Key Considerations in the Health Technology Assessment of Advanced Therapy Medicinal Products in Scotland, The Netherlands, and England.

OBJECTIVES: Advanced therapy medicinal products (ATMPs) are highly innovative therapies. Their costs and uncertain value claims have raised concerns among health technology assessment (HTA) bodies and payers. Little is known about how underlying considerations in HTA of ATMPs shape assessment and reimbursement recommendations. We aim to identify and assess key considerations that played a role in HTA of ATMPs underlying reimbursement recommendations. METHODS: A review of HTA reports was conducted of all authorized ATMPs in Scotland, The Netherlands, and England. Considerations were extracted and categorized into EUnetHTA Core Model domains. Per jurisdiction, considerations were aggregated and key considerations identified (defined as occurring in >1/assessment per jurisdiction). A narrative analysis was conducted comparing key considerations between jurisdictions and different reimbursement recommendations. RESULTS: We identified 15 ATMPs and 18 HTA reports. In The Netherlands and England most key considerations were identified in clinical effectiveness (EFF) and cost- and economic effectiveness (ECO) domains. In Scotland, the social aspects domain yielded most key considerations, followed by ECO and EFF. More uncertainty in evidence and assessment outcomes was accepted when orphan or end-of-life criteria were applied. A higher percentage of considerations supporting recommendations were identified for products with positive recommendations compared with restricted and negative recommendations. CONCLUSIONS: This is the first empirical review of HTA's using the EUnetHTA Core Model to identify and structure key considerations retrospectively. It provides insights in supporting and opposing considerations for reimbursement of individual products and differences between jurisdictions. Besides the EFF and ECO domain, the social, ethical, and legal domains seem to bear considerable weight in assessment of ATMPs.

Ethics of emerging infectious disease outbreak responses: Using Ebola virus disease as a case study of limited resource allocation.

Emerging infectious diseases such as Ebola Virus Disease (EVD), Nipah Virus Encephalitis and Lassa fever pose significant epidemic threats. Responses to emerging infectious disease outbreaks frequently occur in resource-constrained regions and under high pressure to quickly contain the outbreak prior to potential spread. As seen in the 2020 EVD outbreaks in the Democratic Republic of Congo and the current COVID-19 pandemic, there is a continued need to evaluate and address the ethical challenges that arise in the high stakes environment of an emerging infectious disease outbreak response. The research presented here provides analysis of the ethical challenges with regard to allocation of limited resources, particularly experimental therapeutics, using the 2013-2016 EVD outbreak in West Africa as a case study. In-depth semi-structured interviews were conducted with senior healthcare personnel (n = 16) from international humanitarian aid organizations intimately engaged in the 2013-2016 EVD outbreak response in West Africa. Interviews were recorded in private setting, transcribed, and iteratively coded using grounded theory methodology. A majority of respondents indicated a clear propensity to adopt an ethical framework of guiding principles for international responses to emerging infectious disease outbreaks. Respondents agreed that prioritization of frontline workers' access to experimental therapeutics was warranted based on a principle of reciprocity. There was widespread acceptance of adaptive trial designs and greater trial transparency in providing access to experimental therapeutics. Many respondents also emphasized the importance of community engagement in limited resource allocation scheme design and culturally appropriate informed consent procedures. The study results inform a potential ethical framework of guiding principles based on the interview participants' insights to be adopted by international response organizations and their healthcare workers in the face of allocating limited resources such as experimental therapeutics in future emerging infectious disease outbreaks to ease the moral burden of individual healthcare providers.

Regulatory oversight of cell therapy in China: Government's efforts in patient access and therapeutic innovation.

In recent years, remarkable progress has been made in the fundamental research and on clinical development of cell therapy. Although China has launched a series of regulations to establish a proper regulatory framework that facilitates the development of cell therapy products, the regulatory framework has not been able to meet the country's regulatory requirements. This article introduced the development of regulation and current regulatory pathways for cell therapy in China and identified the main challenges in clinical studies. China has recently tightened its policy on cell therapy clinical studies after medical chaos occurred in the area of cell therapy over the past few years. Currently the regulatory jurisdiction between NMPA and NHC are not very clear, especially for clinical somatic cell research, further efforts are necessary to establish a legislative system with a clear and functional regulatory framework for cell therapy.

Alive inside.

This article provides an ethical analysis of the U.S. practice guideline update on disorders of consciousness. Our analysis focuses on the guideline's recommendations regarding the use of investigational neuroimaging methods to assess brain-injured patients. Complex and multifaceted ethical issues have emerged because these methods alter the clinical understanding of consciousness. We address issues of false hope, patient suffering, and cost. We argue that, in spite of these concerns, there is significant benefit to using neuroimaging to assess brain-injured patients in most cases.

Should a Caregiver's QoL Be Considered in Decisions About Whether a Patient Has an Experimental Double-Hand Transplant?

A goal of hand and upper extremity transplantation is to return motor and sensory function to an amputee. Given the integral roles of one's hands in activities of daily living and social interaction, however, restoring psychosocial well-being should also be a priority. Based on the authors' experience, double-hand transplantation success depends significantly on strong social support, physical rehabilitation, medication adherence, and social integration. Because caregiving is demanding, tasks should be distributed among members of a patient's family and social network. This article analyzes how to respond to an overwhelmed caregiver by drawing on solid organ transplant literature about caregiver fatigue.

Unproven stem cell therapies: is it my right to try?

BACKGROUND: Nowadays one of the most critical aspects of innovative cell-based therapies is the unregulated industry, as it is becoming a competitor of the regulated system. Many private clinics, worldwide, advertise and offer cell-based interventions treatments directly to the consumer and this poses a risk to both vulnerable patients and health systems. Several countries have implemented Compassionate Use Programmes (CUP) that provide patients with medicines that have not yet completed the approval pathway, in the event that no reasonable alternative exists. Recently, in the public discourse, compassionate use has been increasingly associated with a patient's right to try. Thus, the aim of this study was to assess public knowledge of the clinical trials process with specific reference to innovative stem cell treatments, and trust in the institutions responsible for regulatory activities. We also asked people about their "right" to use unregulated therapies. METHODS: We developed an ad hoc questionnaire on three main areas of concern and administered it to 300 people in the patient waiting room at an Italian university hospital. RESULTS: Our findings suggest that people have a good knowledge of the clinical trials process and trust in healthcare institutions. Nonetheless, one person in two believes it is a right to use unregulated therapies. CONCLUSIONS: We stress the need, in the age of cellular therapies, for a commitment to support vulnerable patients and to strengthen awareness among the public about the substantial boundary that differentiates experimental therapies from unproven therapies. There should not be a "right to try" something that is unsafe but rather approved treatments and in line with good clinical practice. The trend, which emerged on this issue from our study, is quite different, confirming the urgent need to improve health information so that it is as complete as possible.

Two's company, is three a crowd? Ethical cognition in decision making and the role of industry third parties in pediatric diabetes care.

Families of children with diabetes increasingly obtain health information from a variety of sources. Doctor-patient relationships have accordingly become more fluid and dynamic with input from other parties. These outside parties include representatives from the diabetes health care industry-industry third parties (ITPs). This review is an exploration of the ethical principles and cognitive processes involved when doctors and patients negotiate around health care practices and the role of ITPs in that dialogue. Ethical principles of conflicts of interest, beneficence (act in the best interests of the patient), non-maleficence (act so as to do no harm) and justice (act so as to allocate resources fairly or justly) are relevant considerations. Reflexive and analytic thinking and various cognitive biases also play a significant part in clinical decision making. A complex case example is analyzed to highlight a process of ethical cognition in decision making to ensure high-value care and optimal patient outcomes.

Implementing post-trial access plans for HIV prevention research.

Ethics guidance increasingly recognises that researchers and sponsors have obligations to consider provisions for post-trial access (PTA) to interventions that are found to be beneficial in research. Yet, there is little information regarding whether and how such plans can actually be implemented. Understanding practical experiences of developing and implementing these plans is critical to both optimising their implementation and informing conceptual work related to PTA. This viewpoint is informed by experiences with developing and implementing PTA plans for six large-scale multicentre HIV prevention trials supported by the HIV Prevention Trials Network. These experiences suggest that planning and implementing PTA often involve challenges of planning under uncertainty and confronting practical barriers to accessing healthcare systems. Even in relatively favourable circumstances where a tested intervention medication is approved and available in the local healthcare system, system-level barriers can threaten the viability of PTA plans. The aggregate experience across these HIV prevention trials suggests that simply referring participants to local healthcare systems for PTA will not necessarily result in continued access to beneficial interventions for trial participants. Serious commitments to PTA will require additional efforts to learn from future approaches, measuring the success of PTA plans with dedicated follow-up and further developing normative guidance to help research stakeholders navigate the complex practical challenges of realising PTA.

Medical Negligence Determinations, the "Right to Try," and Expanded Access to Innovative Treatments.

This article considers the issue of expanded access to innovative treatments in the context of recent legislative initiatives in the United Kingdom and the United States. In the United Kingdom, the supporters of legislative change argued that the common law principles governing medical negligence are a barrier to innovation. In an attempt to remove this perceived impediment, two bills proposed that innovating doctors sued for negligence should be able to rely in their defence on the fact that their decision to innovate was "responsible." A decision to innovate would be regarded as responsible if it followed a specified process. Although these changes to the law of medical negligence were not passed, this article argues that the idea of a process-based approach was sound. In the United States, a number of states have passed "Right to Try" laws that permit doctors to prescribe and companies to provide investigational products without the need for FDA approval. These laws do not purport to and nor are they able to alter the obligations of individuals and companies under federal law. They are consequently unlikely to achieve their stated aim of expanding access to investigational products. This article argues that they nevertheless have a cogent rationale in so far as they highlight the need for rights-based reform to federal regulations governing access.

2016 CAPS ethics session/Ein debate: 1. Regionalization of pediatric surgical care 2. Ethical introduction of surgical innovation 3. Addressing stress in a surgical practice: resiliency, well-being, and burnout.

The following is the conference proceeding of the Second Ein Debate from the 48th Annual Meeting of the Canadian Association of Paediatric Surgeons held in Vancouver, BC, from September 22 to 24, 2016. The three main topics for debate, as prepared by the members of the CAPS Ethics Committee, are: 1. Regionalization of care: pros and cons, 2. Innovation in clinical care: ethical considerations, and 3. Surgeon well-being: caring for the caregiver. The authors of this paper, as participants in the debate, were assigned their positions at random. Therefore, the opinions they express within this summary might not reflect their own viewpoints. In the first discussion, arguments for and against the regionalization of pediatric surgical care are discussed, primarily in the context of a case of BA. In the pro argument, the evidence and lessons learned from different European countries are explored as well as different models to provide the best BA care outside of large teaching centers. In the counterargument, the author explains how regionalization of care could be detrimental for the patient, the family, the regional center, and for the health care system in general. In the debate on surgical innovation the authors define surgical innovation. They review the pertinent ethical principles, explore a model for its implementation, and the role of the institution at which the innovation is proposed. In the third section, surgeon well-being is examined, and recent literature on surgeon resiliency and burnout both at the attending and resident level is reviewed.

An analysis of common ethical justifications for compassionate use programs for experimental drugs.

BACKGROUND: When a new intervention or drug is developed, this has to pass through various phases of clinical testing before it achieves market approval, which can take many years. This raises an issue for drugs which could benefit terminally ill patients. These patients might set their hopes on the experimental drug but are unable to wait since they are likely to pass away before the drug is available. As a means of nevertheless getting access to experimental drug, many seriously ill and terminally ill patients are therefore very willing to participate in randomised controlled trials. However, only very few terminally ill patients are able to actually participate, and those that do participate are at risk of participating solely as a way of getting experimental drugs. Currently, there are, however, ways of getting access to drugs that have not (yet) gained market approval. One such mean is via expanded access or compassionate use programs where terminally ill patients receive experimental new drugs that are not yet market approved. In this paper, I examine some of the common justifications for such programs. MAIN BODY: The most frequently voiced justifications for compassionate use or expanded access programs could be put in one of three categories. First, there are justifications of justice, where compassionate use programs could be seen as a just or fair way to distribute experimental new drugs to patients who are denied access to RCT's through no fault of their own. Second, such programs could be justified by reference to the ethical principle of beneficence where it could be claimed that terminally ill patients stand to benefit greatly at very little risk (as they are already dying). Third, there are considerations of autonomy where, it is claimed, patients should be able to exercise their autonomy and have access to such drugs if that is there free choice and they are fully aware of the risks associated with that choice. SHORT CONCLUSION: In this paper, I argue currently all justifications are potentially problematic. If they truly form the basis for justification, compassionate use programs should be designed to maximize justice, beneficence and autonomy.

Is there a right to access innovative surgery?

Demands for access to experimental therapies are frequently framed in the language of rights. This article examines the justifiability of such demands in the specific context of surgical innovations, these being promising but non-validated and potentially risky departures from standard surgical practices. I argue that there is a right to access innovative surgery, drawing analogies with other generally accepted rights in medicine, such as the right not to be forcibly treated, to buy contraceptives, and to choose to have an abortion, including a post-viability abortion where the mother's life or health is threatened by the pregnancy. I argue that we accept these rights because we believe that people are entitled to try to preserve their lives and health and to make choices of an important and intensely personal kind, and I suggest that a person's choice of medical treatment should be seen in the same light. However, since few rights are absolute, I also consider the circumstances in which it may be justifiable to limit the right to access innovative surgery. In discussing this question, I apply the human rights standard of proportionality, comparing the importance of the reasons for limiting the right with the severity of the invasion on liberty.

New treatments compared to established treatments in randomized trials.

BACKGROUND: The proportion of proposed new treatments that are 'successful' is of ethical, scientific, and public importance. We investigated how often new, experimental treatments evaluated in randomized controlled trials (RCTs) are superior to established treatments. OBJECTIVES: Our main question was: "On average how often are new treatments more effective, equally effective or less effective than established treatments?" Additionally, we wanted to explain the observed results, i.e. whether the observed distribution of outcomes is consistent with the 'uncertainty requirement' for enrollment in RCTs. We also investigated the effect of choice of comparator (active versus no treatment/placebo) on the observed results. SEARCH METHODS: We searched the Cochrane Methodology Register (CMR) 2010, Issue 1 in The Cochrane Library (searched 31 March 2010); MEDLINE Ovid 1950 to March Week 2 2010 (searched 24 March 2010); and EMBASE Ovid 1980 to 2010 Week 11 (searched 24 March 2010). SELECTION CRITERIA: Cohorts of studies were eligible for the analysis if they met all of the following criteria: (i) consecutive series of RCTs, (ii) registered at or before study onset, and (iii) compared new against established treatments in humans. DATA COLLECTION AND ANALYSIS: RCTs from four cohorts of RCTs met all inclusion criteria and provided data from 743 RCTs involving 297,744 patients. All four cohorts consisted of publicly funded trials. Two cohorts involved evaluations of new treatments in cancer, one in neurological disorders, and one for mixed types of diseases. We employed kernel density estimation, meta-analysis and meta-regression to assess the probability of new treatments being superior to established treatments in their effect on primary outcomes and overall survival. MAIN RESULTS: The distribution of effects seen was generally symmetrical in the size of difference between new versus established treatments. Meta-analytic pooling indicated that, on average, new treatments were slightly more favorable both in terms of their effect on reducing the primary outcomes (hazard ratio (HR)/odds ratio (OR) 0.91, 99% confidence interval (CI) 0.88 to 0.95) and improving overall survival (HR 0.95, 99% CI 0.92 to 0.98). No heterogeneity was observed in the analysis based on primary outcomes or overall survival (I(2) = 0%). Kernel density analysis was consistent with the meta-analysis, but showed a fairly symmetrical distribution of new versus established treatments indicating unpredictability in the results. This was consistent with the interpretation that new treatments are only slightly superior to established treatments when tested in RCTs. Additionally, meta-regression demonstrated that results have remained stable over time and that the success rate of new treatments has not changed over the last half century of clinical trials. The results were not significantly affected by the choice of comparator (active versus placebo/no therapy). AUTHORS' CONCLUSIONS: Society can expect that slightly more than half of new experimental treatments will prove to be better than established treatments when tested in RCTs, but few will be substantially better. This is an important finding for patients (as they contemplate participation in RCTs), researchers (as they plan design of the new trials), and funders (as they assess the 'return on investment'). Although we provide the current best evidence on the question of expected 'success rate' of new versus established treatments consistent with a priori theoretical predictions reflective of 'uncertainty or equipoise hypothesis', it should be noted that our sample represents less than 1% of all available randomized trials; therefore, one should exercise the appropriate caution in interpretation of our findings. In addition, our conclusion applies to publicly funded trials only, as we did not include studies funded by commercial sponsors in our analysis.

Innovative surgery: the ethical challenges.

Innovative surgery raises four kinds of ethical challenges: potential harms to patients; compromised informed consent; unfair allocation of healthcare resources; and conflicts of interest. Lack of adequate data on innovations and lack of regulatory oversight contribute to these ethical challenges. In this paper these issues and the extent to which problems may be resolved by better evidence-gathering and more comprehensive regulation are explored. It is suggested that some ethical issues will be more resistant to resolution than others, owing to special features of both surgery and innovation.