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Catastrophic Disruptions in Clinical Trials

2022; Lippincott Williams & Wilkins; Volume: 146; Issue: 5 Linguagem: Inglês

10.1161/circulationaha.122.060541

1524-4539

Josephine Harrington, G. Michael Felker, Robert J. Mentz,

Bipolar Disorder and Treatment

HomeCirculationVol. 146, No. 5Catastrophic Disruptions in Clinical Trials Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBCatastrophic Disruptions in Clinical Trials Josephine Harrington, G. Michael Felker and Robert J. Mentz Josephine HarringtonJosephine Harrington https://orcid.org/0000-0001-5169-117X Department of Medicine, Division of Cardiology, Duke University, Durham, NC. Duke Clinical Research Institute, Durham, NC. , G. Michael FelkerG. Michael Felker https://orcid.org/0000-0002-5931-1239 Department of Medicine, Division of Cardiology, Duke University, Durham, NC. Duke Clinical Research Institute, Durham, NC. and Robert J. MentzRobert J. Mentz Correspondence to: Robert J. Mentz, MD, Duke University School of Medicine, 200 Trent Dr, 4th Floor, Orange Zone, Room 4221, Durham, NC 27710. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3222-1719 Department of Medicine, Division of Cardiology, Duke University, Durham, NC. Duke Clinical Research Institute, Durham, NC. Originally published1 Aug 2022https://doi.org/10.1161/CIRCULATIONAHA.122.060541Circulation. 2022;146:369–371The clinical research community, like others, has watched the unfolding humanitarian crisis in Ukraine with great concern. With >6000 ongoing or planned clinical trials in Ukraine, many global clinical research teams have well-established relationships with sites and local research teams in Ukraine.1 As research teams have worked to understand the optimal ways to support colleagues during the evolving situation, complex decisions have also been faced about plans for trial execution and analytic considerations for data from these regions. Here, we consider the ethical, operational, and scientific considerations surrounding conducting clinical trials after a catastrophic disruption to trial conduct.Although fortunately the violence seen in Ukraine is not commonly encountered in clinical trials, catastrophes affecting clinical trial conduct can and do occur. Wildfires threatening site safety, flooding destroying patient records, and pandemic-related lockdowns have all demanded rapid responses from trial teams in recent years. In these and all instances, the first and most important focus is the safety of the staff and participants in the affected region. For trial participants who have been affected by such a catastrophe, continued participation in the clinical trial may no longer be safe, feasible, or a priority. Sites may be unreachable or even destroyed, trial participants may have relocated, and normal study operations may be impracticable. In such cases, how can research teams respond in a way that acknowledges and supports the evolving needs of sites and trial participants, while simultaneously protecting the integrity of the ongoing trial?One of the most important considerations for a trial during a catastrophe must be the ethics of ongoing trial participation by affected sites and participants. In some cases, ongoing involvement may be impossible. But what to do for participants who want to continue in a trial in the face of such adversity? Patients enter a clinical trial to contribute to progress in a field that is often directly relevant to their own health. Taking an investigational drug or product often comes with an agreement to be exposed to some degree of risk: this risk is accepted by participants with the understanding that the risk is necessary to contribute to the advancement of knowledge. If patients have consented to receive an investigational study drug or device, research teams have an obligation to measure the effect of that intervention, provided that doing so does not fundamentally undermine the trial itself. Otherwise, participants are exposed to the risks of investigational products but deprived of the opportunity to contribute to trial findings.Operationally, efforts to keep participants as involved in the trial as can be safely and reasonably accomplished demand flexibility and creativity (Table). There may be significant challenges involved in these efforts, and research teams need to establish what is possible and practical for both their sites and their participants. Although we propose a number of potential responses to enable patient involvement while safeguarding trial integrity, these strategies may not be appropriate in all settings. A participant whose home has been damaged by a wildfire may face ongoing challenges but is likely no longer in immediate danger. A participant living in a country at war may want to continue in a clinical trial but may need to vary their degree of involvement relative to safety concerns as the situation evolves. These challenges must be faced with flexibility and compassion from research teams.Table. Potential Strategies to Address Unexpected Disruptions in Clinical TrialsChallengePreemptive strategyPost-disruption response optionsOperational Patients or staff unable to travel to research siteIncorporate options for remote visits into trial protocolTransition to decentralized trial model (as able)Relocate patients to other local unaffected sites if transfer possible Staff unavailable to dispense drug on siteDirect delivery of drug to patients Limited resources for study laboratory draws; unable to ship samples to central laboratoryMinimize laboratory draws as possible—prioritizing end point and safety considerationsPivot from central to local laboratory testing with clear documentation Inability to collect certain end points in personEmbed patient-reported outcomes (by remote strategies) as end points within trialCollect patient-reported outcomes and events with acquisition of source documents to the extent possibleData management Delayed data entryIncreased flexibility on data entry timelines (ie, broaden documentation windows) Loss of physically recorded dataEmphasize use of backup off-site or cloud-based data storage strategiesAssessment of opportunities to ascertain data by other sources (eg, national data registers)Statistical Potential effect of catastrophic event on study outcomes and event ratesSensitivity analyses excluding affected regions either completely or at specific time points of the catastropheAs research teams gain expertise and experience in decentralized trials, the operational strategies used in decentralized trial conduct may offer tools to be used in times when traditional trial conduct is impossible. Pivoting to these decentralized methods may allow for research conduct to continue in times traditional trial methods are impossible. Telephone or digital check-ins, direct to participant drug delivery, and patient-reported end points are all tools that could be used in situations when participants are no longer able to participate in a traditional trial model with scheduled in-person site visits. Although these decentralized strategies may become substantially more prominent within a trial after a catastrophe, embedding them into a research protocol at the onset of a trial will allow for preliminary logistics to be established during planning, with further adaptation as needed in response to changing conditions. Similarly, establishing strategies to safeguard data must be discussed at the onset of a trial.From a scientific perspective, there may be concern about the effect of major disasters on trial results, either regionally or overall. Nonetheless, a central goal should be to represent each participant as fully and completely as is reasonable to most thoroughly evaluate the totality of the evidence. One practical approach to this is to prespecify sensitivity analyses to evaluate the effect of disruptions on clinical trial findings. Similar strategies have been used previously to assess the effect of the COVID-19 pandemic.2,3 An alternative strategy would be to perform a sensitivity analysis excluding affected participants (for example, Ukrainian trial participants) to characterize the degree to which the catastrophic disruption of trial conduct affected trial outcomes. Such trial modifications must be transparently discussed within both trial manuscripts and protocols. To this end, the recently published CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) consensus reporting guidelines provide a framework for how to report the effect of extenuating circumstances such as war or a pandemic on a trial, and to describe the mitigating strategies used to respond to such challenges.4Ultimately, research teams should consider proactively developing contingency plans in advance that allow trials to efficiently pivot to protect their staff, their participants, and the integrity of their trial. Increasing exposure and experience with decentralized trial methodology may expand the different responses available to research teams if their sites are faced with a catastrophe. Although each situation will demand a personalized response, themes of staff and trial participant safety, flexibility, and a commitment to protecting each participant's right to participate emerge as commonalities. By having a "toolbox" of possible strategies, research teams will be able to help support their patients and staff while protecting both their patients' rights and the integrity of ongoing research.Article InformationSources of FundingNone.Disclosures Dr Felker has received research grants from The National Heart, Lung, and Blood Institute, the American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; he has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, Myovant, Sequana, Windtree Therapuetics, and Whiteswell; and he has served on clinical end point committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Dr Harrington reports no conflicts.FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 370.Correspondence to: Robert J. Mentz, MD, Duke University School of Medicine, 200 Trent Dr, 4th Floor, Orange Zone, Room 4221, Durham, NC 27710. Email robert.mentz@duke.eduReferences1. Clinical Trials Arena. Ukraine: industry-sponsored clinical development at risk.2022. https://www.clinicaltrialsarena.com/analysis/ukraine-industry-sponsored-clinical-trial-development-at-risk/. Accessed March 23, 2022.Google Scholar2. Lindenfeld J, Zile MR, Desai AS, Bhatt K, Ducharme A, Horstmanshof D, Krim SR, Maisel A, Mehra MR, Paul S, et al. Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.Lancet. 2021; 398:991–1001. doi: 10.1016/s0140-6736(21)01754-2CrossrefMedlineGoogle Scholar3. Jankowska EA, Kirwan B-A, Kosiborod M, Butler J, Anker SD, McDonagh T, Dorobantu M, Drozdz J, Filippatos G, Keren A, et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study.Eur Heart J. 2021; 42:3011–3020. doi: 10.1093/eurheartj/ehab234CrossrefMedlineGoogle Scholar4. Orkin AM, Gill PJ, Ghersi D, Campbell L, Sugarman J, Emsley R, Steg PG, Weijer C, Simes J, Rombey T, et al. Guidelines for reporting trial protocols and completed trials modified due to the COVID-19 pandemic and other extenuating circumstances: the CONSERVE 2021 statement.JAMA. 2021; 326:257–265. doi: 10.1001/jama.2021.9941CrossrefMedlineGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bhatt A, Lindholm D, Nilsson A, Zaozerska N, Claggett B, Vaduganathan M, Kosiborod M, Lam C, Hernandez A, Martinez F, Inzucchi S, Shah S, de Boer R, Desai A, Jhund P, Langkilde A, Petersson M, McMurray J and Solomon S (2023) Operational challenges and mitigation measures during the COVID-19 pandemic–Lessons from DELIVER, American Heart Journal, 10.1016/j.ahj.2023.05.013, 263, (133-140), Online publication date: 1-Sep-2023. August 2, 2022Vol 146, Issue 5 Advertisement Article Information Metrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.060541PMID: 35914015 Originally publishedAugust 1, 2022 Keywordsclinical trial protocolrandomized clinical trialsPDF download Advertisement Subjects Quality and Outcomes