자연주의적 탐구조사(Naturalistic Inquiry)

Randomised controlled trials are widely accepted as the most reliable method of determining effectiveness, but most trials have evaluated the effects of a single intervention such as a drug. Recognition is increasing that other, non-pharmacological interventions should also be rigorously evaluated.1-3 This paper examines the design and execution of research required to address the additional problems resulting from evaluation of complex interventions—that is, those “made up of various interconnecting parts.”4 The issues dealt with are discussed in a longer Medical Research Council paper (www.mrc.ac.uk/complex_packages.html). We focus on randomised trials but believe that this approach could be adapted to other designs when they are more appropriate.

#### Summary points

Complex interventions are those that include several components

The evaluation of complex interventions is difficult because of problems of developing, identifying, documenting, and reproducing the intervention

A phased approach to the development and evaluation of complex interventions is proposed to help researchers define clearly where they are in the research process

Evaluation of complex interventions requires use of qualitative and quantitative evidence

There are specific difficulties in defining, developing, documenting, and reproducing complex interventions that are subject to more variation than a drug. A typical example would be the design of a trial to evaluate the benefits of specialist stroke units. Such a trial would have to consider the expertise of various health professionals as well as investigations, drugs, treatment guidelines, and arrangements for discharge and follow up. Stroke units may also vary in terms of organisation, management, and skill mix. The active components of the stroke unit may be difficult to specify, making it difficult to replicate the intervention. The box gives other examples of complex interventions.

#### Examples of complex interventions

Service delivery and organisation:

Stroke units

Hospital at home

Interventions directed at health professionals' behaviour:

Strategies for implementing guidelines

Computerised decision support

Community interventions:

Community …

https://www.bmj.com/content/bmj/321/7262/694.full.pdf

Framework for design and evaluation of complex interventions to improve health

The Consolidated Standards of Reporting Trials (CONSORT) statement was developed to improve the reporting of randomised controlled trials. It was initially published in 1996 and focused on the reporting of parallel group randomised controlled trials. The statement was revised in 2001, with a further update in 2010. A separate CONSORT statement for the reporting of abstracts was published in 2008. In earlier papers we considered the implications of the 2001 version of the CONSORT statement for the reporting of cluster randomised trial. In this paper we provide updated and extended guidance, based on the 2010 version of the CONSORT statement and the 2008 CONSORT statement for the reporting of abstracts.

https://www.bmj.com/content/bmj/345/bmj.e5661.full.pdf

CONSORT statement: extension to cluster randomised trials

Riedel DJ, Gonzalez-Cuyar LF, Zhao XF, Redfi eld RR, Gilliam BL. Plasmablastic lymphoma of the oral cavity: a rapidly progressive lymphoma associated with HIV infection. Lancet Infect Dis 2008; 8: 261–67. In this Grand Round, the references for the sentence “Occasionally, CD138-negative plasmablastic lymphoma cases (such as this case) have been reported” (page 265) should be 32, 34, and 38. Book Systematic reviews: CRD’s guidance for undertaking reviews in health care

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Systematic reviews: CRD's guidance for undertaking reviews in health care

CONTEXT
Despite increasing awareness about the potential impact of financial conflicts of interest on biomedical research, no comprehensive synthesis of the body of evidence relating to financial conflicts of interest has been performed.


OBJECTIVE
To review original, quantitative studies on the extent, impact, and management of financial conflicts of interest in biomedical research.


DATA SOURCES
Studies were identified by searching MEDLINE (January 1980-October 2002), the Web of Science citation database, references of articles, letters, commentaries, editorials, and books and by contacting experts.


STUDY SELECTION
All English-language studies containing original, quantitative data on financial relationships among industry, scientific investigators, and academic institutions were included. A total of 1664 citations were screened, 144 potentially eligible full articles were retrieved, and 37 studies met our inclusion criteria.


DATA EXTRACTION
One investigator (J.E.B.) extracted data from each of the 37 studies. The main outcomes were the prevalence of specific types of industry relationships, the relation between industry sponsorship and study outcome or investigator behavior, and the process for disclosure, review, and management of financial conflicts of interest.


DATA SYNTHESIS
Approximately one fourth of investigators have industry affiliations, and roughly two thirds of academic institutions hold equity in start-ups that sponsor research performed at the same institutions. Eight articles, which together evaluated 1140 original studies, assessed the relation between industry sponsorship and outcome in original research. Aggregating the results of these articles showed a statistically significant association between industry sponsorship and pro-industry conclusions (pooled Mantel-Haenszel odds ratio, 3.60; 95% confidence interval, 2.63-4.91). Industry sponsorship was also associated with restrictions on publication and data sharing. The approach to managing financial conflicts varied substantially across academic institutions and peer-reviewed journals.


CONCLUSIONS
Financial relationships among industry, scientific investigators, and academic institutions are widespread. Conflicts of interest arising from these ties can influence biomedical research in important ways.

/pdf/scope-and-impact-of-financial-conflicts-of-interest-in-277c0caiki.pdf

Scope and Impact of Financial Conflicts of Interest in Biomedical Research

Are randomized clinical trials good for us (in the short term)? Evidence for a "trial effect".

In most randomised controlled trials, individual patients are randomised to a treatment or control group, but sometimes this is undesirable or even impossible and groups (clusters) of people may be randomised instead. These are called cluster randomised controlled trials, and although they have been around for a long time, the need for them is likely to increase in line with growing concern to evaluate the delivery of health services, public education, and policy on social care.

### Summary points

Need for cluster trials will increase with concern over health service evaluation, but issues of ethics and guardianship must be addressed

In some cluster trials the intervention can be targeted at individuals (individual-cluster); where this would be too difficult or expensive the intervention is targeted at the whole group (cluster-cluster)

Autonomy is important in individual-cluster trials, while the utilitarian welfare of the cluster as a whole is of paramount importance in cluster-cluster trials

In individual-cluster trials the participants should give consent; cluster-cluster trials need procedural safeguards appropriate to the risks carried by the cluster intervention

Guardians should sign a consent form that sets out their duties before they volunteer a cluster for a trial

The ethical aspects of medical practice and medical research are most often discussed in the context of two main moral traditions—utilitarianism and Kantian ethics. Broadly speaking, utilitarianism is concerned with increasing social utility (value), which usually means that the individuals maximise their expected utility and so act in their own best interests. In the long run social utility will not be served by demanding that individuals be self sacrificing for the common good. This leads to matters of distributive justice whereby utility and disutility, benefits and costs, are distributed as fairly and evenly as possible across society. The Kantian tradition shows why we are duty bound to respect a person's …

https://www.bmj.com/content/bmj/318/7195/1407.full.pdf

Ethical issues in the design and conduct of cluster randomised controlled trials

Vascular adhesion protein-1 (VAP-1) is an amine oxidase and adhesion receptor that is expressed by endothelium in the human liver. The hepatic sinusoids are perfused by blood at low flow rates, and sinusoidal endothelium lacks selectin expression and has low levels of CD31, suggesting that VAP-1 may play a specific role in lymphocyte recruitment to the liver. In support of this we now report the constitutive expression of VAP-1 on human hepatic sinusoidal endothelial cells (HSEC) in vitro and demonstrate that VAP-1 supports adhesion and transmigration of lymphocytes across these cells under physiological shear stress. These are the first studies to report the function of VAP-1 on primary human endothelial cells. Under static conditions lymphocyte adhesion to unstimulated HSEC was dependent on VAP-1 and ICAM-2, whereas adhesion to TNF-α-stimulated HSEC was dependent on ICAM-1, VCAM-1, and VAP-1. Under conditions of flow, blocking VAP-1 reduced lymphocyte adhesion to TNF-α-treated HSEC by 50% and significantly reduced the proportion of adherent lymphocytes that transmigrated across cytokine or LPS-activated endothelium. In addition, inhibition of the amine oxidase activity of VAP-1 reduced both adhesion and transmigration of lymphocytes to a level similar to that seen with VAP-1 Ab. Thus, VAP-1 can support transendothelial migration as well as adhesion, and both functions are dependent on its enzymatic activity. In the absence of selectins and CD31, VAP-1 may play a specific role in lymphocyte recruitment via hepatic sinusoidal endothelium. Moreover, since VAP-1 is induced on nonhepatic endothelium in response to inflammation, its ability to support lymphocyte transendothelial migration may be an important systemic function of VAP-1.

https://www.journal-of-hepatology.eu/article/S0168-8278(01)81660-3/pdf

Vascular Adhesion Protein-1 Mediates Adhesion and Transmigration of Lymphocytes on Human Hepatic Endothelial Cells

OBJECTIVE: To review the literature on the role of oral sex in the transmission of viral sexually transmitted infections (STIs). METHOD: A Medline search was performed using the keywords oro-genital sex, and those specific to each infection. Further references from each article identified by Medline were also included, as were relevant references from "Current contents". CONCLUSIONS: Oral sex is a common sexual practice among both heterosexual and homosexual couples. The evidence suggests that HIV transmission can take place through oro-genital sex from penis to mouth and vagina to mouth. Case reports describe apparent transmission from mouth to penis although this appears less likely. The risk of oro-genital transmission of HIV is substantially less than from vaginal and anal intercourse. Receptive oro-genital sex carries a small risk of human papillomavirus infection and possibly hepatitis C, while insertive oro-genital contact is an important risk factor for acquisition of HSV 1. Oro-anal transmission can occur with hepatitis A and B. The transmission of other viruses may occur but is unproved. The relative importance of oral sex as a route for the transmission of viruses is likely to increase as other, higher risk sexual practices are avoided for fear of acquiring HIV infection.

https://sti.bmj.com/content/sextrans/74/1/6.full.pdf

Oral sex and the transmission of viral STIs

ion of results and quality assessment for all studies were carried out independently by SE and JH. Quality assessment was difficult, in many cases, because insufficient information was given by the authors. The dimensions of methodological rigor used are listed in Table 11; we had originally planned a more comprehensive review of methodological issues, but found that some items had to be dropped as they were seldom mentioned by authors, while others failed to gain acceptance from the collaborative group set up to discuss the methods and progress of the review at two intervals during the project, (a list of group members is given in appendix 2). Any disparity in the findings of SE and JH was recorded and resolved by group discussion. Health Technology Assessment 1998; Vol. 2: No. 15 11 Degrees of uncertainty and the ethics of RCTs Obligations to society of physicians and ethics committees Societal benefits The epistemological argument for RCTs. Fortyone articles sought to defend the RCT by using an epistemological argument: a well-designed and conducted RCT is the most reliable method of obtaining epidemiological data and, because valid evidence is needed to inform widespread practice, the RCT can be justified on utilitarian grounds (Baum, 1983; Byar, 1979; Byar, et al., 1976; Cavan, 1981; Chalmers and Chalmers, 1994; Chalmers et al., 1972; Cowan, 1981; Editorial, 1992; Eichler, 1995; Engelhardt, 1988; Ernst and Resch, 1996; Gilbert et al., 1977; Gillon, 1994; Fox, 1960; Haines, 1979; Harrison, 1986; Hill, 1958, 1963; Kardinal, 1994; Lasagna, 1970; Marquis, 1983; Mike, 1988, 1989a, 1993; Miller, 1985, 1993; MRC, 1991; Passamani, 1991; Raju, 1992; Roy, 1986a; Russell, 1989; Schafer, 1982; Shaw and Chalmers, 1970; Silverman, 1985; Smith et al., 1993; Stephenson, 1996; Sutton-Tyrrell et al., 1991; Tukey, 1977; Uberla, 1981; Visscher, 1970; Zelen, 1979). One of the references placed the professional duty not to harm above that to benefit, and so distinguished between the need for scientific evidence to benefit society (collective beneficence) and to prevent possible harm from unproven therapies (collective non-maleficence), claiming that an epistemological argument for RCTs supports the latter, not the former goal (Mike, 1989a). Three of the 41 references stated simply that utilitarian justification is not sufficient; that is, societal benefit is necessary but insufficient to justify the RCT (Fox, 1960; Roy, 1986b; Marquis, 1983). However, they did not take the argument further. Two additional articles attempted to show that the RCT was not the most scientifically reliable method after all, and argued that the randomisation process does not eliminate systematic error as is commonly assumed (Taves, 1974; Urbach, 1993). Taves (1974) proposed a refinement, called ‘minimisation’, to the randomisation process, which matches study and control groups for known confounding variables, thereby reducing bias more effectively. The smaller the study, the more likely a confounding variable is to distribute itself unequally, and the greater the argument for ‘minimisation’ (see ‘under-powered’ studies, on page 12). However, ‘minimisation’ does not tackle the problem of unknown confounders linked to different clinicians or patient variables which are not or cannot be enumerated but which never-theless impact on the clinician’s psyche and skew allocation. Burkhardt and Kienle (1983) further pointed out that the RCT is inevitably flawed in that the sample is inevitably unrepresentative of the population. However, this could be said of any alternative research method and, while randomisation is not a perfect solution, it is perhaps the least bad scientific option for evaluations (Uberla, 1981). When second best is best. Ninety-nine articles recognised that a well-designed and conducted RCT is good science, but observed that good science is not necessarily good ethics and/or pointed out problems with RCTs in particular disciplines or situations (Abraham, 1941; Altman, 1980, 1983; Ambroz, 1978; Anderson, 1980; Angell, 1984; Anonymous, 1979; Baum, 1995; Beauchamp and Childress, 1989; Berkowitz, 1995; Bleich, 1995; Block and Elahoff, 1979; Bonchek, 1979; Burkhardt and Kienle, 1978, 1983; Buyse, 1991; Byer, 1983; Canner, 1970; Caplan, 1984; Cassel, 1985; Challah and Mays, 1986; Cornfield, 1966; Cutler et al., 1966; Day, 1969; De Deyn, 1995; Donner, 1977; Dudley, 1983, 1986; Elander and Hermon, 1995; Ernst and Resch, 1996; Feinstein, 1973; Feenberg, 1992; Fleming, 1982; Fried, 1974; Freireich and Gehan, 1979; Freund, 1970; Ganz, 1989, 1990; Gehan and Freireich, 1974; Giertz, 1980; Gifford, 1986, 1995; Gilbert, 1995; Glasziou, 1995; Gross, 1993; Grunkemeier and Starr, 1992; Hellman, 1979; Hellman and Hellman, 1991; Henry and Hill, 1995; Hilden et al., 1987; Hilden and Habbema, 1990; Kadane, 1986; Kassirer, 1983; Kardinal, 1994; Katz, 1993; Kaufman, 1993; Kleijnen et al., in press; RJ Levine, 1991; Levine and Lebacqz, 1979; Lockwood and Anscombe, 1983; Love, 1975; Lurie, 1994; Mackillop, 1986; McPherson, 1994; Marquis, 1983; Minogue et al., 1995; Morris and Brown, 1995; Neuebauer et al., 1991; Nicholson, 1986; Palmer, 1995; Passamani, 1991; Pollock, 1989; Pringle and Chapter 4

Sarah J L Edwards

Papers

Are randomized clinical trials good for us (in the short term)? Evidence for a "trial effect".

Ethical issues in the design and conduct of cluster randomised controlled trials

Vascular Adhesion Protein-1 Mediates Adhesion and Transmigration of Lymphocytes on Human Hepatic Endothelial Cells

Oral sex and the transmission of viral STIs

Ethical issues in the design and conduct of randomised controlled trials.