Research ethics committees (RECs) evaluate whether the risk-benefit ratio of a study is acceptable. Decentralized clinical trials (DCTs) are a novel approach for conducting clinical trials that potentially bring important benefits for research, including several collateral benefits. The position of collateral benefits in risk-benefit assessments is currently unclear. DCTs raise therefore questions about how these benefits should be assessed. This paper aims to reconsider the different types of research benefits, and their position in risk-benefit assessments. We first propose (...) a categorization of research benefits, based on the types of benefits that can be distinguished from the literature and ethical guidelines. Secondly, we will reconsider the position of collateral benefits. We argue that these benefits are not fundamentally different from other benefits of research and can therefore be included in risk-benefit assessments of DCTs. (shrink)

Regulators rely on clinical trials for drug approval and labeling decisions. Health systems and clinicians rely on the evidence from trials to determine treatment, and patients rely on it to decide which courses of care to undertake. Many of these stakeholders presume that the careful review of individual studies is enough to address the ethical and scientific questions that arise in clinical trials. In what follows, however, we demonstrate that explicit consideration of trial portfolios—series of trials that are (...) interrelated by a common set of objectives—is crucial. the ethical acceptability and evidentiary probity of individual trials can change depending on the characteristics of the portfolios in which they are embedded. Second, how trial portfolios are composed, how well they are coordinated, and how efficiently they use information determines the balance of risks and benefits they present as well as their different prospects for generating socially valuable information; these three factors also raise distinct questions of justice. (shrink)

Xenotransplant patient selection recommendations restrict clinical trial participation to seriously ill patients for whom alternative therapies are unavailable or who will likely die while waiting for an allotransplant. Despite a scholarly consensus that this is advisable, we propose to examine this restriction. We offer three lines of criticism: (1) The risk–benefit calculation may well be unfavorable for seriously ill patients and society; (2) the guidelines conflict with criteria for equitable patient selection; and (3) the selection of seriously ill patients (...) may compromise informed consent. We conclude by highlighting how the current guidance reveals a tension between the societal values of justice and beneficence. (shrink)

When discussing the safety of research subjects, including their exploitation and vulnerability as well as failures in clinical research, recent commentators have focused mostly on countries with low or middle-income economies. High-income countries are seen as relatively safe and well-regulated. This article presents irregularities in clinical trials in an EU member state, Poland, which were revealed by the Supreme Audit Office of Poland (the NIK). Despite adopting many European Union regulations, including European Commission directives concerning Good Clinical (...) Practice, these irregularities occurred. Causes as well as potential solutions to make clinical trials more ethical and safer are discussed. (shrink)

Decentralized clinical trials (DCTs) have the potential to advance the conduct of clinical trials, but raise several ethical issues, including obtaining valid informed consent. The debate on the ethical issues resulting from digitalization is predominantly focused on direct risks relating to for example data protection, safety, and data quality. We submit however, that a broader view on ethical aspects of DCTs is needed to touch upon the new challenges that come with the DCT practice. Digitalization has impacts that (...) go beyond its direct purposes, by shaping behaviors, experiences, social relations, and values. We examine four elements of the informed consent procedure that are affected by DCTs, while taking these soft impacts of technologies into account: (i) informing participants and testing understanding, (ii) freedoms in relation to responsibilities and burdens, (iii) trust in participant-researcher relations, and (iv) impacts on the concept of privacy. Our analysis reveals that a broad view is key for optimal conduct of DCTs. In addition, it provides insight into the ethical impacts of DCTs on informed consent. Technologies such as DCTs potentially have profound impacts which are not immediately addressed by the existing regulatory frameworks, but nonetheless important to recognize. These findings can guide future practices of DCTs to foster the important values of clinical research in this novel approach for conducting clinical trials. (shrink)

Relatively little has been written about the ethics of conducting early phase clinical trials involving subjects from the developing world. Below, I analyze ethical issues surrounding one of gene transfer’s most widely praised studies conducted to date: in this study, Italian investigators recruited two subjects from the developing world who were ineligible for standard of care because of economic considerations. Though the study seems to have rendered a cure in these two subjects, it does not appear to have complied (...) with various international guidelines that require that clinical trials conducted in the developing world be responsive to their populations’ health needs. Nevertheless, policies devised to address large scale, late stage trials, such as the AZT short‐course placebo trials, map somewhat awkwardly to early phase studies. I argue that interest in conducting translational research in the developing world, particularly in the context of hemophilia trials, should motivate more rigorous ethical thinking around clinical trials involving economically disadvantaged populations. (shrink)

ABSTRACTRelatively little has been written about the ethics of conducting early phase clinical trials involving subjects from the developing world. Below, I analyze ethical issues surrounding one of gene transfer’s most widely praised studies conducted to date: in this study, Italian investigators recruited two subjects from the developing world who were ineligible for standard of care because of economic considerations. Though the study seems to have rendered a cure in these two subjects, it does not appear to have complied (...) with various international guidelines that require that clinical trials conducted in the developing world be responsive to their populations’ health needs. Nevertheless, policies devised to address large scale, late stage trials, such as the AZT short‐course placebo trials, map somewhat awkwardly to early phase studies. I argue that interest in conducting translational research in the developing world, particularly in the context of hemophilia trials, should motivate more rigorous ethical thinking around clinical trials involving economically disadvantaged populations. (shrink)

As the_number of clinical trials continues to grow, there is an increasing need for education and training in the field. The clinical research climate is less forgiving of errors and oversights and therefore requires more knowledge of regulations and requirements. This brand new edition details new laws and regulations in protecting children participating in clinical trials and how a new focus on privacy of individual health information in the United States has changed how medical records are handled. (...) Includes a manual for investigators, research nurses and study coordinators with minimal experience or who are new to clinical research An easy-to-read and open text design using ‘sidebars’ of examples and information boxes related to the main text Includes a list of Frequently Asked Questions and Glossary Duke Clinical Research Institute is the world’s largest academic clinical research organisation and is well known and respected within the clinical research community. (shrink)

This systematic review identifies and critically evaluates instruments that have been developed to measure clinical trial informed consent comprehension in non-cognitively-impaired adults.Literature searches were carried out on Medline (Ovid), PsycInfo, CINHAL, ERIC, ScienceDirect, and Cochrane Library for English language articles published between January 1980 and September 2008. Instruments were excluded if they focused on consent onto paediatric trials, the construct under study was primarily capacity or competency, or the instrument was developed specifically for psychiatric or cognitively-impaired populations. Instruments selected (...) for review were evaluated against the following criteria: (1) method of item generation; (2) type and format of test items; (3) administration and interpretation of test results; and (4) psychometric properties.Three instruments met our defined inclusion criteria: the Deaconess Informed Consent Comprehension Test (DICCT), the Quality of Informed Consent (QuIC) questionnaire and the Brief Informed Consent Protocol (BICEP). Each instrument varied in terms of content measured. Significantly, these are the first standardized instruments developed to assess comprehension in non-cognitively-impaired adults. Yet, each instrument had its own set of limitations such as the lack of generalizability and the absence of details pertaining to how test results should be used to guide clinical decision-making.Standardized clinical trial informed consent comprehension assessments have been developed to identify gaps in research participants' understanding and ensure that respect for patient autonomy is satisfied. (shrink)

Pragmatic clinical trials are a relatively new methodological approach to the execution of clinical research that can increase research efficiency and provide access to unique data. Some have suggested that the costs and delays associated with obtaining informed consent could make PCTs difficult or even impossible to execute. Alternative consent models have been proposed, some of which lower standards of disclosure, delay consent, or waive it altogether. We analyze the permissibility of changes to informed consent in the context (...) of Canadian research ethics policies, legislation, common law, professional codes of ethics, and professional standards of practice. We find that Canadian law and policy relating to informed consent clearly applies to any clinician who might be involved in a PCT. In addition, existing consent norms seem unable to accommodate alternative consent models for pragmatic research if such models would involve lowering the standard of disclosure. The strong emphasis on the primacy... (shrink)

The European framework surrounding clinical trials on medicinal products for human use is going to change as demonstrated by the large debate at European institutional level. One of the major challenges is to overcome the lack of harmonisation of clinical trial procedures among countries. This aspect is gaining more and more importance, considering the increasing number of multicentre and multinational studies. In this work, the actual European rules governing the Clinical Trial Application have been analysed throughout the (...) different steps including the registration of the trial in the European database; the preparation of documents to be submitted and their contents; the preparation of documents related to the information and consent process; the submission to competent bodies. Specific issues related to paediatric research and trials involving non EU/EEA countries have been addressed as well. Results reveal that the European legislation offers a well defined set of European rules covering different aspects of a Clinical Trial Application. However, these are not suitable to meet the challenges from multicentre and multinational clinical studies. A stronger set of rules, such as is available in a composite European Regulation has been adopted and is expected to harmonise practices and enable sponsors to carry out well conducted trials. But will the new regulation overcome the existing criticisms of Directive 2001/20/EC? (shrink)

It is not uncommon for multiple clinical trials at the same institution to recruit concurrently from the same patient population. When the relevant pool of patients is limited, as it often is, trials essentially compete for participants. There is evidence that such a competition is a predictor of low study accrual, with increased competition tied to increased recruitment shortfalls. But there is no consensus on what steps, if any, institutions should take to approach this issue. In this article, we (...) argue that an institutional policy that prioritises some trials for recruitment ahead of others is ethically permissible and indeed prima facie preferable to alternative means of addressing recruitment competition. We motivate this view by appeal to the ethical importance of minimising the number of studies that begin but do not complete, thereby exposing their participants to unnecessary risks and burdens in the process. We then argue that a policy of prioritisation can be fair to relevant stakeholders, including participants, investigators and funders. Finally, by way of encouraging and helping to frame future debate, we propose some questions that would need to be addressed when identifying substantive ethical criteria for prioritising between studies. (shrink)

Ethical reasons are presented for requiring 1) that a proposal for a clinical trial should be accompanied by a thorough review of all previous trials that have examined the same and closely related questions, and 2) that a trial should be approved by a research ethics committee only if the investigator undertakes to register it in an appropriate register of clinical trials as soon as one exists.

Clinical trial results are often interpreted by inductive reasoning, in a trial design-limited manner, directed toward modifications of the current clinical practice. Deductive reasoning is an alternative in which results of relevant trials are combined in indisputable premises that lead to a conclusion easily testable in future trials.

This paper describes one possible origin point for fraudulent behavior within the American pharmaceutical industry. We argue that during the late nineteenth century therapeutic reformers sought to promote both laboratory science and increasingly systematized forms of clinical experiment as a new basis for therapeutic knowledge. This process was intertwined with a transformation in the ethical framework in which medical science took place, one in which monopoly status was replaced by clinical utility as the primary arbiter of pharmaceutical legitimacy. (...) This new framework fundamentally altered the set of epistemic virtues—a phrase we draw from the philosophical field of virtue epistemology—considered necessary to conduct reliable scientific inquiry regarding drugs. In doing so, it also made possible new forms of fraud in which newly emergent epistemic virtues were violated. To make this argument, we focus on the efforts of Francis E. Stewart and George S. Davis of Parke, Davis & Company. Therapeutic reformers within the pharmaceutical industry, such as Stewart and Davis, were an important part of the broader normative and epistemic transformation we describe in that they sought to promote laboratory science and systematized clinical trials toward the twin goals of improving pharmaceutical science and promoting their own commercial interests. Yet, as we suggest, Parke, Davis & Company also serves as an example of a company that violated the very norms that Stewart and Davis helped introduce. We thus seek to describe one possible origin point for the widespread fraudulent practices that now characterize the pharmaceutical industry. We also seek to describe an origin point for why we conceptualize such practices as fraudulent in the first place. (shrink)

Mounting evidence suggests that participation in clinical trials confers neither advantage nor disadvantage on those enrolled. Narrow focus on the question of a “trial effect,” however, distracts from a broader mechanism by which patients may benefit from ongoing clinical research. We hypothesize that the existence of clinical trials infrastructure—the organizational culture, systems, and expertise that develop as a product of sustained participation in cooperative clinical trials research—may function as a quality improvement lever, improving the quality of (...) care and outcomes of all patients within an institution or region independent of their individual participation in trials. We further contend that this “infrastructure effect” can yield particular benefits for patients in low- and middle-income countries. The hypothesis of an infrastructure effect as a quality improvement intervention, if correct, justifies enhanced research capacity in LMIC as a pillar of health system development. (shrink)

The relationship between the ethical standards for the governance of clinical trials and market forces can be complex and problematic. This article uses India as a case study to explore this nexus. From the mid-2000s, India became a popular destination for foreign-sponsored clinical trials. The Indian government had sought to both attract clinical trials and ensure these would be run in line with internationally accepted ethical norms. Reports of controversial medical research, however, triggered debate about the robustness (...) and suitability of India's regulatory system. In response to civil society pressure and interventions by the Supreme Court, the Indian government proposed additional measures aimed at strengthening protections for clinical trial participants. Whilst the reforms can be seen as a victory for human rights activists, they have also been criticised as being overly burdensome for sponsors. Indeed, their announcement prompted an exodus of clinical trials from India. Fearful of losing business to ‘rival’ countries, the Indian government is revisiting some of its proposals. The Indian example suggests that research ethics frameworks and national policies for economic development are increasingly intertwined. Host countries are in theory free to improve the lot of research participants, but doing so may make them appear less attractive to foreign sponsors, who can simply shift their activities to more industry-friendly jurisdictions. Although these economic pressures are unlikely to lead to a regulatory ‘race to the bottom’, they may limit host countries' ability to enact socially desirable reforms. (shrink)

Hastings Center Report, Volume 52, Issue 5, Page 42-43, September–October 2022.

This article seeks to advance ethical dialogue on choosing standards of prevention in clinical trials testing improved biomedical prevention methods for HIV. The stakes in this area of research are high, given the continued high rates of infection in many countries and the budget limitations that have constrained efforts to expand treatment for all who are currently HIV-infected. New prevention methods are still needed; at the same time, some existing prevention and treatment interventions have been proven effective but are (...) not yet widely available in the countries where they most urgently needed. The ethical tensions in this field of clinical research are well known and have been the subject of extensive debate. There is no single clinical trial design that can optimize all the ethically important goals and commitments involved in research. Several recent articles have described the current ethical difficulties in designing HIV prevention trials, especially in resource limited settings; however, there is no consensus on how to handle clinical trial design decisions, and existing international ethical guidelines offer conflicting advice. This article acknowledges these deep ethical dilemmas and moves beyond a simple descriptive approach to advance an organized method for considering what clinical trial designs will be ethically acceptable for HIV prevention trials, balancing the relevant criteria and providing justification for specific design decisions. (shrink)

Clinical trials are a central mechanism in the production of medical knowledge. They are the gold standard by which such knowledge is evaluated. They are widespread both in the United States and internationally; a National Institute of Health database reports over 106,000 active industry and government-sponsored trials (National Institutes of Health n.d.). They are an engine of the economy. The work of trials is complex; multiple people with diverse interests working across multiple settings simultaneously participate in them, and they (...) are underwritten by multiple organizational structures and diverse funding mechanisms. In the past several years, concern about the ethics of clinical trials has spiked dramatically .. (shrink)

_Clinical Trials and the African Person_ offers an account of the African notion of the self/person within the clinical trials context. As opposed to autonomy-based principlism, this other-regarding/communalist perspective is touted as the preferred alternative model particularly in multicultural settings.

The quest for effective medicines is very old. In modern times two important tools have been developed to evaluate efficacy of drugs: superiority and non-inferiority types of clinical trials. The former tests the null hypothesis of μ (the difference between a tested drug and comparator) ≤ 0 against μ > 0; the latter tests the null hypothesis of μ ≤ - Δ against, μ > - Δ, where Δ is the clinical difference from the comparator. In a superiority (...) trial, a new drug is tested against a placebo; in a non-inferiority trial, a new drug is tested against active treatment. In this paper, arguments are presented to show that a superiority trial against a placebo is scientifically sound but ethically unacceptable, whereas a non-inferiority trial against active treatment is ethically sound but scientifically not reliable. Switching from a superiority type of trial with placebo to a non-inferiority trial with an active-control — following the latest revision of Declaration of Helsinki — is in practice switching from the violation of the uncertainty principle to uncertainty of results. Given human and financial resources, it appears an academic question as to which is more unethical: to violate patients’ rights or to produce results without scientific value. All presented considerations lead to the conclusion that the use of a superiority trial of design with an active control instead of placebo will satisfy scientific needs, expectation of patients, and the ancient quest for effective medicines. In the era of Good (Clinical, Laboratory, Manufacture) Practice, the attention of those performing clinical trials is focused on the procedure, not always on its essence. However even the excellent performance of a trial which is not worth doing is fruitless. (shrink)

What kind of patients may be recruited to early clinical trials of xenotransplantation? This is discussed under the assumption that the risk of viral infection to the public is non-negligible. Furthermore, the conditions imposed by the Helsinki declaration are analysed. The conclusion is that only patients at risk of dying and with no alternative treatment available should be recruited to xenotransplantation trials in the early phase. For some of the less dangerous cell or islet cell xenotransplantation other categories might (...) be recruited. The risk of cell and islet cell xenotransplantation should, however, be weighted against the development of other technologies.In order to safeguard the public, the opt-out clause in the Helsinki declaration should not be fully applied. Legally binding rules on obligatory monitoring and restrictions should be imposed—before clinical trials start. Journal of Medical Ethics. (shrink)

Xenotransplantation pits clinical research ethics against public health needs because recipients must undergo long-term, perhaps life-long, surveillance for infectious diseases. This surveillance requirement is effectively an abrogation of the right to withdraw from a clinical trial. Ulysses contracts, which are advance directives for future care, may be an ethical mechanism by which to balance public health needs against limitation of individual rights.

Background In modern Russia, any clinical investigation of a pharmaceutical for use in humans is subject to prior evaluation and approval by the Ministry of Health and its Central Ethics Committee. Despite this, some researchers and trial sponsors fail to comply, this is particularly true in case of the studies initiated by domestic sponsors or sponsor-investigators and published in Russian language medical journals. This exploratory research aims to discover whether it is a sporadic non-compliance with regulations or a common (...) practice. Methods We searched the Russian language database eLIBRARY for the phrase ‘results of a randomised trial’. We selected publications reporting clinical trials and conducted in Russia. For each of the selected studies, we searched the state register of the approved clinical trials. We assessed whether the investigational medicinal product was approved for marketing in Russia; the therapeutic indications, posology, and administration method in the clinical trial were consistent with the approved labelling; the issue of the journal included an advertisement of the medicinal product in question; and the full description of the methodology corroborated that the clinical trial was randomised, as was stated in the title or abstract. Results Of the 26 selected articles, 22 reported the results of unauthorised clinical trials. Three of those trials were conducted in children. Twenty-one studies reported on data from unauthorised trials for investigational products approved for marketing in Russia. However, in nine cases, the therapeutic indications, posology, or administration method did not match the conditions indicated in the labelling. Moreover, in one case, the unauthorised trial included a drug therapy intervention where the active substance was not approved for use in any medicinal product marketed in Russia. In 14 of the 26 articles, the issue of the journal or the article itself contained an advertisement for the same medicinal product or, in one case, its manufacturer. All publications accompanied by advertisements claimed that the medicinal product in question was efficacious. Conclusions A substantial fraction of the clinical trials initiated by domestic sponsors and reported in Russian medical journals failed to obtain the mandatory prior evaluation and approval from the regulator. This can affect the rights and well-being of the study participants and the scientific validity of the studies. (shrink)

Xenotransplantation is defined as “any procedure that involves the transplantation, implantation, or infusion into a human recipient of either live cells, tissues, or organs from a nonhuman animal source, or human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs.” Xenotransplantation has been viewed by desperate patients and their surgeons as a solution to the problem of the paucity of human organs available for transplantation. Foes of xenotransplantation argue that (...) the use of animal organs degrades the human race and should be avoided.In this paper, we briefly review the cultural context of xenotransplantation and explore the infectious disease risk of xenotransplantation. The United States Code of Federal Regulations requires life-long surveillance of a xenotransplantation recipient due to the largely unknown risk of novel infectious disease transmitted across species, known as xenogeneic infectious disease. We argue that despite being in the interest of protecting the public health, the imposition of lifelong surveillance requirements on xenotransplant recipients effectively abrogates the right to withdraw from a clinical trial after the transplantation has taken place. Moreover, we argue that a waiver of the right to withdraw should be made explicit in the interest of full disclosure, out of respect for the research subject’s right of self-determination. (shrink)

The West African Ebola epidemic has set in motion a collective endeavour to conduct accelerated clinical trials, testing unproven but potentially lifesaving interventions in the course of a major public health crisis. This unprecedented effort was supported by the recommendations of an ad hoc ethics panel convened in August 2014 by the WHO. By considering why and on what conditions the exceptional circumstances of the Ebola epidemic justified the use of unproven interventions, the panel's recommendations have challenged conventional thinking (...) about therapeutic development and clinical research ethics. At the same time, unanswered ethical questions have emerged, in particular: the specification of exceptional circumstances, the specification of unproven interventions, the goals of interventional research in terms of individual versus collective interests, the place of adaptive trial designs and the exact meaning of compassionate use with unapproved interventions. Examination of these questions, in parallel with empirical data from research sites, will help build pragmatic foundations for disaster research ethics. Furthermore, the Ebola clinical trials signal an evolution in the current paradigms of therapeutic research, beyond the case of epidemic emergencies. (shrink)

Although data sharing platforms host diverse data types the features of these platforms are well-suited to facilitating biomarker research. Given the current state of biomarker discovery, an innovative paradigm to accelerate biomarker discovery is to utilize platforms such as Vivli to leverage researchers' abilities to integrate certain classes of biomarkers.

The case of clinical trials for convalescent plasma during COVID-19 illustrates important lessons for realizing public sector approaches to biomedical research and development. These lessons, centering on mission, transparency, and spillover effects, can be translated to wider efforts to develop a “public option” for clinical trials.

The West African Ebola epidemic has set in motion a collective endeavour to conduct accelerated clinical trials, testing unproven but potentially lifesaving interventions in the course of a major public health crisis. This unprecedented effort was supported by the recommendations of an ad hoc ethics panel convened in August 2014 by the WHO. By considering why and on what conditions the exceptional circumstances of the Ebola epidemic justified the use of unproven interventions, the panel's recommendations have challenged conventional thinking (...) about therapeutic development and clinical research ethics. At the same time, unanswered ethical questions have emerged, in particular: the specification of exceptional circumstances, the specification of unproven interventions, the goals of interventional research in terms of individual versus collective interests, the place of adaptive trial designs and the exact meaning of compassionate use with unapproved interventions. Examination of these questions, in parallel with empirical data from research sites, will help build pragmatic foundations for disaster research ethics. Furthermore, the Ebola clinical trials signal an evolution in the current paradigms of therapeutic research, beyond the case of epidemic emergencies. (shrink)

The outsourcing of clinical trials to Latin America by the transnational innovative pharmaceutical industry began about twenty years ago. Using archival information and field work in Argentina, Brazil, Costa Rica, Mexico and Peru, the authors discuss the regulatory contexts and the ethical dimensions of human experimentation in the region. More than 80% of all clinical trials in the region take place in these countries, and the European Medicines Agency has defined them as priority countries in Latin America. The (...) authors raise questions about the quality of data obtained from the trials and the violation of human rights during their implementation. Their findings are presented in this volume, the first in-depth analysis of clinical trials in the region.. (shrink)

This paper explores the connection of offshoring and outsourcing to nonconsensual global pharmaceutical trials in low-income countries. After discussing reasons why the topic of nonconsensual offshored clinical trials may be overlooked in bioethics literature, I suggest that when pharmaceutical corporations offshore clinical trials today, nonconsensual experiments are often foreseeable and not simply the result of aberrant ethical conduct by a few individuals. Offshoring of clinical trials is structured so that experiments can be presented as health care in (...) a unique form of outsourcing from the host country to pharmaceutical corporations. Bioethicists’ assessments of the risks and potential benefits of offshore corporate pharmaceutical trials should therefore systematically include not only the hoped for benefits and the risks of the experimental drug but also the risk that subjects will not have consented, as well as the broader international consequences of nonconsensual experimentation. (shrink)

Monitoring ongoing clinical trials for early signs of effectiveness is an option for improving cost-effectiveness of trials that is becoming increasingly common. Alongside the obvious advantages made possible by monitoring, however, there are some downsides. In particular, there is growing concern in the medical community that trials stopped early for benefit tend to overestimate treatment effect. In this paper, I examine this problem from the point of view of statistical methodology, starting from the observation that the overestimation is caused (...) by the statistical method adopted. Consequently, I argue that some modifications can and should be made to the present statistical framework in order not to miss the advantages the possibility of monitoring can grant. (shrink)

Selective reporting is prevalent in the medical literature, particularly in industry-sponsored research. In this paper, we expose selective reporting that is not evident without access to internal company documents. The published report of study 329 of paroxetine in adolescents sponsored by GlaxoSmithKline claims that “paroxetine is generally well tolerated and effective for major depression in adolescents”. By contrast, documents obtained during litigation reveal that study 329 was negative for efficacy on all 8 protocol specified outcomes and positive for harm.

The participation of minors in clinical trials is essential to provide safe and effective medical care to children. Because few drugs have been tested in children, pediatricians are forced to prescribe medications off-label with uncertain efficacy and safety. In this article, we analyze how the enrollment of minors in clinical trials is negotiated within relationships of mutual trust between clinicians, minors, and their parents. After a brief description of the problems associated with involving minors in clinical research, (...) we consider how existing “relationships of trust” can be used as a place where the concerns of research subjects can be more fully discussed and addressed. Building on the tacit recognition of trust found in The European Clinical Trials Directive we make policy recommendations that allow for clearer, more ethically informed guidelines for enrolling minors in clinical research. (shrink)

The article presents the advantages and limitations of adaptive clinical trials for assessing the effectiveness of medical interventions and specifies the conditions that contributed to their development and implementation in clinical practice. I advance two arguments by discussing different cases of adaptive trials. The normative argument is that responsible adaptation should be taken seriously as a new way of doing clinical research insofar as a valid justification, sufficient understanding, and adequate operational conditions are provided. The second argument (...) is historical. The development of adaptive trials can be related to lessons learned from research in cases of urgency and to the decades-long efforts to end the productivity crisis of pharmaceutical research, which led to the emergence of translational, personalized, and, recently, precision medicine movements. (shrink)

The routine practice of clinical research involving patient-subjects without informed consent prior to 1966 unquestionably was unethical. Does it follow that all clinical research involving competent adult patient-subjects is unethical without informed consent?In his landmark 1966 paper, Henry Beecher noted that of the 50 example studies he had originally compiled in preparation for that paper, only two even mentioned consent, and he observed further that mention of consent is “meaningless unless one knows how fully the patient was informed”. (...) Some of the studies in Beecher’s paper, such as one comparing sulfadiazine with no treatment to assess the complications of streptococcal pharyngitis (when the... (shrink)

Abstractabstract:Expectations about future events underlie practically every decision we make, including those in medical research. This paper reviews five studies undertaken to assess how well medical experts could predict the outcomes of clinical trials. It explains why expert trial forecasting was the focus of study and argues that forecasting skill affords insights into the quality of expert judgment and might be harnessed to improve decision-making in care, policy, and research. The paper also addresses potential criticisms of the research agenda (...) and summarizes key findings from the five studies of trial forecasting. Together, the studies suggest that trials frequently deliver surprising results to expert communities and that individual experts are often uninformative when it comes to forecasting trial outcome and recruitment. However, the findings also suggest that expert forecasts often contain a "signal" about whether a trial will be positive, especially when forecasts are aggregated. The paper concludes with needs for further research and tentative policy recommendations. (shrink)

Mood disorders, including major depressive disorder and bipolar disorder, are highly prevalent, frequently disabling, and sometimes deadly. Additional research and more effective medications are desperately needed, but clinical trials research in mood disorders is fraught with ethical issues. Although many authors have discussed these issues, most do so from a theoretical viewpoint. This manuscript uses available empirical data to inform a discussion of the primary ethical issues raised in mood disorders research. These include issues of consent and decision-making capacity, (...) including patients’ motivations for participating in research. We also address drug withdrawals, placebo controls, and the overall safety of research. Finally, we examine the extant literature for studies discussing potential indirect benefits of clinical trials research to participants. Taken together, the evidence suggests that clinical trials research incorporating drug withdrawals and placebo controls can be conducted safely and ethically, even in patients with severe or treatment-resistant mood disorders. In fact, given the dearth of effective treatment options for this population, it is our opinion that a moral imperative exists to extend the offer of research participation to severely ill or treatment-resistant groups. (shrink)

The need for informed consent is considered from the patient's viewpoint by an examination of the shortcomings of the UK Ductal Carcinoma In Situ (DCIS) trial and its failure satisfactorily to accrue both profession and patient. The impersonal, negative aspects of the informed consent process in the research situation are contrasted with the positive benefits of confidence fostered by the traditional doctor/patient relationship. The need for new research with a partnership between patient and profession, the necessity for rigorous re-assessment of (...) treatments and care both within and outside of trials to avoid waste by the perpetration of unnecessary treatments together with the need for evaluation of the efficacy of treatments employed outside of trials, especially in 'new' conditions, to foster progress and maintain public confidence in the profession, is advocated. (shrink)