Ethical Issues Involved in Solid Organ Xenotransplantation.

Xenotransplant research offers hope to individuals waiting for vital organ transplants. Nascent first-inhuman xenotransplantation research trials present unique ethical challenges which may translate into obligations for researchers and special considerations for institutional review boards (IRBs). Contextual vulnerability is an important consideration in reviewing proposed subject selection methods. Some recipients are uniquely prone to receiving an unfair offer to enroll in an experimental clinical trial when excluded from allograft waitlists due to psychosocial or compliance evaluations. These exclusions represent an allocational injustice. Enrolling research subjects subjectively excluded from allotransplantation into xenotransplant research is not a mechanism of fair access but rather an exploitation of an unjustly optionconstrained vulnerable group by the clinical transplant system. Carefully considering contextual vulnerability can help researchers and IRBs clarify eligibility criteria for xenograft clinical trials. A requirement for simultaneous allograft co-listing can safeguard the interests of vulnerable potential subjects.

2014 National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: Preface to the Series

Salivary Gland Involvement in Chronic Graft-Versus-Host Disease: Prevalence, Clinical Significance, and Recommendations for Evaluation

Clinical trial eligibility criteria are necessary to define the patient population under study and improve trial safety. However, there are concerns that eligibility criteria for cancer clinical trials are too restrictive and limit patient enrollment in clinical trials. Recently, there have been initiatives to re-examine and modernize eligibility criteria for oncology clinical trials. To assess current eligibility requirements for cancer clinical trials, we have conducted a comprehensive review of eligibility criteria for commercial investigational new drug clinical trial applications submitted to the US Food and Drug Administration Office of Hematology and Oncology Products in 2015. Our findings suggest that eligibility criteria for current cancer clinical trials tend to narrowly define the study population and limit the study to lower-risk patients, which may not be reflective of the greater patient population outside of the study. We discuss potential areas for expanding eligibility criteria to include more patients in clinical trials and design options for clinical trials incorporating expanded eligibility criteria. The broadening of clinical trial eligibility criteria can be considered to better reflect the real-world patient population, improve clinical trial participation, and increase patient access to new investigational treatments.

The medical treatment of patients with chronic, life-threatening or seriously disabling diseases can be very disappointing both for the suffering patient and their physicians in cases where patients cannot be treated satisfactorily with currently authorized medicines. It may be possible to successfully treat such patients with new pharmaceuticals that have not yet been authorized by suitable clinical trials. But clinical trials are time-consuming and costly, and not every patient meets the enrolment criteria for specific clinical trials. An aggravating factor is that the marketing authorization of promising new pharmaceuticals can take several years, which is valuable time lost from the patient’s perspective. One way to tackle this problem is to allow seriously-ill patients to obtain the medicines through a “compassionate-use” programme. The term “compassionate use” is defined in Article 83 no. 2 of the Regulation (EC) no. 726/2004 of the European Parliament and of the Council1 as “… making a medicinal product belonging to the categories referred to in Article 3 (1) and (2) available for compassionate reasons to a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily by an authorized medicinal product. The medicinal product concerned must either be the subject of an application for a marketing authorization in accordance with Article 6 of this Regulation or must be undergoing clinical trials.” This regulatory framework was created by the European Legislature in 2004. Until then, France and Italy were the only two European countries with compassionate-use programmes incorporated into national law. However, the European framework does not include any binding process regulations for countries on how to introduce and implement their own compassionate-use programmes. At present, there is only a nonbinding guideline by the Committee for Medicinal Products for Human Use (CHMP),2 the scientific committee of the European Medicines Agency (EMA). Member States should notify the EMA when they make use of the compassionate-use provision outlined in paragraph 1 of Article 83 of the Regulation (EC) no. 726/2004. The CHMP, after consulting the manufacturer or the applicant, may adopt opinions on the conditions for use and distribution and the patients targeted for compassionate use in a given therapeutic indication. The opinions will be updated on a regular basis. In January 2010, the CHMP published its first opinions on two compassionate-use programmes in the European Union.3 The first opinion was about the compassionate use of intravenous oseltamivir (Tamiflu®), notified to the EMA by Finland.4 The CHMP has also published an assessment report on the compassionate use of this medicinal product.5 The other opinion, which was notified by Sweden and published by the CHMP, was about the compassionate use of intravenous zanamivir.6 Due to the nonbinding nature of the European Regulation and the CHMP guideline, it is up to each Member State to adopt its own corresponding national legal procedures for the introduction and implementation of compassionate-use programmes. Germany introduced its own regulations in July 2010 and has created a quick and efficient procedure for establishing compassionate-use-programmes.7 At time of publication, there were four notifications confirmed by the national pharmaceutical authority in Germany.8 Other European countries, such as the Netherlands, Norway and Spain, have also established national regulations. Austria and the United Kingdom of Great Britain and Northern Ireland plan to present their new procedural rules soon. The strict conditions of the national procedural rules mean that the use of not-yet authorized pharmaceuticals will continue to be an exception. Only a few national cases are expected to meet these conditions in any year but, in these cases, the new regulations may save valuable time for patients who have run out of treatment options. This is exactly why such regulations with clear guidelines and a fast-track procedure were long overdue. It is desirable that the other Member States of the European Union follow these examples, so that seriously ill patients throughout Europe can access promising alternative medical therapies.

Organ Trafficking: Global Solutions for a Global Problem

Imagine the following: A 58-year-old surgeon recently diagnosed with Stage 4 lung cancer comes to see you for clinical trial options. He is otherwise in excellent health, and he takes no medications. He is highly motivated to receive cutting-edge treatments, has a thorough understanding of the nature of the disease and potential therapies, and states he will be strictly adherent to any recommended treatment regimen. However, he is not eligible for any clinical trial available at your institution due to a history of localized prostate cancer treated surgically three years previously.

Clinical Applications for Biomarkers of Acute and Chronic Graft-versus-Host Disease

Graft-versus-Host Disease: State of the Science

Organ Procurement and Transplant Equity Among US Residents: The 5% Guideline

Same-Day Consent for Regional Anesthesia Clinical Research Trials: It's About Time.

Gender and sex bias in clinical trial recruitment in Alzheimer's disease: Findings from Fundació ACE

To identify the percentage of patients with Alzheimer's disease (AD) in a general clinic population who would be provisionally eligible for randomized clinical trials and the extent to which these patients represent the overall clinic-based population. Many randomized clinical trials have restricted enrollment criteria that may limit generalizability, i.e., AD patients who fulfill selection criteria for phase III clinical trials may not be representative of other AD patients in clinical settings. Patients diagnosed as probable or possible AD from the nine clinical sites of the State of California's Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) were selected on the basis of their provisionally fulfilling the inclusion and exclusion criteria of two typical AD clinical trials at the time of their first visit (ECG and brain imaging criteria were not available). From a sample of 3470 subjects with possible or probable AD, overall, only 4.4% or 7.9% would have been provisionally eligible for each of two trials. Patients provisionally eligible were younger, relatively underrepresented by women, better educated, wealthier, and more likely to be white than ineligible patients. The major independent demographic predictors for eligibility were (1) income greater than $15,000 per year, (2) male gender, and (3) college education. More than 60% of probable AD patients were excluded because of significant behavioral problems; approximately one-quarter each were excluded because of significant medical or neurological problems. Allowing patients with probable or possible AD to enroll would have resulted in 10.6% being eligible. Selection criteria for AD clinical trials result in a demographically and clinically constrained subgroup that is not representative of the overall clinic population.

Conditioning with Treosulfan and Fludarabine followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

How Do Patients With Idiopathic Pulmonary Fibrosis in the Real World Compare With Eligibility Criteria for Clinical Trials?