Choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial - the development of the DELTA2 guidance.

BACKGROUND: A key step in the design of a randomised controlled trial is the estimation of the number of participants needed. The most common approach is to specify a target difference in the primary outcome between the randomised groups and then estimate the corresponding sample size. The sample size is chosen to provide reassurance that the trial will have high statistical power to detect the target difference at the planned statistical significance level. Alternative approaches are also available, though most still require specification of a target difference. The sample size has many implications for the conduct of the study, as well as incurring scientific and ethical aspects. Despite the critical role of the target difference for the primary outcome in the design of a randomised controlled trial (RCT), the manner in which it is determined has received little attention. This article reports the development of the DELTA2 guidance on the specification and reporting of the target difference for the primary outcome in a sample size calculation for a RCT. METHODS: The DELTA2 (Difference ELicitation in TriAls) project has five components comprising systematic literature reviews of recent methodological developments (stage 1) and existing funder guidance (stage 2), a Delphi study (stage 3), a 2-day consensus meeting bringing together researchers, funders and patient representatives (stage 4), and the preparation and dissemination of a guidance document (stage 5). RESULTS: The project started in April 2016. The literature search identified 28 articles of methodological developments relevant to a method for specifying a target difference. A Delphi study involving 69 participants, along with a 2-day consensus meeting were conducted. In addition, further engagement sessions were held at two international conferences. The main guidance text was finalised on April 18, 2018, after revision informed by feedback gathered from stages 2 and 3 and from funder representatives. DISCUSSION: The DELTA2 Delphi study identified a number of areas (such as practical recommendations and examples, greater coverage of different trial designs and statistical approaches) of particular interest amongst stakeholders which new guidance was desired to meet. New relevant references were identified by the review. Such findings influenced the scope, drafting and revision of the guidance. While not all suggestions could be accommodated, it is hoped that the process has led to a more useful and practical document.

Are recent statin recommendations to employ fixed doses and abandon targets effective for treatment of hypercholesterolaemia? Investigation based on number needed to treat.

BACKGROUND: Assessed by number needed to treat (NNT) to prevent one event, it was previously shown that for those at similar atherosclerotic cardiovascular disease (CVD) risk, the benefit accruing from treating people with higher cholesterol levels with statins is greater than for those with lower levels. METHOD: By estimating NNT from both the absolute atherosclerotic cardiovascular risk and the pre-treatment low density lipoprotein cholesterol (LDL-C) concentration, recent recommendations for fixed dose high and moderate intensity statin treatment in the primary and secondary prevention of CVD were compared with cholesterol-lowering therapy aimed at a target LDL-C. RESULTS: We report that the USA and UK recommendations to employ a fixed dose of atorvastatin 20 mg daily for primary prevention will produce good results in people with low cholesterol levels, but are a disadvantage for those with higher levels who benefit more from a therapeutic target and statin dose titration and, where necessary, adjunctive cholesterol-lowering therapy to achieve this target. The higher dose of atorvastatin 80 mg daily with no target recommended for secondary prevention is generally more effective than aiming for a LDL-C goal except in people with particularly high cholesterol. CONCLUSION: For optimum clinical effectiveness, initial LDL-C concentration must be considered in deciding whether a target will allow a greater decrease in LDL-C and thus a lower NNT than a fixed dose regimen. Individual variation in the LDL-C response to statins also makes post-treatment cholesterol measurement essential.

CHEMOPROPHYLAXIS TO CONTROL LEPROSY AND THE PERSPECTIVE OF ITS IMPLEMENTATION IN BRAZIL: A PRIMER FOR NON-EPIDEMIOLOGISTS / Quimioprofilaxia para prevenção de hanseníase e sua implantação no Brasil: uma explicação introdutória para não epidemiologistas

The occurrence of leprosy has decreased in the world but the perspective of its elimination has been questioned. A proposed control measure is the use of post-exposure chemoprophylaxis (PEP) among contacts, but there are still questions about its operational aspects. In this text we discuss the evidence available in literature, explain some concepts in epidemiology commonly used in the research on this topic, analyze the appropriateness of implementing PEP in the context of Brazil, and answer a set of key questions. We argue some points: (1) the number of contacts that need to receive PEP in order to prevent one additional case of disease is not easy to be generalized from the studies; (2) areas covered by the family health program are the priority settings where PEP could be implemented; (3) there is no need for a second dose; (4) risk for drug resistance seems to be very small; (5) the usefulness of a serological test to identify a higher risk group of individuals among contacts is questionable. Given that, we recommend that, if it is decided to start PEP in Brazil, it should start on a small scale and, as new evidence can be generated in terms of feasibility, sustainability and impact, it could move up a scale, or not, for a wider intervention.

A ocorrência de hanseníase tem diminuído no mundo apesar de que a perspectiva de sua eliminação tem sido questionada. Uma proposta para o controle da endemia é a quimioprofilaxia pós-exposição entre contatos (post-exposure chemoprophylaxis, PEP), embora ainda existam dúvidas quanto aos seus aspectos operacionais e generalização de resultados. Nesse texto nós discutimos as evidências disponíveis na literatura, explicamos alguns conceitos epidemiológicos comumente encontrados em pesquisa sobre PEP e a implantação da PEP no contexto brasileiro. Nós argumentamos que: (1) a estimativa em diferentes estudos do numero de contatos necessário para receber PEP para prevenir um novo caso de hanseníase (number needed to treat, NNT) não é facilmente generalizável; (2) áreas cobertas pelo programa de saúde da família são as áreas prioritárias onde PEP poderia ser implantado; (3) não existe necessidade de segunda dose da quimioprofilaxia; (4) o risco de resistência à droga usada na PEP parece ser muito pequeno; (5) questionamos a necessidade de teste sorológico para identificar indivíduos entre os contatos que tenham maior risco de doença. Nós opinamos que, se houver uma decisão para se iniciar PEP no Brasil, essa intervenção deveria ser iniciada em pequena escala e, à proporção que novas evidências são geradas sobre a factibilidade, sustentabilidade e impacto da intervenção, a intervenção com PEP poderia ou não ser usada em larga escala.

The numbers needed to treat and harm (NNT, NNH) statistics: what they tell us and what they do not.

Research papers and research summaries frequently present information in the form of derived statistics such as the number needed to treat (NNT) and the number needed to harm (NNH). These statistics are not always correctly understood by the reader. This article explains what NNT and NNH mean; presents a simple, nontechnical explanation for the calculation of the NNT; addresses the interpretation of the NNT; considers applications of the NNT; and discusses the limitations of this statistic. The NNH is also briefly considered.

CHEMOPROPHYLAXIS TO CONTROL LEPROSY AND THE PERSPECTIVE OF ITS IMPLEMENTATION IN BRAZIL: A PRIMER FOR NON-EPIDEMIOLOGISTS.

The occurrence of leprosy has decreased in the world but the perspective of its elimination has been questioned. A proposed control measure is the use of post-exposure chemoprophylaxis (PEP) among contacts, but there are still questions about its operational aspects. In this text we discuss the evidence available in literature, explain some concepts in epidemiology commonly used in the research on this topic, analyze the appropriateness of implementing PEP in the context of Brazil, and answer a set of key questions. We argue some points: (1) the number of contacts that need to receive PEP in order to prevent one additional case of disease is not easy to be generalized from the studies; (2) areas covered by the family health program are the priority settings where PEP could be implemented; (3) there is no need for a second dose; (4) risk for drug resistance seems to be very small; (5) the usefulness of a serological test to identify a higher risk group of individuals among contacts is questionable. Given that, we recommend that, if it is decided to start PEP in Brazil, it should start on a small scale and, as new evidence can be generated in terms of feasibility, sustainability and impact, it could move up a scale, or not, for a wider intervention.

Uses and misuses of statistics: the case of strontium ranelate and the number needed to treat.

In the last 15 years, several pharmacological agents for the prevention of fractures have been developed and commercialized. Most of them showed to be effective in reducing fracture risk. The enhanced availability of drugs to prevent fractures has generated a fierce competition among pharmaceutical companies to conquer a share of the potential market, often with claims of superiority of a drug over another without direct comparisons. The definitive way to compare different treatments would require randomized head to head trials. These trials are expensive, need large samples and are unlikely to be ever performed. Therefore, it has become a common practice to compare pharmacological agents through observational studies on administrative databases or by the indirect comparison of the results of individual randomised-controlled trials (RCT) and their meta-analyses. These studies may produce evidence of clinical value, complementary to that given by RCT. However, without a proper and complete analysis, they may result in a biased picture of effectiveness and be completely misleading. In this article, we critically disclose how such competition may produce biased and misleading picture of evidence, by reviewing the significance of the number needed to treat, absolute risk reduction and relative risk reduction in relation to vertebral fractures prevention with available drugs.