Search

Background: Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)., Methods: Through comprehensive examination of data from nearly 4000 participants enrolled in six registrational trials for HABP/VABP submitted to the Food and Drug Administration (FDA) between 2005 and 2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that a participant assigned to the study treatment arm would have a more favorable overall DOOR or component outcome than a participant assigned to comparator., Results: DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 48.3% to 52.9% and were not statistically different. There were no significant differences between treatment arms in the component analyses. Although infectious complications and serious adverse events occurred more frequently in ventilated participants compared to non-ventilated participants, the types of events were similar., Conclusions: Through a data-driven approach, we constructed and applied a potential DOOR endpoint for HABP/VABP trials. The inclusion of syndrome-specific events may help to better delineate and evaluate participant experiences and outcomes in future HABP/VABP trials and could help inform data collection and trial design., Competing Interests: Potential conflicts of interest. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Deep Blue, Basilea, Janssen; Royalties from UpToDate, stock options from Valanbio and ArcBio, Honoraria from Infectious Diseases of America for his service as Associate Editor of Clinical Infectious Diseases, and a patent sepsis diagnostics pending. H. W. B. reports royalties to author from Sanford Guide; editorial consulting fees from Sanford Guide, Antimicrobial Agents and Chemotherapy/ASM, ID Clinics of North America/Elsevier; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Grand Rounds at Temple; IDWeek lecture travel support from Finland Award; role as PACCARB Voting Member (travel reimbursed) and on Board of Trustees, College of the Holy Cross (travel reimbursed). T. H. reports grants or contracts from Aceragen; consulting fees from Astellas Pharma US and Mitsubishi Tanabe Pharma; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Cancer and Chemotherapy KK. S. R. E. reports NCI/NIH grant, NHLBI/NIH grant, CDC grant, and grants or contracts from Degruyter (Editor-in-Chief: Statistical Communications in Infectious Diseases); book royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickenson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, SVB Leerink, Medtronic, Regeneron, Wake Forest University, Recor, Janssen, IDDI; honorarium from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), and payment or honorarium for travel from Liver Forum and Paris NASH Meeting; support for attending meetings and/or travel from FDA (honorarium); paid participation on a Data Safety Monitoring Board or Advisory Board for NIH, BARDA, Breast International Group, University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, Abbvie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, Novartis; unpaid Board member for American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. J. H. A. reports grant funding to institution for work unrelated to this from the Centers for Disease Control and Prevention (CDC); support for speaking at SHEA Spring Conference from SHEA. S. N. reports support for travel to meetings is supported by my employer, Johnson and Johnson; stocks in J&J, author's employer. T. H. reports grant from NIH to Antibacterial Resistance Leadership Group and grants or contracts from Karius for Adjudication committee; royalties or licenses from UpToDate; consulting fees from Aridis, Pfizer, Lysovant, Affinivax, Basilea, Concert Genetics; participation on Data and Safety Monitoring Board (DSMB) for Staphylococcus aureus Network Adaptive Platform (SNAP) trial and Spero and on Advisory Board for Basilea and Paul Scherrer Institut (PSI). S. B. D. reports grants or contracts to University of California San Francisco (UCSF) from Gilead, Pfizer, F2G, Regeneron, Chan Zuckerberg Biohub, and NIAID/NIH; consulting fees to author from Genentech and Janssen/J + J; support for travel to speak at IDWeek from Infectious Diseases Society of America (IDSA); patent US20100143379A1 for Mif agonists and antagonist and therapeutic uses thereof; leadership or fiduciary roles on IDSA Antibacterial Resistance Committee, CADPH HAI Advisory Committee, Antibacterial Resistance Leadership Group Innovations Group, Laboratory Center, Mentorship Committee, Gram Positive Committee, Immunosuppressed Host Group; payment for clinical events committee/adjudication committee participation from Shinogi, Basilea, Duke Clinical Research Institute. H. C. reports stock or stock options from Merck and Moderna; membership of DSMB for COVID antiviral RCT for Merck. D. C. reports grants or contracts from Duke University for COMET study (cancer) Patient Leadership Group, from UCSF for STORMing Cancer Patient Advocate Team, and from MD Anderson for PRECISION Patient Advisory Involvement Panel; consulting fees for ongoing projects from SimBioSys and MaxisHealth, from Health Literacy Media (HLM) for Patient Advisor for ongoing projects, and from Appelis Pharmaceuticals, Inc., for consulting/project ended in 12/2022 and from Kinnate Biopharma for consulting/project ended in 06/2022; honoraria and travel support from HMP Education; support for travel from Agile Falcon Strategic Group, DGE Events, and Informa; participation on DSMB for American Society for Clinical Oncology and on Patient Partner Council for Evidera; a role on Executive Group for Metastatic Breast Cancer Alliance and a role as committee member for Alliance for Clinical Trials in Oncology; receitp of manuscript writing support from IQVIA through Regeneron. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Clinical research networks conduct important studies that would not otherwise be performed by other entities. In the case of the Antibacterial Resistance Leadership Group (ARLG), such studies include diagnostic studies using master protocols, controlled phage intervention trials, and studies that evaluate treatment strategies or dynamic interventions, such as sequences of empiric and definitive therapies. However, the value of a clinical research network lies not only in the results from these important studies but in the creation of new approaches derived from collaborative thinking, carefully examining and defining the most important research questions for clinical practice, recognizing and addressing common but suboptimal approaches, and anticipating that the standard approaches of today may be insufficient for tomorrow. This results in the development and implementation of new methodologies and tools for the design, conduct, analyses, and reporting of research studies. These new methodologies directly impact the studies conducted within the network and have a broad and long-lasting impact on the field, enhancing the scientific value and efficiency of generations of research studies. This article describes innovations from the ARLG in diagnostic studies, observational studies, and clinical trials evaluating interventions for the prevention and treatment of antibiotic-resistant bacterial infections., Competing Interests: Potential conflicts of interest. All authors report funding support from the Antibacterial Resistance Leadership Group (ARLG) of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID) (grant number UM1AI104681). S. R. E. reports grants from the NIAID and the NIH and Degruter (Editor-in-Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, Medtronic, Regeneron, Wake Forest University, Recor, Janssen, IDDI, and SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); meeting support from the US Food and Drug Administration, Deming Conference on Applied Statistics, Clinical Trial Transformation Initiative, Council for International Organizations of Medical Sciences, International Chinese Statistical Association Applied Statistics Symposium, and Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, Breast International Group, Washington University, University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, Abbvie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, Novartis, American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. R. P. reports grants or contracts from ContraFect, TenNor Therapeutics Limited, BIOFIRE, and Adaptive Phage Therapeutics; a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics through the Mayo Clinic; consulting fees from PhAST, Torus Biosystems, Day Zero Diagnostics, Mammoth Biosciences, HealthTrackRx, Netflix, Abbott Laboratories, Trellis Bioscience, Inc, Oxford Nanopore Technologies, and CARB-X; honoraria from the National Board of Medical Examiners, Up-to-Date, and the Infectious Diseases Board Review Course; a patent on Bordetella pertussis/parapertussis polymerase chain reaction (PCR) issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued; and a financial relationship with Pathogenomix through the Mayo Clinic. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma and honoraria from Duke University and Cancer and Chemo Therapy. J. H.-A. reports funding from the Centers for Disease Control and Prevention unrelated to the report reported in this manuscript, honoraria from the Infectious Diseases Society of America, and travel and meeting support from the Society for Healthcare Epidemiology of America (SHEA) and the ARLG. D. C. reports personal consulting fees from AstraZeneca, Incyte, Apellis Pharmaceuticals, Inc, Kinnate Biopharma, Maxis Health, Parexel, and Health Literacy Media (nonprofit); travel and meeting support from M2GEN and the American Society of Clinical Oncology; participation on a Data and Safety Monitoring Board (DSMB) for the American Society of Clinical Oncology; and leadership in the Metastatic Breast Cancer Alliance. H. C. reports salary support from the ARLG via Duke University. H. F. C. reports royalties from the Sanford Guide to Antimicrobial Therapy, payment for expert testimony from Nexus Pharmaceuticals, participation on a Merck DSMB for molnupiravir, and stock ownership in Moderna and Merck. V. G. F. reports personal consulting fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer (paid to the author); grants from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases Society of America for his service as Associate Editor of Clinical Infectious Diseases; travel support from Contrafect to the 2019 European Society of Clinical Microbiology and Infectious Diseases (ECCMID); and a sepsis diagnostics patent pending. H. B. reports royalties from the Sanford Guide; consulting fees from the Sanford Guide, Antimicrobial Agents and Chemotherapy/ASM, and ID Clinics of North America/Elsevier; honoraria for Grand Rounds at Temple University; travel and meeting support for an IDWeek Lecture; and membership as a voting member on the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB) and membership on the Board of Trustees at the College of the Holy Cross. H. K. reports funding awarded to her institution(s) from the Durham Center of Innovation to Accelerate Discovery and PracticeTransformation (CIN 13-410) at the Durham Veterans Affairs Health Care System, NIH, and Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA. They also report serving on the editorial board for the Journal of Antimicrobial Chemotherapy- Antimicrobial Resistance (JAC-AMR). T. K. reports no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Desirability of outcome ranking (DOOR) is a novel approach to clinical trial design that incorporates safety and efficacy assessments into an ordinal ranking system to evaluate overall outcomes of clinical trial participants. Here, we derived and applied a disease-specific DOOR endpoint to registrational trials for complicated intra-abdominal infection (cIAI)., Methods: Initially, we applied an a priori DOOR prototype to electronic patient-level data from 9 phase 3 noninferiority trials for cIAI submitted to the US Food and Drug Administration between 2005 and 2019. We derived a cIAI-specific DOOR endpoint based on clinically meaningful events that trial participants experienced. Next, we applied the cIAI-specific DOOR endpoint to the same datasets and, for each trial, estimated the probability that a participant assigned to the study treatment would have a more desirable DOOR or component outcome than if assigned to the comparator., Results: Three key findings informed the cIAI-specific DOOR endpoint: (1) a significant proportion of participants underwent additional surgical procedures related to their baseline infection; (2) infectious complications of cIAI were diverse; and (3) participants with worse outcomes experienced more infectious complications, more serious adverse events, and underwent more procedures. DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 47.4% to 50.3% and were not significantly different. Component analyses depicted risk-benefit assessments of study treatment versus comparator., Conclusions: We designed and evaluated a potential DOOR endpoint for cIAI trials to further characterize overall clinical experiences of participants. Similar data-driven approaches can be utilized to create other infectious disease-specific DOOR endpoints., Competing Interests: Potential conflicts of interest. H. W. B. declares consulting fees from Antimicrobial Agents and Chemotherapy, Sanford Guide, and ID Clinics of North America. H. C. reports grant funding from the NIH; participation in a data and safety monitoring board (DSMB) for Merck; and stock in Merck and Moderna. D. C. reports grant funding from Apellis Pharmaceuticals, CRUK Cancer Grand Challenges, Kinnate Biopharma, and Incyte; consulting fees from Health Literacy Media and MaxisIT Clinical Science; payment for expert panel session from Pfizer; participation on a patient advisory council and travel support for meetings from M2GEN; and participation in the American Society of Clinical Oncology TAPUR Study DSMB and Parexel patient advisory council. S. B. D. reports grant funding from NIH; grant funding for COVID-19–related clinical trials from Gilead and Regeneron; payments for clinical event adjudication committees from Basilea and Shinogi; and consulting fees from Genentech. S. E. reports grant funding from NIH, Degruyter, and Aceragen; royalties from Taylor & Francis; consulting fees from Genetech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, and SVB Leerink; payments for lectures from the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); support for attending meetings from FDA, Deming Conference on Applied Statistics, Clinical Trial Transformation Initiative, Council for International Organization of Medical Sciences, International Chinese Statistical Association Applied Statistics Symposium, and Antimicrobial Resistance and Stewardship Conference; participation on DSMB for NIH, Breast International Group, University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouous, Appelis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, and Candel; and board membership for the American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. V. G. F. reports grant funding or contracts from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genetech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; consulting fees from Novartis, Debiopharm, Genetech, Achaogen, Affinium, The Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer; support from Contrafect to present phase 2 data at 2019 European Congress of Clinical Microbiology and Infectious Diseases; a patent for sepsis diagnostics; serving as Associate Editor of Clinical Infectious Diseases in 2017–2022; and stock options from ArcBio and Valanbio. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma K.K; a contract from Aceragen; payment for lectures from Duke University and Johnson & Johnson K.K.; and payment for manuscript preparation from Cancer and Chemotherapy K.K. (Japanese Journal of Cancer and Chemotherapy). T. L. H. reports grant funding from NIH; royalties from UpToDate; consulting fees from Lysovant and Affinivax; and participation on DSMB for SNAP Trial Platform. J. H.-A. reports grant funding from NIH. S. N. is an employee of Johnson & Johnson. U. W. reports support from the American Society for Microbiology to attend ASM Microbe 2022 as a speaker. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience., Methods: Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTIs). ZEUS compared fosfomycin to piperacillin/tazobactam, APEKS-cUTI compared cefiderocol to imipenem, and DORI-05 compared doripenem to levofloxacin. Using DOOR, we estimated the probability of a more desirable outcome with each investigational antibacterial drug., Results: In each RCT, the DOOR distribution was similar and the probability that a patient in the investigational arm would have a more desirable outcome than a patient in the control arm had a 95% confidence interval containing 50%, indicating no significant difference between treatment arms. DOOR facilitated improved understanding of potential trade-offs between clinical efficacy and safety. Partial credit and subgroup analyses also highlight unique attributes of DOOR., Conclusions: DOOR can effectively be used in registrational cUTI trials. The DOOR end point presented here can be adapted for other infectious disease syndromes and prospectively incorporated into future clinical trials., Competing Interests: Potential conflicts of interest. H. W. B. declares consulting fees from Antimicrobial Agents and Chemotherapy, Sanford Guide, and ID Clinics of North America. T. B. is an employee of and holds stock in Shionogi & Co and reports a nondisclosure agreement between Duke University and Shionogi (to share the analysis conducted by Shionogi with the Antibacterial Resistance Leadership Group [ARLG]). H. F. C. reports grant funding from NIH; consulting fees from Johnson & Johnson; participation on a data and safety monitoring board (DSMB) for Merck; and stock in Merck and Moderna. S. B. D. reports research funding from Gilead, Regeneron, and NIH; payments for clinical event adjudication committees from Basilea and Shionogi (pending); and consulting fees from Genentech. S. R. E. reports grant funding from NIH and Degruyter; royalties from Taylor & Francis; consulting fees from Genetech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Bickenson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, and SVB Leerink; payments for lectures from the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks; support for attending meetings from FDA, Clinical Trial Transformation Initiative, Council for International Organization of Medical Sciences, International Chinese Statistical Association, participation on DSMBs for NIH, Breast International Group, University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouous, Appelis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, and Advantagene; and being a board member for the American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche; grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases of America for service as associate editor of Clinical Infectious Diseases; and a patent for sepsis diagnostics is pending. S. P. G. is an employee of Nabriva Therapeutics and holds stock in Nabriva Therapeutics. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma and payment for lectures from Johnson & Johnson and Duke University. T. L. H. declares royalties from UpToDate and consulting fees from Basilea Pharmaceutica, MotifBio, Genentech, and Lysovant. D. M. is an employee of Nabriva Therapeutics and holds stock in Nabriva Therapeutics. S. N. is an employee of Johnson & Johnson and holds stock in Johnson & Johnson. J. H.-A. report grants from NIH (funding to ARLG, payments made to institution). S. B. D. reports grants or contracts from NIH funding to the ARLG; research funding from Gilead, Regeneron, and NIH; payments for clinical event adjudication committees from Basilea and Shionogi (pending); and consulting fees from Genentech. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To explore patient, caregiver and physician perceptions and attitudes regarding the balance of benefit and risk in using antibacterial drugs developed through streamlined development processes., Design: Semistructured focus groups and in-depth interviews were conducted to elicit perceptions and attitudes about the use of antibacterial drugs to treat multidrug-resistant infections. Participants were given background information about antibiotic resistance, streamlined drug development programmes and FDA drug approval processes. Audio recordings of focus groups/interviews were reviewed and quotes excerpted and categorised to identify key themes., Participants: Two primary stakeholder groups were engaged: one comprising caregivers, healthy persons and patients who had recovered from or were at risk of resistant infection (N=67; 11 focus groups); and one comprising physicians who treat resistant infections (N=23)., Results: Responses from focus groups/interviews indicated widespread awareness among patients/caregivers and physicians of the seriousness of the problem of antibacterial resistance. Both groups were willing to accept a degree of uncertainty regarding the balance of risk and benefit in a new therapy where a serious unmet need exists, but also expressed a desire for rigorous monitoring and rapid, transparent reporting of safety/effectiveness data. Both groups wanted to ensure that >1 physician had input on whether to treat patients with antibiotics developed through a streamlined process. Some patients/caregivers unfamiliar with exigencies of critical care suggested a relatively large multidisciplinary team, while physicians believed individual expert consultations would be preferable. Both groups agreed that careful oversight and stewardship of antibacterial drugs are needed to ensure patient safety, preserve efficacy and prevent abuse., Conclusions: Groups comprising patients/caregivers and physicians were aware of serious issues posed by resistant infections and the lack of effective antibacterial drug therapies and shared a consensus that streamlined development programmes represent a necessary response to the resistance crisis, but one that requires enhanced safeguards and risk communication., Competing Interests: Three authors (JS, RT, JT.) are employees of the US Food and Drug Administration, a funder of the Clinical Trials Transformation Initiative and the present study. The FDA is responsible for the review and approval of antibacterial drugs, including those developed using streamlined approaches., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)