The European framework surrounding clinicaltrials 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)
This article seeks to advance ethical dialogue on choosing standards of prevention in clinicaltrials 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)
It is not uncommon for multiple clinicaltrials 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)
Clinicaltrials 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 clinicaltrials has spiked dramatically .. (shrink)
The relationship between the ethical standards for the governance of clinicaltrials 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 clinicaltrials. The Indian government had sought to both attract clinicaltrials 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 clinicaltrials 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)
Mounting evidence suggests that participation in clinicaltrials 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 clinicaltrials infrastructure—the organizational culture, systems, and expertise that develop as a product of sustained participation in cooperative clinicaltrials 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)
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 clinicaltrials may be overlooked in bioethics literature, I suggest that when pharmaceutical corporations offshore clinicaltrials today, nonconsensual experiments are often foreseeable and not simply the result of aberrant ethical conduct by a few individuals. Offshoring of clinicaltrials 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)
As the_number of clinicaltrials 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 clinicaltrials 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)
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)
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.
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 clinicaltrials as soon as one exists.
What kind of patients may be recruited to early clinicaltrials 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 clinicaltrials start. Journal of Medical Ethics. (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, 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: method of item generation; type and format of test items; administration and interpretation of test results; and psychometric properties. Three instruments met our defined inclusion criteria: the Deaconess Informed Consent Comprehension Test, the Quality of Informed Consent questionnaire and the Brief Informed Consent Protocol. 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)
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 clinicaltrials and conducted in Russia. For each of the selected studies, we searched the state register of the approved clinicaltrials. 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 clinicaltrials. 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 clinicaltrials 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)
Pragmatic clinicaltrials 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)
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.
_Clinical Trials and the African Person_ offers an account of the African notion of the self/person within the clinicaltrials context. As opposed to autonomy-based principlism, this other-regarding/communalist perspective is touted as the preferred alternative model particularly in multicultural settings.
Several high-profile episodes have recently thrust drug safety and the pharmaceutical industry's practices into the spotlight. Merck's recall of the drug Vioxx, for instance, was a major news event. GlaxoSmithKline's suppression of data linking suicidal behavior among children to Paxil also galvanized tremendous public attention. What differentiates these events from the usual evolving process of scientific knowledge, and marks them with an aura of “scandal,” are questions about the propriety of corporate behavior. Who knew what, and when did they know (...) it? Concerns are growing about the potential for industry sponsors to suppress negative results from clinicaltrials research. Scientists, medical journal editors, legislators, and the public have called for greater transparency in the conduct of clinicaltrials and the drug approval process. (shrink)
Several high-profile episodes have recently thrust drug safety and the pharmaceutical industry's practices into the spotlight. Merck's recall of the drug Vioxx, for instance, was a major news event. GlaxoSmithKline's suppression of data linking suicidal behavior among children to Paxil also galvanized tremendous public attention. What differentiates these events from the usual evolving process of scientific knowledge, and marks them with an aura of “scandal,” are questions about the propriety of corporate behavior. Who knew what, and when did they know (...) it? Concerns are growing about the potential for industry sponsors to suppress negative results from clinicaltrials research. Scientists, medical journal editors, legislators, and the public have called for greater transparency in the conduct of clinicaltrials and the drug approval process. (shrink)
ABSTRACTRelatively little has been written about the ethics of conducting early phase clinicaltrials 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 clinicaltrials 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 clinicaltrials involving economically disadvantaged populations. (shrink)
The article presents the advantages and limitations of adaptive clinicaltrials 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 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 clinicaltrials. 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 clinicaltrials 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)
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 clinicaltrials 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)
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)
The outsourcing of clinicaltrials 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 clinicaltrials 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 clinicaltrials in the region.. (shrink)
ABSTRACTRelatively little has been written about the ethics of conducting early phase clinicaltrials 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 clinicaltrials 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 clinicaltrials involving economically disadvantaged populations. (shrink)
This paper discusses several philosophical problems with the use of randomized clinicaltrials in psychotherapy outcome research. The problems include: the impermanence problem, the identification problem, and idiographic problems. The paper concludes with an assessment of the overall case for and against the use of RCTs in psychotherapy outcome research.
Participants in some clinicaltrials are at risk of being harmed and sometimes are seriously harmed as a result of not being provided with available, relevant risk information. We argue that this situation is unacceptable and that there is a moral duty to disclose all adverse clinical trial results to participants in clinicaltrials. This duty is grounded in the human right not to be placed at risk of harm without informed consent. We consider objections (...) to disclosure grounded in considerations of commercial interest, and we argue that these concerns are insufficient to override the moral duty to disclose adverse clinical trial results. However, we also develop a proposal that enables commercial interests to be protected, while promoting the duty to disclose adverse clinical trial results. (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 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)
Design of clinicaltrials for germline gene editing stretches current accepted standards for human subjects research. Among the challenges involved is a set of issues concerning intergenerational monitoring—long-term follow-up study of subjects and their descendants. Because changes made at the germline would be heritable, germline gene editing could have adverse effects on individuals’ health that can be passed on to future generations. Determining whether germline gene editing is safe and effective for clinical use thus may require intergenerational (...) monitoring. The aim of this paper is to identify and argue for the significance of a set of ethical issues raised by intergenerational monitoring in future clinicaltrials of germline gene editing. Though long-term, multigenerational follow-up study of this kind is not without precedent, intergenerational monitoring in this context raises unique ethical challenges, challenges that go beyond existing protocols and standards for human subjects research. These challenges will need to be addressed if clinicaltrials of germline gene editing are ever pursued. (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 clinicaltrials 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 (...) class='Hi'>Clinical Practice, these irregularities occurred. Causes as well as potential solutions to make clinicaltrials more ethical and safer are discussed. (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.
Monitoring ongoing clinicaltrials 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)
I will open the first part of this paper by trying to elucidate the frequentist foundations of RCTs. I will then present a number of methodological objections against the viability of these inferential principles in the conduct of actual clinicaltrials. In the following section, I will explore the main ethical issues in frequentist trials, namely those related to randomisation and the use of stopping rules. In the final section of the first part, I will analyse why (...) RCTs were accepted for regulatory purposes. I contend that their main virtue, from a regulatory viewpoint, is their impartiality, which is grounded in randomisation and fixed rules for the interpretation of the experiment. Thus the question will be whether Bayesian trials can match or exceed the achievements of frequentist RCTs in all these respects. In the second part of the paper, I will first present a quick glimpse of the introduction of Bayesianism in the field of medical experiments, followed by a summary presentation of the basic tenets of a Bayesian trial. The point here is to show that there is no such thing as “a” Bayesian trial. Bayesianism can ground many different approaches to medical experiments and we should assess their respective virtues separately. Thus I present two actual trials, planned with different goals in mind, and assess their respective epistemic, ethical and regulatory merits. In a tentative conclusion, I contend that, given the constraints imposed by our current regulatory framework, impartiality should preside over the design of clinicaltrials, even at the expense of many of their inferential and ethical virtues. (shrink)
The Blueprint for Transparency at the FDA recommends that the FDA proactively release more clinical trial data. We show that the FDA possesses the legal authority to act on this recommendation, and describe several reasons that the agency should do so. In particular, the primary existing route for researchers to obtain access to this data, the Freedom of Information Act, has important limits, as our own recent experience shows.
Randomised clinicaltrials involve procedures such as randomisation, blinding, and placebo use, which are not part of standard medical care. Patients asked to participate in RCTs often experience difficulties in understanding the meaning of these and their justification.
Medical research involving human subjects can be risky and burdensome. Therefore, such research must be reviewed and approved by a Research Ethics Committee (REC). To guarantee the safety of the subjects, it is very important that these studies be conducted in accordance with the approved protocol. An important issue in this respect is whether studies include the requisite number of subjects based on the research question. The research question is unlikely to be answered reliably if the requisite number of subjects (...) is not met. In such cases, subjects are exposed to unnecessary risks and burdens. In this descriptive study, the authors evaluated how frequently studies are completed with the required number of subjects. Moreover, the authors identified the characteristics of research that does and does not include the required number of subjects. The results of this study show that a considerable proportion of studies (41/107) were terminated although they failed to recruit a sufficient number of subjects. Furthermore, the authors found that investigator-initiated studies have significantly (p=0.028) more problems in recruiting the requisite number of subjects than studies initiated by pharmaceutical companies. Potential solutions are discussed to reduce the number of studies that do not include a sufficient number of subjects. (shrink)
In this commentary on the previous paper it is explained that screen-detected Duct Carcinoma In Situ is effectively a new disease of unknown natural history. It is therefore impossible that 'the doctor knows best' and it is therefore both in the patient and the public's best interests that such cases are submitted to the rigours of the randomised controlled trial. Inevitably this brings the ethical dilemma of how to explain to patients the uncertainty and how to involve them in a (...) rational decision to take part in the randomised controlled trial. It is argued that as well as there being a collective benefit for future generations of women, that we should resolve this problem now, the individual woman is likely to benefit from being treated according to a strict protocol. Nevertheless the time of diagnosis is paradoxically not the best time for a patient to become aware of these matters and it is about time that the lay public and the opinion formers recognized their responsibility to become acquainted with the benefits and the needs of the randomised controlled trial in anticipation of the day when they themselves will be patients. (shrink)
One of the arguments against conducting human subject trials in the Third World adopts a distributive justice principle found in a commentary of the CIOM'S Eighth Guideline for international research on human subjects. Critics argue that non-participant members of the community in which the trials are conducted are exploited because sponsoring agencies do not ensure that the products developed have been made reasonably available to these individuals. I argue that the distributive principle's wording is too vague and ambiguous (...) to be used to criticize any trial. Furthermore, the mere fact that an experiment does not fulfill this particular distributive justice principle does not entail that it is unethical. (shrink)
The participation of minors in clinicaltrials 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 clinicaltrials 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 (...) class='Hi'>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 ClinicalTrials Directive we make policy recommendations that allow for clearer, more ethically informed guidelines for enrolling minors in clinical research. (shrink)
