Publication ethics: Patient consent for publishing case reports of adverse drug reactions is important yet absent from several recent manuscripts
A. Kumar
Ethics, Medicine and Public Health, October 2022; 24
Summary
Background
Case reports of adverse drug reactions (ADRs) constitute an important source of medication safety information. Detailed description of patients in such reports could potentially make subjects identifiable, thereby emphasizing the importance of consent for publication. The Committee on Publication Ethics and the International Committee of Medical Journal Editors recommend obtaining patient consent prior to publishing potentially identifiable patient information. However, this report shows absence of information regarding patient consent for publication from several recently-published ADR case reports.
Methodology
A sample of 100 most-recent ADR case reports with free full-text indexed in PubMed was qualitatively reviewed for information regarding publication consent and other ethical disclosures.
Results
Of the 100 most-recently-published ADR case reports, only 52 (52%) manuscripts clearly described obtaining patient consent for publication. Thirty-seven (37%) manuscripts made no mention of such consent or approval from an ethics committee. Eleven (11%) manuscripts contained ethical disclosures such as patient consent to undergo treatment and study approval from an institutional ethics committee, but without a clear statement regarding patient consent for publication.
Conclusion
A significant number of recently-published ADR case reports do not clearly describe if patient consent for publication was obtained. This could be attributable to various factors, including lack of clarity in journals’ guidelines regarding publication consent for case reports and dilemma regarding what constitutes identifiable patient information. This report calls for diligence of all stakeholders involved in medical manuscript publishing, viz. authors, manuscript reviewers, editors, and journal publishers to ensure that information regarding patient consent for publication is properly disclosed in ADR case reports.

Consensus on informed consent for participants in cancer clinical studies
Dawei Wu, Meimei Chen, Jing Liang, Shuang Li, Weijing Zhang, Yu Lei, Jing Ding, Yumeng Wang, Zhen Chen, Ning Li, Suxia Luo, Jie Li, Minghuang Hong, Zhao Yan
Asia-Pacific Journal of Oncology Nursing, 15 September 2022
Abstract
To fully protect the rights of participants in cancer clinical studies and clarify the key points for the ethics review of the content of informed consent forms and the process of collecting informed consent, the Medical Ethics Professional Committee of the China Anti-Cancer Association engaged in joint discussions with the ethics committees of well-known cancer hospitals in China to formulate this consensus, along with the attached general template for informed consent forms for cancer clinical studies. This work is expected to provide guidance and suggestions for the practice of the sponsors, researchers, and ethics committees.

Identification and Re-consent of Existing Cord Blood Donors for Creation of Induced Pluripotent Stem Cell Lines for Potential Clinical Applications
Keren M Abberton, Tricia L McDonald, Mary Diviney, Rhonda Holdsworth, Stephen Leslie, Martin B Delatycki, Lin Liu, Guy Klamer, Phillip Johnson, Ngaire J Elwood
Stem Cells Translational Medicine, 8 September 2022
Abstract
We aim to create a bank of clinical grade cord blood-derived induced pluripotent stem cell lines in order to facilitate clinical research leading to the development of new cellular therapies. Here we present a clear pathway toward the creation of such a resource, within a strong quality framework, and with the appropriate regulatory, government and ethics approvals, along with a dynamic follow-up and re-consent process of cord blood donors from the public BMDI Cord Blood Bank. Interrogation of the cord blood bank inventory and next generation sequencing was used to identify and confirm 18 donors with suitable HLA homozygous haplotypes. Regulatory challenges that may affect global acceptance of the cell lines, along with the quality standards required to operate as part of a global network, are being met by working in collaboration with bodies such as the International Stem Cell Banking Initiative (ISCBI) and the Global Alliance for iPSC Therapies (GAiT). Ethics approval was granted by an Institutional Human Research Ethics Committee, and government approval has been obtained to use banked cord blood for this purpose. New issues of whole-genome sequencing and the relevant donor safeguards and protections were considered with input from clinical genetics services, including the rights and information flow to donors, and commercialization aspects. The success of these processes has confirmed feasibility and utility of using banked cord blood to produce clinical-grade iPSC lines for potential cellular therapies.

Editor’s note: BMDI Cord Blood Bank is one of three public cord blood banks in Australia, which form the AusCord network.

Informed Consent for Placebo-Controlled Trials: Do Ethics and Science Conflict?
Hope A. Feldman, James A. Feldman, Charles C. Miller, Garrett Walsh, Jon E. Tyson
Ethics & Human Research, 1 September 2022
Abstract
The use of a placebo has been considered the best method for controlling bias in a prospective randomized clinical trial and provides the most rigorous test of treatment efficacy for evaluating a medical therapy. Placebos commonly produce clinically important effects particularly in studies where the primary outcomes are subjective. Yet the potential beneficial or harmful effects of placebos are often not addressed in designing a clinical trial, calculating the sample size, seeking consent, or interpreting clinical trial results. In this manuscript, we use an actual study to indicate three approaches that might be considered in seeking informed consent for placebo-controlled trials, and we explore the fundamental ethical and scientific complexities involved with each.

An Expanded Role for IRBs in the Oversight of Research Biopsies
Laura A. Levit, Julie Kaneshiro, Jeffrey Peppercorn, Mark J. Ratain
Ethics & Human Research, 1 September 2022
Abstract
Research biopsies included in cancer clinical trials have the goal of advancing scientific understanding of the biological bases of cancer and its treatments, but may offer no prospect of direct benefit to participants and often pose more than minimal risk. The research community is examining the ethics of research biopsies increasingly often, especially when they are mandatory for study participation but do not support primary study objectives and thus are “nonintegral” to the study. Ethical concerns center on the limited scientific justification supporting some biopsies, risks to research participants, and the potential for coercion and therapeutic misconception during the informed consent process. There is also a lack of comprehensive oversight of research biopsies by regulatory agencies and institutions. This paper reviews these ethical concerns, discusses the scope of federal oversight, and suggests that institutional review boards (IRBs) should assume a larger role in ensuring the ethical conduct of research biopsies. It concludes with guidance to IRBs on how to weigh the risks, benefits, and acceptability of such biopsies in different contexts that is based on a framework the American Society of Clinical Oncology developed for the inclusion of research biopsies in oncology clinical trials.

Initial Steps in Creating a Patient-Centric Addendum to Clinical Trial Informed Consent Forms
King-Kallimanis, A. Ferris, L. Dropkin, M. Molina, L. Redway, U. Basu Roy
Journal of Thoracic Oncology, September 2022; 17(9) pp S71-S72
Abstract
Introduction
The purpose of the informed consent form (ICF) is to outline risks and benefits of an interventional clinical trial to a patient. In reality, most ICFs are written using scientific jargon, are long, and include extraneous information not pertinent to the patient (e.g., legalities of trial participation). Using lung cancer as a case study, we are conducting a multi-step project involving patients and caregivers, trialists, regulators, and clinical trial sponsors to streamline the informed consent process by creating a 1-2 page template addendum to the ICF summarizing key points relevant to patients.
Methods
Step 1 included an audit of 20 ICFs guided by 45 CFR 46, HHS regulations for the protection of human subjects in research, which requires the ICF to explain elements like which procedures are experimental. Step 2 included focus groups and in-depth interviews with patients with lung cancer (n=9) to learn what information was critical when considering a hypothetical ICF. In this abstract key, findings from steps 1/2 are summarized. Additional steps are planned to reach our final outcome.
Results
The 20 ICFs reviewed were from phases 1, 2, and 3, expanded access and single patient trials covering predominantly non-small cell lung cancer and 60% were global trials. Average length of the ICFs was 21 (range 15-34) pages and most required CFR topics were covered. “What would happen if the trial failed” was least often covered (14 of 20). Average reading level was 10th grade, whereas average US reading level is 8th grade. Readability varied by section, “the purpose of the study” section had the highest reading level (11.5). In the qualitative research component (step 2), all participants were “overwhelmed” by the hypothetical ICF. When asked the intent of the forms, one participant noted “to cover their butts”. The idea of an addendum that provides a summary with reference to page numbers in the ICF for more details was well received. Participants were asked to list information they wanted included in the addendum (table). Suggestions broadly map to HHS regulations.
Conclusions
While ICFs place greatest emphasis on trial procedures and risks, variations in ICF architecture and readability mean it is difficult for patients to make an informed decision to participate in a clinical trial. Our study implications extend beyond lung cancer, highlighting key areas for improvements to the ICFs and providing a clear roadmap for developing a patient-centric addendum for ICFs in all cancer clinical trials.

A Census of Clinical Trials Conducted Under the US Exception from Informed Consent Rule
Krista L. Snyder, Jon F. Merz
medRxiv, 24 August 2022
Abstract
Background
The US Food and Drug Administration and National Institutes of Health adopted the Exception from Informed Consent (EFIC) rule in 1996, permitting waiver of informed consent for certain emergency research, including trials funded by the federal government. The rule requires that prospective consent be sought when practicable from patients or their Legally Authorized Representative(s) (LAR), and for those enrolled without consent, the patient or their LAR must be given information and an opportunity to opt-out from continued participation at the earliest opportunity. We sought to census the trials conducted under the EFIC rule to facilitate research to better understand how the rule is being used.
Methods
We conducted a multi-pronged search to try and identify all trials conducted under the EFIC rule, drawing on numerous reviews, Medline and Google searches (including of the clinicaltrials.gov registry), examination of the FDA’s docket, posting an inquiry on the IRB Forum, and email requests to lead authors of all published EFIC trials and related review articles. We describe the trials, when they were started and completed, and whether they were terminated early.
Results
We identified a total of 105 trials as of April 1, 2022: 77 complete, 10 recruiting, 10 registered on clinicaltrials.gov but not yet recruiting, 5 trials that were abandoned before enrolling any subjects, and 3 trials in early planning. Nine of the 77 completed trials were pilot or feasibility trials. Of 68 completed full trials, 30 (44.1%) were terminated early. The most common reason for early termination was futility or safety (17 trials, 25.0%) followed by poor recruitment (9 trials, 13.2%). The rate of conduct of trials has been remarkably constant since 2001, with roughly 18 trials started in each 5-year period.
Conclusions
The rate of early termination of EFIC trials for futility or safety appears higher than for other kinds of clinical research. We provide the list of trials in a Supplement for further in-depth data collection and analysis of this set of trials.

Use Of Teach-Back During Informed Consent In Cancer Clinical Trials
Christa Varnadoe
Yale School of Nursing Digital Theses, 2022
Open Access
Abstract
Five percent of the 1.8 million patients diagnosed with cancer in the United States (US) enroll annually in a clinical trial (American Cancer Society, 2021; Institute of Medicine Committee on Cancer Clinical Trials; National Cancer Institute Cooperative Group Program, 2010). Flawed research consent practices are detrimental to patient safety and costly to the US Healthcare system (Eisenberg et al., 2012; Unger et al., 2019). Well trained nurses are imperative to conducting rigorous, reproducible, and quality research (Brandt et al., 2011). Programs designed to educate nurses on how to implement comprehensive communication strategies confidently during the Cancer Clinical Trials (CCT) consent process remain scarce (Nusbaum et al, 2019; Purdom et al., 2017). The purpose of this quality improvement project was to develop, implement, and evaluate the effects of an evidenced-based education program on nurse confidence with use of the teach-back method during the CCT consent process. An evidenced based education program was developed. It was implemented as a synchronous webinar to members of the International Association of Clinical Research Nurses. Pre and post test program surveys measuring confidence levels were disseminated. There was an overall increase in postsurvey responses suggesting an improvement in confidence levels with use of the teach-back method during the CCT IC process. Further study can explore if patient understanding of CCTs during the IC process is developed proportionally to levels of nurse confidence with use of the teach-back method.

Ethical Considerations during the Informed Consent Process for Acute Ischemic Stroke in International Clinical Trials
Tiffany Bellomo, Jennifer Fokas, Noah Tsao, Clare Anderson, Christopher Becker, Rachel Gioscia-Ryan, William Meurer
Ethics & Human Research, 8 July 2022; 44(4) pp 14-25
Abstract
We sought to investigate the experiences of researchers in existing active-control trials in acute ischemic stroke comparing investigational therapy to tissue plasminogen activator (tPA) in order to identify the approaches and challenges in obtaining informed consent. Out of 401 articles evaluated, 14 trials met inclusion criteria. Trial representatives were contacted to complete a survey concerning the consent process. None of the 14 trials published materials related to the informed consent process. Trials with 75% to 100% of patients directly consented had shorter door-to-treatment (DTT) times than trials that directly consented less than 50% of patients. Trials that had translators available (for recruiting participants who were not native speakers in the local language) and translated consent documents had longer DTT times. The study findings suggest that differences in the standards of informed consent internationally may allow more patients with moderate strokes to provide direct consent without delaying DTT time. Future trials should emphasize transparency to the public and scientific community in the informed consent process.

Developing and Implementing Electronic Consent Procedures in Response to Covid-19 Restrictions
Julie R. Bromberg, Evelyn Nimaja, Andrew W. Kiragu, Karla A. Lawson, Lois Lee, Isam W. Nasr, Charles Pruitt, Stephanie M. Ruest, Michael J. Mello
Ethics & Human Research, 8 July 2022; 44(4) pp 34-38
Open Access
Abstract
The Covid-19 pandemic resulted in unprecedented restrictions on many public, private, and workplace activities throughout the United States and elsewhere. When restrictions were imposed, we were conducting a type III hybrid effectiveness-implementation trial in 10 pediatric trauma centers. In response to several pandemic-based restrictions, we had to develop procedures for engaging with potential research participants while limiting nonclinical, in-person interactions. This manuscript describes the procedures and challenges of obtaining electronic informed consent and assent in a multisite trauma center-based research study. We developed, tested, and trained staff to implement three options for obtaining informed consent. Twenty-five participants were enrolled in the effectiveness-implementation multisite trial during the first six months of utilization of the consent options, with eleven of these individuals enrolled using hybrid or electronic consent procedures. The challenges we identified involving electronic consent procedures included confusion over who would complete the electronic consent process and difficulties reconnecting with families. Lessons learned can strengthen electronic consent and assent procedures for future studies. More research is needed to further strengthen this process and increase its utilization.