJ, Horby PW, Olliaro P, et al. (2015) Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease. PLoS Med 12(4): e1001815. https://doi.org/10.1371/journal.pmed.1001815
Academic Editor: Edward J. Mills, Stanford University, UNITED STATES
Received: December 3, 2014; Accepted: March 5, 2015; Published: April 14, 2015
Copyright: © 2015 Cooper et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: This is a simulation study so all data are synthetic. A link to the code used to generate these synthetic data is included in the supplementary (S1 Text).
Funding: The work was supported by the Wellcome Trust of Great Britain (grant number 106491/ Z/14/Z and 089275/Z/09/Z) and by the EU FP7 project PREPARE (602525). BSC was supported by The Medical Research Council and Department for International Development (grant number MR/K006924/1). MFB is supported by the Wellcome Trust (grant number 098511/Z/12/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: NJW is a member of the Editorial Board of PLOS Medicine. PO is a staff member of the World Health Organization (WHO); the authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy, or views of the WHO. The authors have declared that no other competing interests exist.
Abbreviations:: EVD, Ebola virus disease; MSA, multi-stage approach; RCT, randomised controlled trial; SRCT, sequential randomised controlled trial
The largest ever outbreak of Ebola virus disease (EVD) is ongoing in west Africa, killing up to 70% of those infected [1,2]. Whilst there is no available vaccine and no proven treatments specific to EVD, there are several investigational treatments that might reduce mortality [3]. How should they be evaluated? Evaluations of novel treatments for EVD can take place only during an epidemic, and they need to have a high probability of identifying treatments able to provide clinically significant benefits, and a low probability of recommending ineffective or harmful interventions. They should produce results rapidly, to ensure maximum benefit (or minimum harm), and they need to be practical, implementable, and acceptable to those delivering and receiving care under very challenging conditions. Randomised controlled trials (RCTs) are the most reliable route to definitive answers on therapeutic benefits and harms, but there has been considerable debate about whether they can meet these additional needs in this EVD epidemic [4–6]. While some have argued that no other design would give reliable answers [5], others have countered that practical and ethical considerations mean that alternative study designs must also be considered [4]. In particular, when conventional care is associated with a very high probability of death, it may not be socially, operationally, or ethically acceptable to assign patients randomly to conventional care versus an experimental treatment that has a possibility of substantially increasing survival. Moreover, for investigational treatments that have a possibility of being highly effective (or highly harmful), using single-arm studies and adaptive designs (where enrolment depends on emerging efficacy data) as part of the evaluation process can reach conclusions faster, preventing unnecessary deaths.
In practice, drug development programmes seldom comprise a single clinical trial. Usually a series of studies is involved, with phase I establishing the safety and pharmacokinetic properties of the treatment and phase II providing early indications of efficacy, which, if found, are then confirmed in large-scale phase III trials. Typically, evidence from two phase III trials, or from a large and relevant phase II trial and one phase III trial, are required for a new drug to be licensed. In this paper we evaluate a multi-stage approach (MSA) to drug evaluation, where the first stage is a single-arm uncontrolled phase II study, which may lead on to the conduct of either one or two subsequent phase III trials, one of which may be a sequential RCT (SRCT). The performance of the MSA and potential impact on the current EVD epidemic is compared with the use of an SRCT alone or the use of a conventional RCT.
Since most deaths from EVD occur within 14 d of admission to an Ebola treatment centre [1], all study designs we consider have survival to day 14 after randomisation (if performed) or admission to the treatment centre (otherwise) as the primary endpoint. Preliminary analysis of data from 1,820 adult patients with confirmed EVD and known disease outcome from four west African treatment centres shows that the proportion of patients surviving to 14 d lies consistently between 40% and 50% (personal communication Médecins Sans Frontières). Thus 50% is taken to be the 14-d survival for a new intervention to beat.
Three possible study designs were compared for evaluating novel EVD treatments where the primary outcome was 14-d post-enrolment survival (Fig 1). Design 1 is a conventional RCT with no interim analysis, powered to give a 90% chance of detecting an increase in 14-d survival from 50% to 66.7% with a two-sided 5% significance level. We include Design 1 here to establish a baseline performance against which other designs are to be compared. We do not consider it an option that should be considered seriously. In practice, no trial in EVD would be conducted without a series of interim analyses and a pre-defined stopping rule.
Fig 1. Three possible study designs.
Design 1 uses an RCT with a predetermined number of participants, so time to roll-out or rejection of the treatment is determined only by the rate of enrolment of patients into the study. In Design 2, an interim analysis is performed for each additional group of 25 patient outcomes (group SRCT). For Design 3, if the single-arm phase II study indicates a large beneficial effect (conclusion a), the treatment is rolled out, and a phase III single-arm confirmation study is performed. Roll-out continues if this confirmation study gives a positive result; otherwise, an SRCT is employed. In the event of evidence of a moderate effect from the phase II study (conclusion b), the SRCT is employed. The treatment is rejected in the event of no evidence of benefit in the phase II study or negative results from an SRCT. In Designs 2 and 3, the number of participants recruited depends on the outcomes for patients already enrolled, and the study duration is uncertain (as indicated by the colour gradient).
https://doi.org/10.1371/journal.pmed.1001815.g001
Design 2 is a group SRCT that is particularly well-suited to situations where investigators wish to identify effective treatments but do not need to distinguish between ineffective and harmful treatments. It is based on the triangular test [7,8], with up to 20 interim analyses occurring every time 25 new day-14 records are received (so that a maximum of 500 patients are enrolled). The trial terminates when it is clear either that the treatment is better than the control or that evidence of superiority will not be found. The design is asymmetric, with higher power to detect a beneficial effect than a comparable harmful effect. This is appropriate because it is less important to determine whether a treatment offering no benefit is ineffective or harmful; in either case it should be rejected. The trial benefits from this asymmetry by having an expected sample size that is considerably smaller than rival group sequential approaches, especially when the treatment is less effective than control. The design is powered to match that of the conventional RCT, and provides a 90% chance of detecting an increase in 14-d survival from 50% to 66.7% with a two-sided 5% significance level.
Design 3, the MSA, uses an initial phase II trial where all patients receive the treatment. The trial is monitored continuously, and each time a new 14-d outcome is received, a decision is made (based on all 14-d outcomes received) to do one of the following: stop and conclude that the treatment is very effective (conclusion a), stop and conclude that the treatment is promising (conclusion b), stop and conclude that the treatment is ineffective (conclusion c), or continue to enrol patients. The stopping rules ensure that conclusion a is reached with probability 0.900 if treated patients have a 14-d survival rate of 80.0%, conclusion b is reached with probability 0.950 if the survival rate is 66.7%, and conclusion c is reached with probability 0.900 if the survival rate is 50.0%. Note that the MSA does not assume knowledge of the true standard care survival rate: if no RCT is performed, this rate is not estimated. The method is similar to the sequential medical plans of Bross [9] and is related to the double triangular test [10].
In the event of conclusion a, the treatment is rolled out immediately and further evaluated through a phase III single-arm confirmatory study using a form of futility design [11]. This phase III study is also monitored continuously, with a stopping rule that ensures that the treatment is confirmed as very effective with probability 0.900 if the 14-d survival rate is 80%. If this phase III study fails to confirm the treatment's benefit, an SRCT is performed.
If conclusion b is reached in the phase II trial, the study proceeds directly to the phase III SRCT (Design 2). If conclusion c is reached, i.e., the SRCT or phase II single-arm trial provides no evidence of benefit, the treatment is rejected.
Full study details of all designs and stopping rules are provided in the section Study Protocol Details below.
For each of these three designs, for assumed survival rates in the treated population of between 10% and 90%, the following were determined: the probability of concluding that the treatment is effective, the sample size needed, the time to roll-out (if the treatment is not rejected), and the time to the final decision (assuming a capacity to enrol five patients in the study per day, based on assessment of potential study sites). The probability of concluding that the treatment is effective and the total sample size were computed for the different designs using methods that were either exact or provided very close approximations. Other quantities were determined by simulation. The potential impact of the three designs on mortality in the wider community amongst those with EVD onset in the 100 d following recruitment of the first patient was determined under two scenarios: one scenario assumed 100 new cases per day, and a more pessimistic scenario assumed an initial 200 cases per day, with a constant doubling period of 30 d. Treatment was assumed to be made available immediately to all new EVD cases after the roll-out time. Simulation results are based on 100,000 simulation runs for each value of the survival rate in the treated population. Simulations were performed using R [12]. Details are given in S1 Text.
Study Protocol Details
For every patient, death or survival is recorded 14 d after entry into the trial. Even if deaths are known about earlier, they are not counted in the primary analysis until day 14. This is because we cannot assess survival until day 14.
Design 1 is a conventional RCT with 1:1 randomisation and no interim analysis. When 14-d outcomes have been obtained from all patients (n = 360), analysis is performed using Pearson's chi-squared test without continuity correction.
Design 2, a group SRCT, is also used as part of Design 3 (Fig 2). In Design 2, up to 20 interim analyses of the data are conducted. At each interim analysis (performed every time that 25 new day-14 records are received), the statistics Z and V are calculated. These are of the form given in Chapter 3.2 of Whitehead [7]. If sample sizes in the experimental treatment and control groups are equal, Z is simply the number of successes in the experimental treatment group minus the number in the control group, divided by two. The value of V is proportional to the sample size. The trial is stopped with the conclusion that the experimental treatment is significantly better than control if Z ≥ 6.3990 + 0.2105V. The trial is stopped with the conclusion that the experimental treatment is not significantly better than control if Z ≤ −6.3990 + 0.6315V. Otherwise, the trial is continued until the next interim analysis. These stopping rules are illustrated in Fig 2C. The design is set to conclude wrongly that the experimental treatment is better than control with probability 0.025 if the experimental treatment is actually associated with the same 14-d survival rate as the control, and to conclude rightly that the experimental treatment is better than the control with probability 0.900 if the odds ratio for 14-d survival is two. Such an advantage occurs if the 14-d survival rates for the experimental treatment and control are 66.7% and 50.0%, respectively, or if they are 80.0% and 66.7%. The final total sample size when using this design is likely to be between 100 and 200. The method is based on Whitehead [7,8].
Fig 2. Stopping rules for the component trials of the multi-stage approach.
(A) The single-arm phase II design, (B) the phase III single-arm confirmatory design, and (C) the phase III SRCT.
Design 3, the MSA, has three component trials. The phase III SRCT is described above (Design 2). The phase II single-arm trial and the phase III single-arm confirmatory trial are described below.
For the phase II single-arm trial, all patients receive the experimental treatment, and a continuous record is maintained of the number of patients who have survived to day 14 (S) and the number of reports of day-14 status received (n). The record is used to determine when the trial should stop and what the conclusion should be, as follows:
Conclusion a: if n ≥ 24 and S ≥ 7.117 + 0.7034n, then the trial stops with the conclusion that the experimental treatment is very effective. This is likely to occur if around 80% of patients survive to day 14.
Conclusion b: if n ≥ 52 and either S ≤ −7.117 + 0.7970n or S ≥ 7.117 + 0.5164n, then the trial stops with the conclusion that the experimental treatment is promising. This is likely to occur if around 67% of patients survive to day 14.
Conclusion c: if n ≥ 12 and S ≤ −7.117 + 0.6099n, then the trial stops with the conclusion that the treatment does not appear to be promising. This is likely to occur if around 50% of patients survive to day 14.
These stopping rules are shown graphically in Fig 2A. This design was chosen as it ensures that (1) conclusion a is reached with probability 0.900 if the 14-d survival rate is truly equal to 80.0%, (2) conclusion b is reached with probability 0.950 if the rate is 66.7%, and (3) conclusion c is reached with probability 0.900 if the rate is 50.0%. The maximum sample size is 140 patients, and the trial is most likely to stop after between 50 and 100 day-14 records have been received.
The phase III single-arm confirmatory trial recruits a maximum of 132 patients, all receiving the experimental treatment. This trial is also monitored continuously, and stops to reject the experimental treatment early if it is ever observed that S ≤ −5.2425 + 0.7747n (Fig 2B). The criteria chosen ensure that the experimental treatment is correctly confirmed as very effective with a probability 0.900 if the 14-d survival rate is 80.0% and is wrongly confirmed as very effective with probability 0.025 if the rate is 66.7%. The method is based on the futility design of Whitehead and Matsushita [11].
The final analysis of the group SRCT that forms Design 2 and features as the third component of Design 3 is designed to avoid potential biases due to the use of the stopping rule [7,13]. The final analysis of the phase II single-arm component of Design 3 uses the stopping rule employed by Jovic and Whitehead [14], which is a generalisation of the better known exact approach of Clopper and Pearson [15].
An ethics statement was not required for this work.
Based on the assumption that a patient with EVD in west Africa has a 50% chance of surviving to day 14 with standard care alone, all three designs gave similar probabilities of identifying effective treatments correctly, and low probabilities of recommending those that were ineffective or harmful. The MSA was least likely to lead to the recommendation of ineffective treatments or of those conferring only a small benefit (Table 1; Fig 3A). This was also true if standard care day-14 survival was only 40% (S1 Fig).
Fig 3. Comparison of the three designs for evaluating treatments assuming 50% 14-d survival probability in the standard care group.
The designs compared are a conventional RCT without interim analysis (red), a group SRCT with interim analyses for every 25 patients with 14-d outcomes (green), and an MSA (blue). (A) Probability of concluding an experimental treatment is effective (defined as a treatment where the probability of surviving to day 14 is greater than 0.5). (B) Mean time to rolling out or discarding the treatment (solid and dotted lines) and associated 5th and 95th percentiles (shaded regions). In the MSA, a phase III single-arm confirmation study may be performed following roll-out. Time to reach a conclusion from this study is shown by the dashed line. (C) Probability that an RCT is performed in the MSA. (D) Mean number of deaths amongst patients enrolled for the three study designs. (E) Mean percentage reduction in mortality amongst EVD cases in the wider population over 100 d following the start of evaluation compared with no treatment scenarios. Results are shown for two scenarios: one scenario assumes 100 new cases per day (solid lines and filled circles), and the other assumes exponential epidemic growth (dashed lines and open circles). Treatment is assumed to be made available immediately to all new EVD cases after the roll-out time. (F) Mean number of patients starting treatment each day under the scenarios in (E) assuming that the experimental treatment increases 14-d survival probability to 80%.
Table 1. Probabilities of recommending treatment and mean sample size for the three different study designs for various combinations of survival rates.
https://doi.org/10.1371/journal.pmed.1001815.t001
If the true survival rate without the experimental treatment was better than anticipated (66.7% instead of 50%), then the probability of wrongly recommending an ineffective treatment was 0.025 in all three designs, while MSA had substantially greater power to recommend a treatment that increased survival to about 80% (Table 1; S2 Fig). The expected sample sizes using the MSA (including the patients recruited for the phase III single-arm confirmatory trial, if used) were considerably smaller than those required for the single-stage designs if the treatment was ineffective, although they could be larger in the case of effective treatments. However, sample sizes and times to reach a conclusion varied substantially (Fig 3B). A conventional RCT would require about 12 wk to recruit and follow up the required 360 participants. For the other two designs, expected study duration depended on treatment effectiveness, though in all cases the mean duration was substantially shorter than with the conventional RCT. For very effective or ineffective treatments, the MSA gave the most rapid time to roll-out or rejection, respectively (Fig 3B). For promising treatments, the phase II study in the MSA usually led to conclusion b, leading to an SRCT (Fig 3C). This resulted in longer times to reach a conclusion, and under these circumstances the SRCT typically had the shortest time to roll-out or rejection. Estimated numbers of deaths amongst those enrolled into the study were highest for the conventional RCT and lowest for the MSA for ineffective and very effective treatments (Fig 3D). For promising treatments, they were similar in the SRCT and the MSA.
The more rapidly an effective treatment can be rolled out to patients outside a study population, the greater the overall mortality reduction in an epidemic. As a consequence, because it takes longer to reach a conclusion, the conventional RCT compares poorly with the other designs for reducing total mortality (Fig 3E). For very effective treatments (where the probability of survival if treated is at least 80%), the potential for mortality reduction is substantial with the other two designs under both epidemic scenarios (Fig 3E). Under the scenario of 100 new cases per day, using the MSA led to a reduction in mortality for very effective treatments that was between 6% and 15% higher than that achieved by the SRCT; for a treatment conferring an 80% or 90% 14-d survival probability and 100% treatment take-up, this corresponds to an average of 124 and 434 additional deaths prevented over 100 d, respectively. The corresponding deaths prevented by using the MSA instead of a conventional RCT were 1,589 and 2,673. For less effective treatments, a greater mortality reduction could be achieved using the SRCT, owing to its faster rollout. For example, for a treatment conferring a 70% survival probability, compared to a 50% survival probability without the treatment, the mortality reduction achieved over 100 d was 10% with the MSA but 19% with the SRCT, corresponding to 515 fewer deaths. If a treatment is effective, then for the potential benefits of the MSA and SRCT to be realised, large numbers of treatment courses need to be made available early on (Fig 3F).
The evaluation of multiple experimental treatments in series or parallel was not considered in detail in this study, but suppose that treatments A, B, and D are tested one after the other (where treatment C is the control). Suppose further that the 14-d survival rates for treatments A, B, and D are 50.0%, 50.0%, and 80.0%, respectively, while the survival rate for the control is 50.0%. The MSA correctly recommends only treatment D with probability 0.996, after an expected sample size of 361. The SRCT recommends only treatment D with probability 0.951, after an expected sample size of 479.
While the three designs have similar power to detect effective EVD treatments if day-14 survival in the standard care population is 50%, their performances differ importantly in other respects. In particular, adaptive designs are likely to produce results faster than a conventional RCT, and if the treatment is ineffective or very effective, the MSA is likely to give the shortest time to rejection or roll-out, respectively. If day-14 survival in the standard care population is 66.7%, the MSA has the same probability of wrongly recommending ineffective treatments as the other two designs, but can have substantially greater power to detect effective treatments. For promising treatments (e.g., those that increase day-14 survival from 50.0% to 66.7%), the MSA has a high probability of including a randomised trial, though this comes at the cost of somewhat longer times to reach a conclusion than the SRCT.
Our analysis assumed equal rates of recruitment in all study designs. In practice, difficulties in recruiting patients into randomised trials might give the MSA a further advantage. For harmful treatments, the MSA minimises in-study deaths and wasted investigator effort. If a number of treatments are to be evaluated in sequence, the MSA could reduce substantially the time needed to find one that is effective. For beneficial treatments, the MSA allows faster roll-out to the wider population.
RCTs are usually the best method for evaluating interventions because, if conducted well, they minimise the potential for reaching incorrect conclusions by controlling for both known and unknown confounders. However, the current Ebola epidemic in west Africa is an unprecedented situation where there is substantial uncertainty that RCTs can be conducted successfully and safely [3]. RCTs have been conducted for diseases with high fatality (e.g., trauma), but never before in a setting where there are major safety concerns for healthcare workers (where every procedure involves a life-threatening risk), additional ethical dilemmas (such as the likelihood of having to randomise family members), and widespread mistrust amongst the community. Given these operational concerns and the results of our analysis, the MSA—which begins with a less operationally challenging design and yet retains the ability to provide robust and informative results—must be considered. Although the single-arm phases of the MSA are more vulnerable to spurious conclusions if the case fatality rate varies for reasons unrelated to the intervention, the risk of an incorrect conclusion depends on the true effect size. For larger effect sizes (whether harmful or beneficial), the risk is smaller. Indeed, decisions to discard or pursue interventions further with evidence of large harmful effects or large beneficial effects are often made without evidence from RCTs (e.g., in early evaluations of new drugs for treatment of cancers with poor prognosis).
In the proposed MSA, the major threats to the validity of the results of the non-randomised components are that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. However, the stopping rules applied in this analysis are likely to be robust to fluctuations in case fatality rate, since a 50% survival rate has been achieved with the current standard of care in west Africa, whereas an 80% survival rate has not been observed to our knowledge in any west African Ebola treatment centre. Our results also show that even if the baseline 14-d survival rate increases by more than 30% (to 66.7%), the MSA has only a 2.5% chance of recommending an ineffective treatment and a much greater chance of correctly recommending a treatment that increased the survival rate to 80%. An acknowledged weakness of the uncontrolled design is that adverse events are much harder to quantify without a concurrent control group. However, in the context of an illness with a fatality risk of 50% or greater and very limited possibilities to monitor adverse events, life-threatening adverse events are the most relevant safety measure, and these are captured with the fatality endpoint.
Many alternative designs are, of course, possible. For example, response adaptive designs aim to reduce the number of patients receiving ineffective treatment by putting more patients in the better treatment arm based on results accrued in the trial. However, such designs provide little further benefit when used in conjunction with sequential procedures. Moreover, when there is a substantial delay from treatment allocation to the primary response (as in our case), the scope for using emerging data in determining the treatment allocation of subsequent patients will be limited [16,17].
The MSA might lead to the identification of more than one promising treatment, or other trial groups might find such treatments. Then the SRCT component in the MSA could be replaced by a clinical comparison of more than one active treatment using a multi-arm multi-stage (MAMS) design [18]. Unless any of the new treatments have been found to be very effective (conclusion a in our scheme), a standard therapy arm should also be included.
Finally, it is conceivable that an intervention may improve 14-d mortality but worsen overall mortality. Whatever the study design, it will therefore be important to monitor 30-d mortality as a secondary outcome measure.
In summary, our results show that in the case of experimental treatments offering either no clinically significant benefit or large reductions in mortality, the MSA can reach a conclusion faster than the other approaches, minimising patient harm, wasted investigator effort, or time to roll-out. While some have objected to the use of evidence from studies where patients have not been randomised to interventions, we strongly believe the unrandomised design in phase II (as we propose) is appropriate. It is the quickest way to triage the treatments and decide how to test them further. The MSA does have the capacity to proceed to recommend an experimental treatment without the conduct of an RCT. However, this will happen only following strong and confirmed evidence of a success rate that is well in excess of that which has been observed with conventional treatment. For treatments with more modest benefits, an RCT will be needed as the second stage of the procedure. It is hoped that, having ruled out exceptional benefit, the barriers to randomisation might then be overcome more easily.
S1 Fig. Comparison of the three designs for evaluating treatments assuming a 40% 14-d survival probability in the standard care group.
https://doi.org/10.1371/journal.pmed.1001815.s001
(TIF)
S2 Fig. Comparison of the three designs for evaluating treatments assuming a 66.7% 14-d survival probability in the standard care group.
S1 Text. Simulation details.
Analyzed the data: BSC MFB WP NPJD PWH NJW LJW JW. Wrote the first draft of the manuscript: BSC. Wrote the paper: BSC MFB WP NPJD PWH PO TL NJW LJW JW. Conceived and designed the MSA and SRCT designs: JW. Conceived and designed simulation studies: BSC MFB WP NPJD PWH PO TL NJW LJW JW. Performed exact calculations to evaluate performance characteristics: JW. Performed simulation studies: BSC MFB WP LW. Contributed tools for exact analysis: JW. Contributed analysis tools for the simulation study: BSC WP LW MFB. Agree with manuscript results and conclusions: BSC MFB WP NPJD PWH PO TL NJW LJW JW. All authors have read, and agree that they meet, ICMJE criteria for authorship.
1. WHO Ebola Response Team (2014) Ebola virus disease in West Africa—the first 9 months of the epidemic and forward projections. N Engl J Med 371: 1481–1495. pmid:25244186
2. Farrar JJ, Piot P (2014) The Ebola emergency—immediate action, ongoing strategy. N Engl J Med 371: 1545–1546. pmid:25244185
3. Heymann DL (2014) Ebola: learn from the past. Nature 514: 299–300. pmid:25318509
4. Adebamowo C, Bah-Sow O, Binka F, Bruzzone R, Caplan A, et al. (2014) Randomised controlled trials for Ebola: practical and ethical issues. Lancet 384: 1423–1424. pmid:25390318
5. Joffe S (2014) Evaluating novel therapies during the Ebola epidemic. JAMA 312: 1299–1300. pmid:25211645
6. Rid A, Emanuel EJ (2014) Ethical considerations of experimental interventions in the Ebola outbreak. Lancet 384: 1896–1899. pmid:25155413
7. Whitehead J (1997) The design and analysis of sequential clinical trials, revised 2nd edition. Chichester: Wiley.
8. Whitehead J (2011) Group sequential trials revisited: simple implementation using SAS. Stat Methods Med Res 20: 635–656. pmid:20876163
9. Bross I (1952) Sequential medical plans. Biometrics 8: 188–205.
10. Whitehead J, Todd S (2004) The double triangular test in practice. Pharm Stat 3: 39–49.
11. Whitehead J, Matsushita T (2003) Stopping clinical trials because of treatment ineffectiveness: a comparison of a futility design with a method of stochastic curtailment. Stat Med 22: 677–687. pmid:12587099
12. R Core Team (2014) R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing.
13. Fairbanks K, Madsen R (1982) P values for tests using a repeated significance test design. Biometrika 69: 69–74.
14. Jovic G, Whitehead J (2010) An exact method for analysis following a two-stage phase II cancer clinical trial. Stat Med 29: 3118–3125. pmid:21170906
15. Clopper CJ, Pearson ES (1934) The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26: 404–413.
16. Rout CC, Rocke DA, Levin J, Gouws E, Reddy D (1993) A reevaluation of the role of crystalloid preload in the prevention of hypotension associated with spinal anesthesia for elective cesarean section. Anesthesiology 79: 262–269. pmid:8192733
17. Rosenberger WF, Stallard N, Ivanova A, Harper CN, Ricks ML (2001) Optimal adaptive designs for binary response trials. Biometrics 57: 909–913. pmid:11550944
18. Magirr D, Jaki T, Whitehead J (2012) A generalized Dunnett test for multiarm-multistage clinical studies with treatment selection. Biometrika 99:494–501.
Is the Subject Area "Death rates" applicable to this article?
Phase II clinical investigation
Is the Subject Area "Phase II clinical investigation" applicable to this article?
Is the Subject Area "Drug therapy" applicable to this article?
Phase III clinical investigation
Is the Subject Area "Phase III clinical investigation" applicable to this article?
Ebola hemorrhagic fever
Is the Subject Area "Ebola hemorrhagic fever" applicable to this article?
Phase I clinical investigation
Is the Subject Area "Phase I clinical investigation" applicable to this article?


text:
Kim Wilson , amerikai blueszenész: szájharmonikás, énekes.

Pályafutása

Detroitban született 1951-ben, de a kaliforniai Goletában nőtt fel. Itt ezért  Goletai Slimnek nevezték. Az 1960-as évek végén kezdett a blues-t játszani. Muddy Waters, Jimmy Rogers, Eddie Taylor, Albert Collins, George "Harmonica" Smith, Luther Tucker, Pee Wee Crayton, és Little Walter, James Cotton, Big Walter Horton, Slim Harpo, Lazy Lester voltak rá nagy hatással.

Mielőtt 1974-ben a texasi Austinba költözött volna, az Aces, Straights and Shuffles együttes vezetője volt a Minneapolisban. Austinban Jimmie Vaughan gitárossal megalakította a  The Fabulous Thunderbirds-t.

Különböző blues zenei fesztiválon és klubokban rengeteget lép fel a világ minden táján, mind a Fabulous Thunderbirds vezetőjeként, mind a Kim Wilson Blues Allstarssal.

Lemezei
Szólólemezek
 1993: Tigerman
 1994: That's Life
 1997: My Blues
 2001: Smokin' Joint
 2003: Looking for Trouble
 2006: My Blues Sessions: Kim's Mix, Volume I
 2017: Blues and Boogie, Vol. 1
 2020: Take Me Back – The Bigtone Sessions
→ Mint vendégzenész

Díjai, elismerései

2016-ban Wilson Blues Music Awardot kapott az "Instrumentalist, Harmonica" kategóriában.

Film

Sajátmagát alakította az 1989-es "Sleepwalk" című tévésorozat egyik epizódjában.

Jegyzetek

Források
 https://www.encyclopedia.com/education/news-wires-white-papers-and-books/wilson-kim
 https://www.hohner.de/en/kim-wilson
 https://www.discogs.com/es/artist/282127-Kim-Wilson
 https://www.bluesblastmagazine.com/kim-wilson-take-me-back-the-bigtone-sessions-album-review/

Amerikai dzsesszzenészek
1951-ben született személyek
Szájharmonikások
Élő személyek
Detroitiak

redpajama_set_name: RedPajamaWikipedia


text:
Home » IoT » Groundbreaking AI Center will Facilitate Smart City Development in Moscow
Groundbreaking AI Center will Facilitate Smart City Development in Moscow
March 12, 2020 DIT
A 'Center for the Fourth Industrial Revolution' is to be established in Russia, dedicated primarily to smart city developments across Moscow. The institute, which is a part of a global initiative by the World Economic Forum (WEF), is to be dedicated to the development of AI technology. Its establishment is currently under negotiated with the Russian government.
"This groundbreaking center in Russia will help to facilitate smart city developments across Moscow. AI is already crucial to the provision of many of the city's e-services. However, with a centralized learning center for the implementation of AI, we will be able to optimize these services with the end goal of improving urban living in the capital," said Eduard Lysenko, Head of the Department of Information Technology, Moscow.
Upon establishment, the center will work to develop proposals on the use of AI and the IoT to facilitate the collection and processing of big data and inform smart city development. In addition, the new institute will work on solving AI-related regulatory issues.
According to WEF, the center could also work on projects related to information politics and blockchain technology. By 2025, over 40 billion devices will be IoT ready. As such, the issues of intellectual property and personal data protection will become even more critical.
The center will operate on Sberbank's platform, the largest Russian transnational bank. In turn, Sberbank's senior executives will be educated on the advantages of AI in decision-making and the need for digital transformation.
Similar centers have been established in the USA, China, Canada and Japan. Their primary purpose is to provide means for cooperation, learning and exchange in the field of AI development. Creation of the center will furthermore enable Russia to achieve AI goals as set out in its National Development strategy for 2030.
The Department of Information Technologies of Moscow (DIT) has been rapidly developing and actively growing for the past 5 years. During these years we have created over a thousand systems and services and we are pursuing the target of launching around 300 new projects annually. Today, we are proud of having digitalized over 166 state services, this is obviously more than any other region of Russia. Moreover, within the last years we have created an outstanding number of 178 portals, including the official Mayor
and Government of Moscow web-site "mos.ru". Our systems cover over 60 industries and penetrate into each aspect of
Moscow citizens' everyday lives, our products and services include:
• Electronic queue for Civil registry office;
• Arrangement of remote medical appointments;
• Personal electronic medical records;
• Children assignment to kindergardens/schools/extracurricular activities;
• Providing schools with cutting edge technological equipment;
• Obtaining references, enquiries and services remotely;
• Numerous projects in housing and public amenities, starting from telemetrics and
• Energetics to the possibility of submitting water usage information.
Current structure of the Department distinguishes up to 30 unique products and programs, including medical and education systems informatization, creation of crowdsourcing platforms, development of various resources and portals for Moscow and its citizens. We are aimed at continuing the process of effective informatization of the city with an emphasis on innovation development and advanced technologies application.
For more information, visit: https://www.mos.ru/en/
Laird Releases New Bluetooth 5.1 Module
Laird announced the new BL653 embedded Bluetooth 5.1 module series which enables industrial OEMs to impleme...
Lanner Launches New Intelligent Edge Solutions
Lanner announced its dual wireless IoT gateway appliances and GPU powered Industrial Edge computers.
The Best Approaches to Automating IoT-Enabled HVAC System Testing
In order to ensure the overall system integrity of HVAC system, there are three different approaches to consider: 1. Functional Feature Validation 2. API Testing 3. Performance/Load Testing
IoT to Enable RTLS for Higher Productivity
Real-Time Locating Systems (RTLS) are used to identify and track the location of objects or people in real time, usually within a building or other contained area.
Maxim Integrated Announces Industry's Smallest Solar Harvesting Solution to Increase the Runtime of Wearable and IoT Applications
MAX20361 reduces solution size by at least 50 percent while also improving harvest efficiency.
Push Technology Expands Support for Open Protocols, Adds MQTT
Push Technology announced the expansion of its support for open protocols by adding the MQTT protocol that is used by IoT and mobile applications.
Sequans, e-peas Develop Joint Solution for Self-Powered Cellular IoT Connectivity
Sequans announced the demonstation of a joint solution that combines e-peas' AEM energy harvesting IC with Sequans' Monarch LTE-M/NB-IoT platform to provide a self-powered cellular IoT connectivity.
RT-Thread Studio IoT IDE v2.0 Offers a Host of New Features
New version of IoT IDE adds lots of features.
OmniVision Release OS04C10 Image Sensor
OmniVision announced the release of the OS04C10, a 2.0 micron pixel, 4 megapixel (MP) resolution image sensor for both IoT and home security cameras.
Embedded Executive: Alan Grau, VP of IoT, Embedded Solutions, Sectigo
Should you fear the quantum security apocalypse? Do you even know it is and what it means and how it can occur? If you have any doubt, I suggest you listen to this week's Embedded Executives podcast.
Product of the Week: MultiTech QuickStart AWS IoT Core for LoRaWAN®
Looking for a kit that lets you aggregate sensor data from the edge and visualize it in the cloud in minutes? Check out the MultiTech QuickStart AWS IoT Core for LoRaWAN® kit.
Kerlink Announces its LoRaWAN Gateways are Certified to Support AWS IoT Core
Kerlink announced that its LoRaWAN gateways are certified to support the new AWS IoT Core for LoRaWAN, a new feature from AWS.
Will 2021 finally bring together IT and OT?
It's hard to think about the convergence of IT and OT as a prediction for 2021 because the broader concept has been the topic of conversation for nearly 10 years.
Sectigo Releases Advancements for IoT Manager
Sectigo has released new advancements its IoT Manager, the company's IoT Security and Identity Management Platform.
Top 25 Innovators in 3D Printing for 2020
Ultimaker Releases Its 2020 Innovators List
The Future of Screens
At the end of 2019, Apple, Amazon, Google, and the Zigbee Alliance announced they were joining forces to develop and promote the adoption of a new IP-based connectivity standard for the smart home.

redpajama_set_name: RedPajamaCommonCrawl


text:
Xconomy Detroit Ann Arbor
As Drone Navigation Advances, SlantRange Focuses on Farm Analytics
Nobel Laureate, Professor of Biology, Caltech
Andy Liu
Co-Founder, BuddyTV
Detroit/Ann Arbor Home
Detroit/Ann Arbor Events
X Lists
Chinese Companies Flock to Metro Detroit in Search of Automotive Expertise
Sarah Schmid Stevenson
When Tianhai Electric North America won a $300,000 incentive from the Michigan Economic Growth Authority to establish a world headquarters in Orion Township this past May, it was the latest example of a Chinese automotive company choosing to locate operations in Southeast Michigan—and part of a growing trend that has the Detroit area playing an increasingly prominent role in the Chinese auto industry.
According to the Detroit Regional Chamber, at least 50 Chinese companies serving the auto industry have established new ventures in metro Detroit during the past decade—up from 5 in 2000. (See the list on the next page for some prominent players.) The companies range in size from a handful of employees to several hundred, but all are united in a common goal: to make better cars.
"China's auto industry is booming," said LianneYan, Executive Vice President of the Detroit Chinese Business Association. "But it's trying to raise the quality of the cars it produces. Detroit's strength is in auto parts and research and development, and that's why the companies come here."
Hong Su, Vice President of the Changan US Research and Development Center in Plymouth—which is wholly owned by Chongqing Changan Automobile, the first major Chinese automotive manufacturer to open a facility in the United States—said that Detroit is like no other place in the world in terms automotive know-how.
"Detroit has more than 100 years of design and development expertise, in addition to many experienced engineers and a whole spectrum of service providers, from tooling to testing to consulting firms," Su said. "The biggest plus to doing business in Southeast Michigan is its concentration of talent, resources and supplies."
Detroit's century-plus of experience is something the burgeoning Chinese auto industry needs, as it wasn't until 1956 that China's very first road vehicle rolled out of the Changchun No. 1 Automotive Works. In late 2000, the first car to be made … Next Page »
Single PageCurrently on Page: 1 2
MEDC Leader Details Michigan's Road to the Waymo AV Factory Deal
Plymouth Growth Partners Backs Fort Wayne's Allied Payment Network
Roundup: QL Demo Day, Millendo Therapeutics, Strata Oncology, More


text:
Quagga mussels are displacing zebra mussels in lakes
Spreading much farther, they could impact fish
By: Kevin Bunch | Roseville - Eastpointe Eastsider | Published April 12, 2016
Researcher Ashley Baldridge shows off the tripod and mesh cage used for quagga mussel growth experiments in Lake Michigan.
Photo provided by Ashley Baldridge
METRO DETROIT — Invasive quagga mussels are pushing out invasive zebra mussels from the Great Lakes, but researchers warn this is not necessarily a cause for celebration.
Ashley Baldridge, a research benthic ecologist with the National Oceanic and Atmospheric Administration said NOAA has been researching the mussel populations in Lake Michigan annually for two decades, and the other Great Lakes on a five-year rotating basis. They use a claw called a PONAR grab to pull up a section of mud from the lake bottom and then count and measure the mussels, she said.
This year, NOAA also has started using cages to measure mussel growth and what impact lake temperature and food conditions have on that rate, Baldridge said; between the two, they have found that zebra mussels invaded the lakes first, but after five to 10 years, their cousins started overtaking them.
"The quagga mussels came in and they have pushed out the zebra mussels," Baldridge said. "We don't see zebra mussels out in the lake anymore — they're only very close to the shore. And now, the quagga mussels are at 10 times higher density than the zebra mussels (have ever been).
"We've seen one invasive species overtake another invasive (species)," she added.
The researchers have realized that quagga mussels not only like deeper water than zebra mussels, they have been found as far as 100 meters deep in the lakes. In contrast, Baldridge said, zebra mussels do not go deeper than 50 meters. Since quagga mussels can get more widespread, they can have a more pronounced impact on the water column and the food chain there.
Baldridge said that this time of year there is usually a spring bloom of algae on the lakes, which creates food for zooplankton, which in turn creates food for fish. Since the water column is mixed up in the spring after the winter ice melts, mussels are able to feast on that bloom, leaving less food for other species.
For example, she said, the U.S. Geological Survey, which also surveys the lakes, has seen smaller alewife catches lately, which in turn should have an impact on the salmon that eat those smaller fish.
Mussel population control is still extremely limited, she added. While people have been able to control populations on water intake pipes and other pieces of infrastructure, the broader lakes are so large and deep that there is no effective chemical control or equipment at this time that could help manage them at a sustainable level. And while fish like round goby and whitefish will eat the mussels, it is not at a great enough rate to curtail the population.
Native bivalve species have already been severely depleted or rendered locally extinct due to the invasive zebra and quagga mussels, Baldridge said, and the native species were never as numerous as the invasive species are now.
Quagga and zebra mussels are partially blamed for the toxic algal blooms in Lake Erie, Sonia Joseph Joshi, a communications and outreach specialist with the Cooperative Institute for Limnology and Ecosystems Research with NOAA, told C&G Newspapers in February 2015.
She said their tendency to eat other, benign types of algae leaves a gap in the ecosystem that lets the toxic blue-green algae, known as microcystis, grow unimpeded.
"That's just allowing for the blue-green algae to grow more prolifically because they have no competitors," she said at the time.
The mussel growth experiment could help researchers understand how the quagga mussels mature over the course of a year and how quickly. She said the creatures' growth — particularly in deeper waters — is not as well-studied as zebra mussels, and is virtually unknown in the winter months.
The growth experiments should continue for a year, Baldridge said, at which point she hopes to set up cages in the other lakes to see if there are any differences in growth rates in other lakes.
"I'd be interested in doing these experiments in the other lakes so I can then compare how they're growing in Lake Huron, Lake Ontario, versus Lake Michigan," she said. "Every lake has a different personality and conditions, but they all have mussels."
'I can't think of a better community partner'
'Approving this shows we oppose any attempts to undermine our rights'
Experts want to raise awareness of human trafficking
Dinner dance to support student scholarships
Roseville receives 2019 financial report
Roseville approves redevelopment of Sacred Heart property


Across Switzerland, a substantial number of new mobile antennae may be added soon, reports NZZ in its Sunday edition. The construction of 5G networks may result in more antennae or more radiation, or both. According to Christian Grasser, CEO of the industry association Asut, around two thirds of the antennae do not have enough spare capacity, and especially in urban areas, 90 percent of their capacity is used. It thus approaches the strict non-ionising radiation limits valid in Switzerland and as a result, more antennae locations will be necessary to build 5G networks.


Did Neighbor Gary Make Up For Blowing Off John's Call Last Week?
Last week, Neighbor Gary totally blew off John's phone call when they scheduled and John was not happy. This week...are they happier? Is their BROmance off to a good start this week?


text:
You are here: Home / Articles / Davidson: all spin and theatricals?
Davidson: all spin and theatricals?
October 4, 2016 by James Mitchell Leave a Comment
For three decades, senior Tories in London were perplexed by political developments in Scotland.
As they saw it, the party's support receded as Scots embraced their policies. Scots bought their council houses but showed little gratitude to the party that had made this possible. Margaret Thatcher reflected that her legacy had been one of economic success but political failure.
The tables appear to have been turned. Tories in London look to Scotland and Ruth Davidson for inspiration. There has been no shortage of plaudits for Ruth Davidson following her performance in May's Holyrood election when the Tories overtook Labour as Scotland's second party and during the Brexit referendum when her debating prowess was on show in the BBC's 'Great Debate' at Wembley. The Scottish Tories are today more buoyant than at any time since 1979, even if much of the praise for Ruth Davidson's leadership may have been orchestrated and overtaking Labour owed most to the decline of Labour and playing down the Conservative brand.
Nonetheless, in May the Tories fought the most disciplined campaign witnessed in Scotland. Not even New Labour at its apogee managed to combine obeisance to the leader with an unrelenting focus on a simple message. Ruth Davidson, we were told repeatedly, would provide strong opposition to the SNP, independence and an independence referendum and Labour and the Liberal Democrats could not be trusted to do this. Party literature was repetitive – often almost identical leaflets posted in some areas on a daily basis in the final stages of the campaign.
Threatened union
Ironically, the Tories need the union to be under threat. Their current appeal is heavily dependent on the prospect of an independence referendum. Hence, Ruth Davidson and the Tories constantly raise the issue. They hope to force the electorate to make a choice between true blue Unionists and Scottish nationalists, removing the centre ground. They run the risk that if forced to choose many more voters might chose independence. It is a high risk strategy but the only one available to the Tories.
Labour and LibDem opponents stand on the outside of this polarized debate, excluded by erstwhile colleagues in Better Together. A generation ago, SNP activists dreamed of a scenario in which the SNP would replace Labour and confront a Tory Government in Westminster with little support in Scotland. Even then few in the SNP imagined that support for independence would be as high as it is today.
It is unclear where the Tories can pick up sufficient votes to close the massive gap with the SNP. Voters who switched to the SNP from Labour did so because they saw the SNP as a more effective vehicle for championing their values and views – central to which is opposing the Tories. These voters have not in essence so much altered their core beliefs. When the SNP falters and voters become disillusioned, Labour are more likely to be the beneficiary. But the polarized nature of the debate may make such a return less likely.
And, while the SNP Government does not have to look far for challenges ahead, this is even more true for the Scottish Tories. Ruth Davidson will have to confront the same painful problems her Labour opposite numbers faced. The Scottish Tories under Ruth Davidson look even more like a branch office than Labour ever did. She promised to draw a 'line in the sand' – no more devolution – when she stood as Scottish Tory leader but soon backed down when London insisted that more powers had to be granted to Holyrood. Similarly, vehement denunciation of Brexit before the EU referendum has melted away. Her record suggests that this lady is for turning.
Does Ruth speak for Scotland?
Claiming to have the ear of the Prime Minister is far from demonstrating that she speaks for Scotland especially when the Scottish Tories are out of step with Scottish public opinion. The Scottish electorate have fairly unambiguously decided who they want to speak for Scotland and it is not Ruth Davidson. Unless Ruth Davidson can demonstrate that she stands firmly with majority of Scots on a major issue, and is willing to challenge her party colleagues in London and win then she will face the inevitable accusation that she is London's poodle.
Ruth Davidson's response to the problem that Scottish Labour grappled with has been to fall into line with London. Picking fights with Boris Johnson, her mirror image as a celebrity politician in London, will be welcomed by the Prime Minister and leaves the impression that she is there to do Prime Minister's May's dirty work. She may well find she needs to adopt more than Murdo Fraser's idea of abandoning the Conservative label, which was done so effectively back in May, and create a truly independent Scottish Tory Party.
The emphasis today is on the leader. Though Ruth Davidson had fiercely opposed the idea of changing the party's name during the Tory leadership contest in 2011, she showed a remarkable willingness to ignore her own strictures in demoting the 'Conservative' brand in favour of Brand Ruth. The tight campaign message eschewed any ambition to govern and thus discouraged any unwelcome scrutiny of Tory policies. Her Labour opponents may have stood little chance of governing but at least presented themselves as an alternative party of government.
In the event, the Scottish Tories bask in the honeymoon of victory having achieved their goal. But Ruth Davidson's favourable popular standing as an effective leader of her party is not matched in her standing as a potential First Minister. Being top of a lower league does not equate with being near the top of the premier league. The Scottish Tories have not begun to play in the premier league and appear reluctant to take up promotion while insisting they will win the championship.
Scotland's second party?
The Tories first need to secure their position as Scotland's second party. This is far from secure at present. The electoral system worked for the Tories in May but Labour won more constituency votes and are not far behind on the list. Last year's UK election saw the electoral system cheat Labour of representation leaving it with a solitary Scottish MP on a par with the Tories but with 24.3% of the vote to the Tories 14.9%. The Scottish Tories can't play the 'strong opposition' card at the next UK general election.
Labour's base in local government looks likely to erode in next year's local elections and the Tories can hardly fall below the 13% of first preferences won in 2012 but closing the gap on Labour will prove difficult. Inexperienced Tory councillors may be returned across Scotland in reasonable numbers and may even play a part in administrations but that can be a very mixed blessing. There can be no certainty that the Scottish Tories will remain in second place at the next Holyrood elections. Having declared her desire to be First Minister, Ruth Davidson invites more scrutiny and a much more substantive policy programme.
The greatest danger facing the Scottish Tories may prove to be unrealistic expectations. The party is far from secure in its position as Scotland's second party and has a long way to go before it can claim to have even won over what many see as its 'natural level of support'. If Ruth Davidson's ambition to become First Minister is serious – and there remains a suspicion that politics is just another joust in a debating society for her – then she needs to develop skills beyond spin and political theatricals.
First published by the Academy of Government and reproduced with permission
Filed Under: Articles, Politics, UK Tagged With: Scottish Government, Scottish politics
About James Mitchell
Professor of Public Policy at Edinburgh University. Former member of the Christie Commission and now member of the 'Enabling group' advising Scottish Government and Convention of Scottish Local Authorities on the review of local governance.