Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis.

BACKGROUND: Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children. METHODS: Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses. RESULTS: Data from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax. CONCLUSIONS: Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.

Delivering compassionate NHS healthcare: A qualitative study exploring the ethical implications of resetting NHS maternity and paediatric services following the acute phase of the COVID-19 pandemic.

A distinction can be drawn between healthcare, where compassion is evident, and the functional delivery of health services. Measures to curb the spread of COVID-19, such as personal protective equipment, telehealth, and visiting restrictions created barriers to service delivery and put pressure on healthcare. Through 37 qualitative interviews with NHS senior managers (n = 11), health professionals (n = 26), and 5 focus group discussions with members of the public (n = 26), we explored experiences of the everyday ethical tensions created as services were being re-established following the acute phase of the COVID-19 pandemic in England. Our analysis enriches an understanding of compassionate care as outlined in NHS operational documents - covering the emotional, moral, and relational components of healthcare beyond the functionalities of treatment. From this analysis, we consider the normative standards underpinning NHS healthcare, concluding that, wherever possible, offering compassionate healthcare to patients and their families should be facilitated, and health professionals should themselves be compassionately supported in the workplace. Our findings foreground the need to consider the consequences of the short-term adoption of a functional treatment approach, including strategies that support health professionals and inform the public, to avoid the long-term damage caused by the fracturing of compassionate healthcare.

The British Transplantation Society guidelines on ethics, law and consent in relation to deceased donors after circulatory death.

The British Transplantation Society (BTS) 'Guideline on transplantation from deceased donors after circulatory death' has recently been updated and this manuscript summarises the relevant recommendations from chapters specifically related to law, ethics, donor consent and informing the recipient.

Pharmacokinetics and cardiac safety of clofazimine in children with rifampicin-resistant tuberculosis.

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children <18 years old routinely treated for RR-TB with a clofazimine-containing regimen was analyzed. Clofazimine 100 mg gelatin capsules were given orally once daily (≥20 kg body weight), every second day (10 to <20 kg), or thrice weekly (<10 kg). PK sampling and electrocardiograms were completed pre-dose and at 1, 4, and 10 hours post-dose, and the population PK and Fridericia-corrected QT (QTcF) interval prolongation were characterized. Fifty-four children contributed both PK and QTcF data, with a median age (2.5th-97.5th centiles) of 3.3 (0.5-15.6) years; five children were living with HIV. Weekly area under the time-concentration curve at steady state was 79.1 (15.0-271) mg.h/L compared to an adult target of 60.9 (56.0-66.6) mg.h/L. Children living with HIV had four times higher clearance compared to those without. No child had a QTcF ≥500 ms. A linear concentration-QTcF relationship was found, with a drug effect of 0.05 (0.027, 0.075) ms/µg/L. In some of the first PK data in children, we found clofazimine exposure using an off-label dosing strategy was higher in children versus adults. Clofazimine concentrations were associated with an increase in QTcF, but severe prolongation was not observed. More data are required to inform dosing strategies in children.

Optimizing dosing of the cycloserine pro-drug terizidone in children with rifampicin-resistant tuberculosis.

There are no pharmacokinetic data in children on terizidone, a pro-drug of cycloserine and a World Health Organization (WHO)-recommended group B drug for rifampicin-resistant tuberculosis (RR-TB) treatment. We collected pharmacokinetic data in children <15 years routinely receiving 15-20 mg/kg of daily terizidone for RR-TB treatment. We developed a population pharmacokinetic model of cycloserine assuming a 2-to-1 molecular ratio between terizidone and cycloserine. We included 107 children with median (interquartile range) age and weight of 3.33 (1.55, 5.07) years and 13.0 (10.1, 17.0) kg, respectively. The pharmacokinetics of cycloserine was described with a one-compartment model with first-order elimination and parallel transit compartment absorption. Allometric scaling using fat-free mass best accounted for the effect of body size, and clearance displayed maturation with age. The clearance in a typical 13 kg child was estimated at 0.474 L/h. The mean absorption transit time when capsules were opened and administered as powder was significantly faster compared to when capsules were swallowed whole (10.1 vs 72.6 min) but with no effect on bioavailability. Lower bioavailability (-16%) was observed in children with weight-for-age z-score below -2. Compared to adults given 500 mg daily terizidone, 2022 WHO-recommended pediatric doses result in lower exposures in weight bands 3-10 kg and 36-46 kg. We developed a population pharmacokinetic model in children for cycloserine dosed as terizidone and characterized the effects of body size, age, formulation manipulation, and underweight-for-age. With current terizidone dosing, pediatric cycloserine exposures are lower than adult values for several weight groups. New optimized dosing is suggested for prospective evaluation.

Two Times Versus Four Times Daily Cephalexin Dosing for the Treatment of Uncomplicated Urinary Tract Infections in Females.

Background: The current treatment guidelines of the Infectious Diseases Society of America recommend ß-lactam antibiotics as alternative rather than first-line agents for the treatment of uncomplicated urinary tract infection (uUTI). Cephalexin is a commonly prescribed first-generation cephalosporin with excellent bioavailability and urinary penetration; however, little data exist to support optimal dosing for uUTI. Methods: This retrospective multicenter cohort study included adult female patients who received 5 to 7 days of cephalexin for symptomatic uUTI with a cefazolin-susceptible urine culture. The primary objective was to compare uUTI treatment failure (eg, continued or recurrent symptoms within 30 days) between patients treated with cephalexin 500 mg twice daily (BID group) and 500 mg 4 times daily (QID group) in the outpatient setting. Secondary outcomes included time to treatment failure, reported adverse events within 7 days of treatment, and occurrence of Clostridioides difficile within 30 days of treatment. Results: A total of 261 patients were included (BID, n = 173; QID, n = 88). Baseline characteristics were similar between the groups. Escherichia coli was the most commonly isolated pathogen (85.4%). There was no difference in treatment failure observed between the groups (BID 12.7% vs QID 17%, P = .343), including failure while undergoing therapy (BID 2.3% vs QID 5.7%, P = .438) or recurrence within 30 days (BID 10.4% vs QID 11.3%, P = .438). No differences in reported adverse events (BID 4.6% vs QID 5.6%, P = .103) were observed between groups. Conclusions: Twice-daily cephalexin is as effective as 4-times-daily dosing for uUTI. A twice-daily dosing strategy may improve patient adherence.

Pharmacokinetics and optimized dosing of dispersible and non-dispersible levofloxacin formulations in young children.

BACKGROUND: Levofloxacin is used for treatment and prevention of rifampicin-resistant (RR)-TB in children. Recent data showed higher exposures with 100 mg dispersible compared with non-dispersible tablet formulations with potentially important dosing implications in children. We aimed to verify and better characterize this finding. METHODS: We conducted a crossover pharmacokinetic trial in children aged ≤5 years receiving levofloxacin RR-TB preventive therapy. Pharmacokinetic sampling was done after 15-20 mg/kg doses of levofloxacin with 100 mg dispersible and crushed 250 mg non-dispersible levofloxacin formulations. A population pharmacokinetic model was developed. RESULTS: Twenty-five children were included, median (IQR) weight and age 12.2 (10.7-15.0) kg and 2.56 (1.58-4.03) years, respectively. A two-compartment model with first-order elimination and transit compartment absorption best described levofloxacin pharmacokinetics. Allometric scaling adjusted for body size, and maturation of clearance with age was characterized. Typical clearance in a 12 kg child was estimated at 4.17 L/h. Non-dispersible tablets had 21.5% reduced bioavailability compared with the dispersible formulation, with no significant differences in other absorption parameters.Dosing simulations showed that current recommended dosing for both formulations result in median exposures below adult-equivalent exposures at a 750 mg daily dose, mainly in children >6 months. Higher levofloxacin doses of 16-30 mg/kg for dispersible and 20-38 mg/kg for crushed non-dispersible tablets may be required in children >6 months. CONCLUSIONS: The dispersible paediatric levofloxacin formulation has improved bioavailability compared with the crushed non-dispersible adult formulation, but exposures remain below those in adults. We propose optimized age- and weight-based dosing for levofloxacin, which require further evaluation.

QT Interval Prolongation with One or More QT-Prolonging Agents Used as Part of a Multidrug Regimen for Rifampicin-Resistant Tuberculosis Treatment: Findings from Two Pediatric Studies.

Rifampicin-resistant tuberculosis (RR-TB) involves treatment with many drugs that can prolong the QT interval; this risk may increase when multiple QT-prolonging drugs are used together. We assessed QT interval prolongation in children with RR-TB receiving one or more QT-prolonging drugs. Data were obtained from two prospective observational studies in Cape Town, South Africa. Electrocardiograms were performed before and after drug administration of clofazimine (CFZ), levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), and delamanid. The change in Fridericia-corrected QT (QTcF) was modeled. Drug and other covariate effects were quantified. A total of 88 children with a median (2.5th-to-97.5th range) age of 3.9 (0.5 to 15.7) years were included, of whom 55 (62.5%) were under 5 years of age. A QTcF interval of >450 ms was observed in 7 patient-visits: regimens were CFZ+MFX (n = 3), CFZ+BDQ+LFX (n = 2), CFZ alone (n = 1), and MFX alone (n = 1). There were no events with a QTcF interval of >500 ms. In a multivariate analysis, CFZ+MFX was associated with a 13.0-ms increase in change in QTcF (P < 0.001) and in maximum QTcF (P = 0.0166) compared to those when other MFX- or LFX-based regimens were used. In conclusion, we found a low risk of QTcF interval prolongation in children with RR-TB who received at least one QT-prolonging drug. Greater increases in maximum QTcF and ΔQTcF were observed when MFX and CFZ were used together. Future studies characterizing exposure-QTcF responses in children will be helpful to ensure safety with higher doses if required for effective treatment of RR-TB.

Exploring Staff Attitudes Towards Unspecified Kidney Donors in the United Kingdom: Results From the BOUnD Study.

Unspecified kidney donation (UKD) has made substantial contributions to the UK living donor programme. Nevertheless, some transplant professionals are uncomfortable with these individuals undergoing surgery. This study aimed to qualitatively explore the attitudes of UK healthcare professionals towards UKD. An opportunistic sample was recruited through the Barriers and Outcomes in Unspecified Donation (BOUnD) study covering six UK transplant centres: three high volume and three low volume centres. Interview transcripts were analysed using inductive thematic analysis. The study provided comprehensive coverage of the UK transplant community, involving 59 transplant professionals. We identified five themes: staff's conception of the ethics of UKD; presence of the known recipient in the donor-recipient dyad; need for better management of patient expectations; managing visceral reactions about the "typical" unspecified kidney donor; complex attitudes toward a promising new practice. This is the first in-depth qualitative study of attitudes of transplant professionals towards UKD. The data uncovered findings with strong clinical implications for the UKD programme, including the need for a uniform approach towards younger candidates that is adhered to by all transplant centres, the need to equally extend the rigorous assessment to both specified and unspecified donors, and a new approach to managing donor expectations.

Donating a Kidney to a Stranger: Are Healthcare Professionals Facilitating the Journey? Results From the BOUnD Study.

Unspecified kidney donors (UKDs) are approached cautiously by some transplant professionals. The aim of this study was to interrogate the views of UK transplant professionals towards UKDs and identify potential barriers. A purposely designed questionnaire was validated, piloted and distributed amongst transplant professionals at each of the 23 UK transplant centres. Data captured included personal experiences, attitudes towards organ donation, and specific concerns about UKD. 153 responses were obtained, with representation from all UK centres and professional groups. The majority reported a positive experience with UKDs (81.7%; p < 0.001) and were comfortable with UKDs undergoing major surgery (85.7%; p < 0.001). 43.8% reported UKDs to be more time consuming and 52% felt that a mental health assessment should take place before any medical tests. 77% indicated the need for a lower age limit. The suggested age range was broad (16-50 years). Adjusted mean acceptance scores did not differ by profession (p = 0.68) but higher volume centres were more accepting (46.2 vs. 52.9; p < 0.001). This is the first quantitative study of acceptance by transplant professionals to a large national UKD programme. Support is broad, however potential barriers to donation have been identified, including lack of training. Unified national guidance is needed to address these.

Feasibility evaluation to expand a collaborative practice agreement and discontinue antibiotics after an emergency department or urgent care visit.

PURPOSE: The impact of pharmacist-led culture follow-up programs for positive cultures is well established. The benefits and feasibility of evaluating negative cultures and deprescribing unnecessary antibiotics after emergency department (ED) and urgent care (UC) visits are unknown; therefore, this evaluation characterized the burden of negative urine cultures and chlamydia tests and estimated how many potential antibiotic days could be saved with deprescribing. METHODS: This retrospective, descriptive study evaluated patients discharged from an ED or UC location with a pharmacist-led culture follow-up program. The primary objective was to characterize the proportion of patients with a negative urine culture or chlamydia test where an opportunity would exist to deprescribe antibiotics at follow-up. Secondary endpoints included estimating the number of potential antibiotic days that could be saved, postvisit healthcare utilization, and documented adverse drug reactions (ADRs). RESULTS: For a 1-month period, pharmacists reviewed 398 cultures, of which 208 (52%) were urine cultures or chlamydia tests with negative results. Fifty patients (24%) with negative results had been prescribed empiric antibiotics. The median duration of antibiotic treatment was 7 days (interquartile range [IQR], 5-7 days), while the median time to culture finalization was 2 days (IQR, 1-2 days). There was an opportunity to save a median of 5 antibiotic days per patient. Thirty-two patients (15.3%) followed up with their primary care physician within 7 days; of these patients, 1 (0.05%) had their antibiotic prescription discontinued by the primary care physician. There were no documented ADRs. CONCLUSION: Expansion of pharmacist-led culture follow-up programs to deprescribe antibiotics for patients with negative cultures has the potential to save significant antibiotic exposure.

Proposal to support making decisions about the organ donation process.

In this paper, we propose a novel approach to permit members of the public opportunity to record more nuanced wishes in relation to organ donation. Recent developments in organ donation and procurement have made the associated processes potentially more multistaged and complex than ever. At the same time, opt-out legislation has led to a more simplistic recording of wishes than ever. We argue that in order to be confident that a patient would really wish to go ahead with the various interventions and procedures that now accompany organ donation, more nuanced information than a simple 'yes' or 'no' may be required. This is of particular importance for donation after circulatory death, where some interventions to facilitate donation occur when the patient is still alive. We propose the implementation of an online form to allow people to record more nuanced wishes in relation to donation, including an indication of competing wishes and how these should be weighed into decision-making. We argue that this approach will promote autonomous decision-making for the public, potentially reduce difficulties that family members encounter at the time of organ donation, and should make medical staff more confident that they are truly acting according to the wishes and best interests of their patients.

RELATIONSHIPS, RIGHTS, AND RESPONSIBILITIES: (RE)VIEWING THE NHS CONSTITUTION FOR THE POST-PANDEMIC 'NEW NORMAL'.

Action needs to be taken to map out the fairest way to meet the needs of all NHS stakeholders in the post-pandemic 'new normal'. In this article, we review the NHS Constitution, looking at it from a relational perspective and suggesting that it offers a useful starting point for such a project, but that new ways of thinking are required to accommodate the significant changes the pandemic has made to the fabric of the NHS. These new ways of thinking should encompass concepts of solidarity, care, and (reciprocal) responsibility, grounded in an acceptance of the importance of relationships in society. To this end, we explore and emphasise the importance of our interconnections as NHS stakeholders and 're-view' the NHS Constitution from a relational perspective, concentrating on the rights and responsibilities it describes for patients and the public as NHS stakeholders. We argue that the NHS Constitution, of which most stakeholders are probably unaware, can be used as a tool to engage us, and to catalyse conversation about how our responsibilities as NHS stakeholders should change in the post-pandemic 'new normal'.

Hepatocellular Injury in Children Treated for Rifampicin-resistant Tuberculosis: Incidence, Etiology and Outcome.

BACKGROUND: Hepatocellular injury has been reported commonly in adults on rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) treatment. However, there are limited data in children. METHODS: Two pharmacokinetic studies of children (0-17 years) routinely treated for RR/MDR-TB were conducted in Cape Town, South Africa between October 2011 and February 2020. Hepatocellular injury adverse events (AEs; defined as elevated alanine aminotransferase [ALT]) were documented serially. Data were analyzed to determine the incidence, etiology, risk factors, management and outcome of ALT elevation. RESULTS: A total of 217 children, median age 3.6 years (interquartile range, 1.7-7.1 years) at enrollment were included. The median follow-up time was 14.0 months (interquartile range, 9.8-17.2 months). Fifty-five (25.3%) patients developed an ALT AE. Of these, 43 of 55 (78%) patients had 54 ALT AEs attributed to their RR/MDR-TB treatment. The incidence rate of ALT AEs related to RR-TB treatment was 22.4 per 100 person-years. Positive HIV status and having an elevated ALT at enrollment were associated with time to ALT AE attributed to RR/MDR-TB treatment, with P values 0.0427 and P < 0.0001, respectively. Hepatitis A IgM was positive in 11 of 14 (78.6%) severe (grade ≥3) cases of ALT AEs. In 8 of 14 (57%) severe ALT AEs, hepatotoxic drugs were stopped or temporarily interrupted. None had a fatal or unresolved outcome. CONCLUSIONS: Hepatocellular injury in children on RR/MDR-TB treatment is common, although usually mild; having elevated ALT early in treatment and HIV-positive status are possible risk factors. Hepatitis A was a common etiology of severe ALT AE in children treated for RR/MDR-TB.

Challenges and Opportunities in the Supply of Living Kidney Donation in the UK National Health Service: An Economic Perspective.

End-stage kidney disease is a significant burden on the healthcare systems of many countries, and this is likely to continue because of an increasingly aging and comorbid population. Multiple studies have demonstrated a significant clinical benefit in transplantation when compared with dialysis, however, there continues to be a shortage of donor kidneys available. This article provides an economic perspective on issues pertinent to living kidney donation and transplantation. Although ethics, equity, and cultural considerations often seem at odds with economic concepts around resource allocation, this article explains the situation around supply and demand for living kidneys and illustrates how this has been addressed in the economic literature. The article discusses different policy recommendations for resolving the imbalance between supply and demand in kidney donation, through policies under 3 main approaches: increasing supply, decreasing demand, and improving the allocation of kidney supply.

Acceptability of donor funding for clinical trials in the UK: a qualitative empirical ethics study using focus groups to elicit the views of research patient public involvement group members, research ethics committee chairs and clinical researchers.

OBJECTIVES: The Plutocratic Proposal is a novel method of funding early phase clinical trials where a single donor funds the entire trial and in so doing secures a place on it. The aim of this study was to identify and explore concerns that may be raised by UK research ethics committees (RECs) when reviewing clinical trials funded in this way. DESIGN: Empirical ethics combining ethical analysis and qualitative data from three focus groups held online using Frith's symbiotic approach. Data were analysed using inductive thematic approach informed by the study aims and ethical analysis. PARTICIPANTS: 22 participants were recruited: 8 research patient public involvement group members, 7 REC chairs and 7 clinical researchers. All were based in the UK. RESULTS: With one exception, participants thought the Plutocratic Proposal may be 'all things considered' acceptable, providing their concerns were met, primary of which was upholding scientific integrity. Other concerns discussed related to the acceptability of the donor securing a place on the trial including: whether this was an unfair distribution of benefits, disclosing the identity of the donor as the funder, protecting the donor from exploitation and funding a single study with multiple donors on the same terms. Some misgivings fell outside the usual REC purview: detrimental impact of donors of bad character, establishing the trustworthiness of the matching agency and its processes and optimising research funding and resources. Despite their concerns, participants recognised that because the donor funds the whole trial, others would also potentially benefit from participating. CONCLUSIONS: We identified concerns about the Plutocratic Proposal. UK RECs may be open to approving studies if these can be addressed. Existing governance processes will do some of this work, but additional REC guidance, particularly in relation to donors securing a place on the trial, may be necessary to help RECs navigate ethical concerns consistently.

Pharmacokinetics and Dose Optimization Strategies of Para-Aminosalicylic Acid in Children with Rifampicin-Resistant Tuberculosis.

Treatment options for children with Rifampicin-resistant tuberculosis (RR-TB) remain limited, and para-aminosalicylic acid (PAS) is still a relevant component of treatment regimens. Prevention of resistance to companion drugs by PAS is dose related, and at higher concentrations, PAS may exhibit significant bactericidal activity in addition to its bacteriostatic properties. The optimal dosing of PAS in children is uncertain, specifically for delayed-release granule preparations, which are the most used. A population pharmacokinetic model was developed describing PAS pharmacokinetics in children receiving routine RR-TB treatment. Model-based simulations evaluated current World Health Organization (WHO) weight-band doses against the adult pharmacokinetic target of 50 to 100 mg/liter for peak concentrations. Of 27 children included, the median (range) age and weight were 3.87 (0.58 to 13.7) years and 13.3 (7.15 to 30.5) kg, respectively; 4 (14.8%) were HIV positive. PAS followed one-compartment kinetics with first-order elimination and transit compartment absorption. The typical clearance in a 13-kg child was 9.79 liters/h. Increased PAS clearance was observed in both pharmacokinetic profiles from the only patient receiving efavirenz. No effect of renal function, sex, ethnicity, nutritional status, HIV status, antiretrovirals (lamivudine, abacavir, and lopinavir-ritonavir), or RR-TB drugs was detected. In simulations, target concentrations were achieved only using the higher WHO dose range of 300 mg/kg once daily. A transit compartment adequately describes absorption for the slow-release PAS formulation. Children should be dosed at the higher range of current WHO-recommended PAS doses and in a once-daily dose to optimize treatment.

Ethical Considerations for the Inclusion of Patient-Reported Outcomes in Clinical Research: The PRO Ethics Guidelines.

Importance: Patient-reported outcomes (PROs) can inform health care decisions, regulatory decisions, and health care policy. They also can be used for audit/benchmarking and monitoring symptoms to provide timely care tailored to individual needs. However, several ethical issues have been raised in relation to PRO use. Objective: To develop international, consensus-based, PRO-specific ethical guidelines for clinical research. Evidence Review: The PRO ethics guidelines were developed following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network's guideline development framework. This included a systematic review of the ethical implications of PROs in clinical research. The databases MEDLINE (Ovid), Embase, AMED, and CINAHL were searched from inception until March 2020. The keywords patient reported outcome* and ethic* were used to search the databases. Two reviewers independently conducted title and abstract screening before full-text screening to determine eligibility. The review was supplemented by the SPIRIT-PRO Extension recommendations for trial protocol. Subsequently, a 2-round international Delphi process (n = 96 participants; May and August 2021) and a consensus meeting (n = 25 international participants; October 2021) were held. Prior to voting, consensus meeting participants were provided with a summary of the Delphi process results and information on whether the items aligned with existing ethical guidance. Findings: Twenty-three items were considered in the first round of the Delphi process: 6 relevant candidate items from the systematic review and 17 additional items drawn from the SPIRIT-PRO Extension. Ninety-six international participants voted on the relevant importance of each item for inclusion in ethical guidelines and 12 additional items were recommended for inclusion in round 2 of the Delphi (35 items in total). Fourteen items were recommended for inclusion at the consensus meeting (n = 25 participants). The final wording of the PRO ethical guidelines was agreed on by consensus meeting participants with input from 6 additional individuals. Included items focused on PRO-specific ethical issues relating to research rationale, objectives, eligibility requirements, PRO concepts and domains, PRO assessment schedules, sample size, PRO data monitoring, barriers to PRO completion, participant acceptability and burden, administration of PRO questionnaires for participants who are unable to self-report PRO data, input on PRO strategy by patient partners or members of the public, avoiding missing data, and dissemination plans. Conclusions and Relevance: The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare.