A systematic review of sham acupuncture validation studies.

BACKGROUND: Acupuncture is widely used worldwide; however, studies on its effectiveness have been impeded by limitations regarding the design of appropriate control groups. In clinical research, noninvasive sham acupuncture techniques can only be applied through validation studies. Therefore, this systematic review aimed to evaluate the scope of existing literature on this topic to identify trends. METHODS: We queried Pubmed, EMBASE, and the Cochrane Central Register of Controlled Trials databases from inception to July 2022 for relevant articles. Author names were used to identify additional relevant articles. Two independent reviewers assessed the identified articles based on the inclusion and exclusion criteria. The following data were extracted: study design, information regarding acupuncturists and participants, general and treatment-related characteristics of the intervention and control groups, participants' experience of acupuncture, and research findings. RESULTS: The database query yielded 673 articles, of which 29 articles were included in the final review. Among these, 18 involved the use of one of three devices: Streitberger (n = 5), Park (n = 7), and Takakura (n = 6) devices. The remaining 11 studies used other devices, including self-developed needles. All the included studies were randomized controlled trials. The methodological details of the included studies were heterogeneous with respect to outcomes assessed, blinding, and results. CONCLUSIONS: Sham acupuncture validation studies have been conducted using healthy volunteers, with a focus on blind review and technological developments in sham acupuncture devices. However, theren may be language bias in our findings since we could not query Chinese and Japanese databases due to language barriers. There is a need for more efforts toward establishing control groups suitable for various acupuncture therapy interventions. Moreover, there is a need for more rigorous sham acupuncture validation studies, which could lead to higher-quality clinical studies.

Active Placebo, the Parachute Meta-Analysis, the Nobel Prize, and the Efficacy of Electroconvulsive Therapy.

The efficacy of electroconvulsive therapy (ECT) has been recently questioned on the grounds that placebo-controlled (sham ECT) trials are all old and of poor quality; statements have been made that the prescription of ECT should immediately be suspended because its continued use cannot be scientifically justified. These criticisms have come from academicians and have been presented in scientific and news forums with wide readership. A rebuttal is therefore necessary, if only to counter the formation of negative attitudes among patients, health care professionals, and the general public. The quality of sham ECT randomized controlled trials (RCTs) is undoubtedly poor; however, this is so because these RCTs were conducted in an era in which such methodology was par for the field. What critics of ECT have not considered are the large, well-designed, well-conducted, and well-analyzed modern era RCTs that show that bilateral and high dose right unilateral ECT are more effective than low dose right unilateral ECT, or that brief-pulse ECT is more effective than ultrabrief-pulse ECT; in such situations, the inferior form of ECT may be regarded as an active placebo comparison group that represents a scientifically valid substitute for sham ECT. Critics of ECT also do not consider the parachute meta-analysis analogy; just as one does not need a meta-analysis of RCTs to conclude that parachutes work, so too one does not need a meta-analysis of new sham ECT RCTs to conclude that ECT works. ECT is usually recommended to patients who are catatonic, severely ill, or treatment-refractory, and if ECT did not work well in these patients, common sense tells us that it would not continue to be used for such patients more than 80 years after its introduction. Malaria therapy and leucotomy are somatic therapies that were honored with the Nobel Prize, but it is ECT that has survived.

Ethical limits to placebo use and access to Covid-19 vaccines as a human right.

The world is currently facing another severe pandemic, Covid-19, just four decades after the start of AIDS, and the still increasing incidence of HIV infection continues to be one of the greatest global health challenges. The way the latter was confronted is of fundamental importance for a serious discussion on global health, ethics and human rights, and this experience could and can still be applied to Covid-19. The Covid-19 pandemic has specific characteristics and these will be discussed, in relation to vaccine research and especially to the global right to equal access to products proven to be safe and effective. The article focusses primarily on issues related to Covid-19 vaccines, especially the appropriate use and limits on placebo, the right to post-trial access to placebo arm participants, and the use of an active control for subsequent Phase-3 trials after the approval of other safe and efficacious vaccines. Most importantly, it will emphasise that access to Covid-19 vaccines is a human right, which presupposes the establishment of appropriate ethical standards to ensure universal, equal, and affordable access to healthcare and to vaccines for all, and the imperative need for suspension of patents for products developed for Covid-19. It will consider the role of social determinants that contribute to the severity of Covid-19 and that must be addressed to effectively curb the current syndemic.

Covid-19, the WHO, and the apparent collapse of traditional medical research ethics.

On January 14, 2021, a WHO Ad Hoc expert group published an article in the highly influential The New England Journal of Medicine, titled: "Placebo-Controlled Trials of Covid-19 Vaccines - Why We Still Need Them" justifying the use of placebo in further trials of Covid-19 vaccines, even after purported efficacious vaccines have become available. Medical research involving human beings ought to conform strictly to principles, rules and procedures established since the Nuremberg Code (1947), especially as elaborated in the Declaration of Helsinki (2013) and the WHO/CIOMS Guidelines (2016). The NEJM article forms part of an observable trend of moral backsliding that needs to be recorded. In this paper, considering traditional medical research ethics under the impact of the Covid-19 pandemic and its ramifications and effects, and with a particular focus on the highly vulnerable populations and countries of sub-Saharan Africa, I make some relevant remarks. My arguments here are anchored in my observations as a moral philosopher though limited by my lack of expertise in any of the branches of medical science.

Placebo control in Covid-19 trials: A missed opportunity for international guidance.

Vaccines preventing Covid-19 have been approved in several countries. Is it still ethically acceptable to use placebo controls during the development of other vaccine options? If two of the most influential international guidelines of biomedical research are consulted, the Declaration of Helsinki and the CIOMS-guidelines, the answer is "no". We discuss the implications for ongoing vaccine research, and how placebo controls might be justified nevertheless. However, the ethical conflict remains highly problematic. We suggest that such ethical dilemmas should be avoided in the future by the introduction of a new system of global governance. Once vaccines are approved, a global regulation should oblige producers to provide the necessary amount of vaccine doses for the control groups of ongoing vaccine research.

Placebo in new Covid-19 vaccine trials: data quality prioritised over participants' rights.

The WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation makes recommendations on the use of placebo controlled trials in ongoing and future Covid-19 vaccine research. These recommendations unequivocally prioritise data quality over participants' rights and safety. Participants in trials of vaccines which have received emergency use listing or authorisation would be refused available vaccines. Placebo-controlled trials that would be impossible to conduct in rich countries would be permitted in poor countries. If these suggestions are implemented, the major beneficiary will be the vaccine industry.

The continued use of placebo arms in COVID-19 vaccine trials does not adequately protect the well-being of participants.

Covid-19 vaccines are a critical tool for controlling the pandemic. While safe and effective vaccines have been developed, research is expected to continue for many years regarding the optimal implementation of existing vaccines in specific settings, and the development of second-generation vaccines that may offer advantages in terms of either efficacy or ease of implementation. Given this context, some commentators have argued that new Covid vaccine trials should be able to use placebo controls, and that existing studies should be able to continue with blinded participants in order to collect high quality, unbiased data. Using international ethics guidance documents, this paper argues against placebo controls, given the existence of proven effective interventions, and against protracted blinding once safety and efficacy milestones have been met. Instead, it advocates for study designs that allow for direct comparison between approved and experimental vaccines, which facilitates both data collection and greater access to vaccines.

Trials for second generation Covid-19 vaccines: Revisiting the debate over placebo use in developing country clinical trials.

This article compares the current debate over the use of placebos in developing country clinical trials of second generation Covid-19 vaccines with the debates over previous paradigmatic cases raising similar issues. Compared to the earlier zidovudine and Surfaxin trials, Covid-19 vaccine trials are likely to confer lower risk to placebo groups and to offer a greater number and variety of alternative study designs. However, turning to the developing world to conduct studies that would be unacceptable in developed countries, simply on the ground that Covid-19 vaccines are generally unavailable in developing countries, is not ethically justifiable. This is so whether the justification is rooted in total absence of vaccine in a given country or in developing country vaccine prioritisation practices, because at root both derive from economic, not scientific conditions. However, the advent of variants that may create genuine uncertainty as to comparator vaccine effectiveness could justify a placebo control, depending on vaccine characteristics, variant prevalence, the degree of variant resistance, and the acceptability of immune-bridging studies. These factors must be considered together in the necessary case-by-case assessment of the ethical justification for any proposed trial.

Problematic Covid-19 vaccine trials in times of vaccine nationalism.

Thanks to an impressive R&D effort, three vaccines for Covid-19 have been conditionally approved by stringent regulators as of February 2021, and sixteen have entered the WHO evaluation process. However, they all need to keep on being evaluated in clinical trials. The WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine suggested that countries with limited or no access to an effective vaccine could ethically permit placebo-controlled trials, even if effective vaccines were already being marketed elsewhere. Here, I argue that inclusion in a placebo-controlled trial is ethically sound for those who would be in any case ineligible for vaccination outside the trial, and as long as the access to the vaccine outside the trial depends on a transparent and just allocation framework. Conversely, carrying out placebo-controlled studies in countries where vaccines are not (or are insufficiently) available because of unequal global allocation, would be unethical, as an ethical strategy cannot be built on an unethical premise.

Testing vaccines in the time of Covid: The changing landscape.

The initial trials of SARS-CoV-2 vaccines were randomised control trials (RCT) with a placebo as control. The use of a placebo was ethically justified because, as with any new and emerging infectious disease, there was no known vaccine. There are now at least eight vaccines that have been shown to be effective and approved for emergency use, so the use of a placebo in the control group is no longer ethically justified. This article discusses why ethical guidelines should be continually evaluated in a changing landscape and why trust is so important.

Placebo-controlled trials of Covid-19 vaccines - Are they still ethical?

A World Health Organization (WHO) Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation recently recommended placebo-controlled trials (PCT) of Covid-19 vaccines. PCTs are ethically acceptable when there is no proven effective and safe treatment for a certain condition. However, there are already some vaccines that have been approved and which have high levels of efficacy and safety. Any new vaccine under development must be tested against the most effective vaccines available. PCTs go against the participants' best interests, by putting them in a position of disadvantage while taking part in a trial, compared with people who are not in the trial and who could get vaccinated. Particularly in high-income countries, many people are getting vaccinated. This means that, following a recent trend in clinical trials, PCTs would have to be conducted in low- and middle-income countries, where there a number of advantages for drug companies, but where fatality rates of Covid-19 are, in many cases, much higher. For this and other reasons having to do with equal rights, participants in control groups should be protected with the most effective vaccines available.

"No" to placebo-controlled trials of Covid-19 vaccines.

Recently the WHO Ad Hoc Expert Group proposed that it is ethical to continue placebo-controlled Covid-19 vaccine trials in countries where vaccines are not available even if this vaccine is marketed and being used elsewhere. The reason for this proposal is the usual scientific argument claiming that these trials are the most efficient method to obtain reliable results, and individuals in these countries will continue to get the local standard of care, meaning no vaccination, and thus participants are not being left worse off. We refute this argument on two counts. First the global equity and justice issue, that the scarcity of vaccines in most countries is created by the rich nations that have hoarded vaccines. Second, the science versus research ethics issue, that there are valid scientific methods like non-inferiority trials which can give reliable results, and that applying a standard of care imposed by rich nations is both unethical and possibly exploitative. Thus, we feel that the WHO Ad Hoc Expert Group is wrong in proposing to continue placebo-controlled Covid-19 vaccine trials.

Effect of Osteopathic Manipulative Treatment vs Sham Treatment on Activity Limitations in Patients With Nonspecific Subacute and Chronic Low Back Pain: A Randomized Clinical Trial.

Importance: Osteopathic manipulative treatment (OMT) is frequently offered to people with nonspecific low back pain (LBP) but never compared with sham OMT for reducing LBP-specific activity limitations. Objective: To compare the efficacy of standard OMT vs sham OMT for reducing LBP-specific activity limitations at 3 months in persons with nonspecific subacute or chronic LBP. Design, Setting, and Participants: This prospective, parallel-group, single-blind, single-center, sham-controlled randomized clinical trial recruited participants with nonspecific subacute or chronic LBP from a tertiary care center in France starting February 17, 2014, with follow-up completed on October 23, 2017. Participants were randomly allocated to interventions in a 1:1 ratio. Data were analyzed from March 22, 2018, to December 5, 2018. Interventions: Six sessions (1 every 2 weeks) of standard OMT or sham OMT delivered by nonphysician, nonphysiotherapist osteopathic practitioners. Main Outcomes and Measures: The primary end point was mean reduction in LBP-specific activity limitations at 3 months as measured by the self-administered Quebec Back Pain Disability Index (score range, 0-100). Secondary outcomes were mean reduction in LBP-specific activity limitations; mean changes in pain and health-related quality of life; number and duration of sick leaves, as well as number of LBP episodes at 12 months; and consumption of analgesics and nonsteroidal anti-inflammatory drugs at 3 and 12 months. Adverse events were self-reported at 3, 6, and 12 months. Results: Overall, 200 participants were randomly allocated to standard OMT and 200 to sham OMT, with 197 analyzed in each group; the median (range) age at inclusion was 49.8 (40.7-55.8) years, 235 of 394 (59.6%) participants were women, and 359 of 393 (91.3%) were currently working. The mean (SD) duration of the current LBP episode was 7.5 (14.2) months. Overall, 164 (83.2%) patients in the standard OMT group and 159 (80.7%) patients in the sham OMT group had the primary outcome data available at 3 months. The mean (SD) Quebec Back Pain Disability Index scores for the standard OMT group were 31.5 (14.1) at baseline and 25.3 (15.3) at 3 months, and in the sham OMT group were 27.2 (14.8) at baseline and 26.1 (15.1) at 3 months. The mean reduction in LBP-specific activity limitations at 3 months was -4.7 (95% CI, -6.6 to -2.8) and -1.3 (95% CI, -3.3 to 0.6) for the standard OMT and sham OMT groups, respectively (mean difference, -3.4; 95% CI, -6.0 to -0.7; P = .01). At 12 months, the mean difference in mean reduction in LBP-specific activity limitations was -4.3 (95% CI, -7.6 to -1.0; P = .01), and at 3 and 12 months, the mean difference in mean reduction in pain was -1.0 (95% CI, -5.5 to 3.5; P = .66) and -2.0 (95% CI, -7.2 to 3.3; P = .47), respectively. There were no statistically significant differences in other secondary outcomes. Four and 8 serious adverse events were self-reported in the standard OMT and sham OMT groups, respectively, though none was considered related to OMT. Conclusions and Relevance: In this randomized clinical trial of patients with nonspecific subacute or chronic LBP, standard OMT had a small effect on LBP-specific activity limitations vs sham OMT. However, the clinical relevance of this effect is questionable. Trial Registration: ClinicalTrials.gov Identifier: NCT02034864.

Effect of Electroacupuncture vs Sham Treatment on Change in Pain Severity Among Adults With Chronic Low Back Pain: A Randomized Clinical Trial.

Importance: Chronic low back pain has high societal and personal impact but remains challenging to treat. Electroacupuncture has demonstrated superior analgesia compared with placebo in animal studies but has not been extensively studied in human chronic pain conditions. Objective: To evaluate the treatment effect of real electroacupuncture vs placebo in pain and disability among adults with chronic low back pain and to explore psychophysical, affective, and demographic factors associated with response to electroacupuncture vs placebo in treating chronic low back pain. Design, Setting, and Participants: This double-blind randomized clinical trial was conducted between August 2, 2016, and December 18, 2018, at a single center in Stanford, California. Primary outcomes were collected at approximately 2 weeks before and after intervention. Participants included English-speaking adults with at least 6 months of chronic low back pain, pain intensity of at least 4 on a scale of 0 to 10, and no radiculopathy. Data analyses for this intent-to-treat study were conducted from June 2019 to June 2020. Interventions: Twelve sessions of real or placebo (sham) electroacupuncture administered twice a week over 6 weeks. Main Outcomes and Measures: The main outcome was change in pain severity from baseline to 2 weeks after completion of treatment, measured by the National Institutes of Health PROMIS pain intensity scale. A secondary outcome was change in the Roland Morris Disability Questionnaire (RMDQ). Baseline factors potentially associated with these outcomes included psychophysical testing (ie, thermal temporal summation, conditioned pain modulation, pressure pain threshold), participant's self-report (ie, widespread pain, coping strategies, expectations, self-efficacy, and pain catastrophizing), and demographic characteristics (eg, age, sex, and race). Results: A total of 121 adults were recruited to the study, among whom 59 participants (mean [SD] age, 46.8 [11.9] years; 36 [61.0%] women) were randomized to real electroacupuncture and 62 participants (mean [SD] age, 45.6 [12.8] years; 33 [53.2%] women) were randomized to sham electroacupuncture. At baseline, the mean (SD) PROMIS T-score was 50.49 (3.36) in the real electroacupuncture group and 51.71 (4.70) in the sham acupuncture group, and the mean (SD) RMDQ score was 10.16 (4.76) in the real electroacupuncture group and 10.03 (5.45) in the sham acupuncture group. After adjusting for baseline pain scores, there was no statistically significant difference between groups in change in T-scores 2 weeks after completion of treatment (real electroacupuncture: -4.33; 95% CI, -6.36 to -2.30; sham acupuncture: -2.90; 95% CI, -4.85 to -0.95; difference: -2.09; 95% CI, -4.27 to 0.09; P = .06). After adjusting for baseline RMDQ, there was a significantly greater reduction in RMDQ in the real electroacupuncture group (-2.77; 95% CI, -4.11 to -1.43) compared with the sham electroacupuncture group (-0.67; 95% CI, -1.88 to 0.55; difference: -2.11; 95% CI, -3.75 to -0.47; P = .01). Within the real electroacupuncture group, effective coping at baseline was associated with greater RMDQ reduction (r = -0.32; 95% CI, -0.54 to -0.05; P = .02), and White race was associated with worse outcomes in PROMIS score (ß = 3.791; 95% CI, 0.616 to 6.965; P = .02) and RMDQ (ß = 2.878; 95% CI, 0.506 to 5.250; P = .02). Conclusions and Relevance: This randomized clinical trial found no statistically significant difference in change in PROMIS pain score in real electroacupuncture vs sham electroacupuncture. There was a statistically significant treatment effect for the secondary outcome of RMDQ compared with sham electroacupuncture. Effective coping skills and non-White race were associated with response to electroacupuncture. Trial Registration: ClinicalTrials.gov Identifier: NCT02890810.

TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls.

BACKGROUND: Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions. METHODS AND FINDINGS: We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator. CONCLUSIONS: We encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.

Optimizing the design of invasive placebo interventions in randomized controlled trials.

BACKGROUND: Placebo-controlled trials play an important role in the evaluation of healthcare interventions. However, they can be challenging to design and deliver for invasive interventions, including surgery. In-depth understanding of the component parts of the treatment intervention is needed to ascertain what should, and should not, be delivered as part of the placebo. Assessment of risk to patients and strategies to ensure that the placebo effectively mimics the treatment are also required. To date, no guidance exists for the design of invasive placebo interventions. This study aimed to develop a framework to optimize the design and delivery of invasive placebo interventions in RCTs. METHODS: A preliminary framework was developed using published literature to: expand the scope of an existing typology, which facilitates the deconstruction of invasive interventions; and identify placebo optimization strategies. The framework was refined after consultation with key stakeholders in surgical trials, consensus methodology and medical ethics. RESULTS: The resulting DITTO framework consists of five stages: deconstruct treatment intervention into constituent components and co-interventions; identify critical surgical element(s); take out the critical element(s); think risk, feasibility and role of placebo in the trial when considering remaining components; and optimize placebo to ensure effective blinding of patients and trial personnel. CONCLUSION: DITTO considers invasive placebo composition systematically, accounting for risk, feasibility and placebo optimization. Use of the framework can support the design of high-quality RCTs, which are needed to underpin delivery of healthcare interventions.

ANTECEDENTES: Los ensayos controlados con placebo juegan un papel importante en la evaluación de las intervenciones sanitarias. Sin embargo, pueden ser difíciles de diseñar e implementar en el caso de intervenciones invasivas, incluida la cirugía. Se necesita un conocimiento profundo de los componentes de la intervención terapéutica (para determinar qué se debe y qué no se debe administrar como parte del placebo). También se precisa de una evaluación del riesgo para los pacientes y de las estrategias para garantizar que el placebo imite el tratamiento de forma efectiva. Hasta la fecha no existen guías para el diseño de intervenciones invasivas con placebo. Este estudio tuvo como objetivo desarrollar un marco para optimizar el diseño y la práctica de intervenciones invasivas con placebo dentro en los ensayos clínicos aleatorizados (ECA). MÉTODOS: Utilizando la literatura publicada, se desarrolló un marco preliminar para i) ampliar el alcance de los modelos existentes para facilitar la deconstrucción de las actuaciones invasivas, y ii) identificar estrategias para optimizar el placebo. El marco se perfeccionó tras consultar con partes interesadas ​​en ensayos quirúrgicos, metodología de consenso y ética médica. RESULTADOS: El marco DITTO resultantes consiste en cinco etapas: Etapa 1: deconstrucción de la intervención de tratamiento en sus componentes esenciales y co-intervenciones; Etapa 2: identificar el(los) elemento(s) quirúrgico(s) básico(s); Etapa 3: eliminar el(los) elemento(s) básico(s); Etapa 4: considerar el riesgo, la viabilidad y el papel del placebo en el ensayo al tener en cuenta los demás componentes; y Etapa 5: optimizar el placebo para garantizar el cegamiento efectivo de los pacientes y del personal del ensayo. CONCLUSIÓN: DITTO considera de forma sistemática la naturaleza invasiva del placebo, teniendo en cuenta el riesgo, la viabilidad y la optimización del placebo. El uso de este marco de referencia puede ayudar al diseño de ECAs de alta calidad, necesarios para afianzar la implementación de intervenciones sanitarias.