Regulatory Considerations in the Approval of Rezafungin (REZZAYO) for the Treatment of Candidemia and Invasive Candidiasis in Adults.

On March 22, 2023, the FDA approved rezafungin (REZZAYO) for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Rezafungin is an echinocandin that supports weekly dosing, enabling outpatient parenteral treatment that potentially avoids the need for a central venous catheter. Approval of rezafungin was based on a single adequate and well-controlled phase 3 study designed with a Day 30 all-cause mortality primary endpoint and 20% noninferiority margin, which demonstrated that rezafungin is noninferior to the comparator echinocandin. Nonclinical studies of rezafungin in non-human primates identified a neurotoxicity safety signal; however, rezafungin's safety profile in the completed clinical studies was similar to other FDA-approved echinocandins. Here we describe the rationale for this approval and important considerations during the review process for a flexible development program intended to expedite the availability of antimicrobial therapies to treat serious infections in patients with limited treatment options.

FDA Public Workshop Summary-Addressing Challenges in Inhaled Antifungal Drug Development.

Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On September 25, 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights.

FDA Public Workshop Summary-Coccidioidomycosis (Valley Fever): Considerations for Development of Antifungal Drugs.

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

Concordance of Early and Late End Points for Community-acquired Bacterial Pneumonia Trials.

BACKGROUND: While there are ongoing regulatory convergence efforts, differences remain in primary end points recommended for community-acquired bacterial pneumonia (CABP) trials. The US Food and Drug Administration (FDA) recommends assessing CABP symptom resolution at an early time point (3-5 days after randomization). Other regulatory agencies recommend assessing overall clinical response at a later time point (5-10 days after therapy ends). METHODS: We analyzed participant-level data from 6 recent CABP trials submitted to the FDA (n = 4645 participants) to evaluate concordance between early and late end-point outcomes. We used multivariate logistic regression to identify factors associated with discordance. RESULTS: Early and late end-point outcomes were concordant for 85.6% of participants. The proportions of early end-point responders that ultimately failed and early end-point nonresponders that ultimately succeeded were similar (6.0% vs 8.4%, respectively). Early end-point response was highly predictive of late end-point success (positive predictive value, 92.9%). Multivariate logistic regression identified early end-point responders/late end-point failures as less likely to be obese and more likely to be infected with Chlamydophila pneumoniae or Staphylococcus aureus, have received antibacterial drug therapy prior to randomization, and have severe chest pain at baseline. The most common investigator-provided reasons for failure among early end-point responders/late end-point failures were receipt of nonstudy antibacterial drug therapy and loss to follow-up. CONCLUSIONS: Early and late end-point outcomes were highly concordant. These data may be useful in the continuing efforts to reach international regulatory convergence on CABP clinical trial design recommendations.

Trends in Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia Trials.

BACKGROUND: New drug development for hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) is critical. Challenges remain in the conduct of HABP/VABP trials, especially in the contexts of enrollment, endpoints, nonstudy antibacterial drug therapy, and antimicrobial resistance. METHODS: Four Phase 3 noninferiority trials (n = 2433 participants) submitted to the Food and Drug Administration after 2015 were analyzed for enrollment statistics, participant characteristics associated with 28-day all-cause mortality (ACM), microbiology, and receipt of nonstudy antibacterial drugs. All trials primarily enrolled patients with gram-negative bacterial infections. RESULTS: The mean trial length was 2.7 years and the mean recruitment rate was 0.17 participants/site/month. ACM at 28 days was 17.1% and was higher among participants diagnosed with ventilated HABP (31.9%) or VABP (19.0%) than nonventilated HABP (9.9%). VABP participants tended to be younger, less likely to have chronic obstructive pulmonary disease, and more likely to have previously sustained an injury. Age, South American residence, diagnosis of ventilated HABP or VABP, and Acinetobacter baumannii infection were all associated with 28-day ACM in a multivariate logistic regression model. Infection by A. baumannii was most common in Eastern European and Asia/Pacific participants, and Eastern European isolates exhibited the highest levels of meropenem resistance. Concomitant nonstudy antibacterial drug therapy most commonly included beta-lactams and was initiated earliest in Western Europe. CONCLUSION: This analysis of recent trials may assist in trial considerations for HABP/VABP development programs and promote needed antibacterial drug development for patients with serious infections.

Geographic Shifts in Antibacterial Drug Clinical Trial Enrollment: Implications for Generalizability.

BACKGROUND: As drug development has globalized, trials have increasingly enrolled participants from all parts of the world rather than just the United States and Western Europe. For antibacterial drug trials, understanding enrollment trends and regional differences is important for generalizability considerations. METHODS: We retrospectively analyzed 42 phase 3 trials submitted to the US Food and Drug Administration after 2001 for complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), community-acquired bacterial pneumonia (CABP), and acute bacterial skin and skin structure infection (ABSSSI) (n = 29 282 participants). Enrollment numbers, demographics, clinical characteristics, and microbiological data were compared to identify temporal and geographic trends. RESULTS: For cUTI, cIAI, and CABP trials, Eastern European enrollment greatly increased over the study period. For ABSSSI trials, North American enrollment increased. Demographic characteristics and regional microbiology among regions were broadly similar with several exceptions. For cIAI trials, Eastern European participants had the lowest proportion of participants with prior antibacterial drug therapy. For ABSSSI trials, North American participants more commonly reported intravenous drug use. Microbiological differences relative to North America included a greater proportion of Klebsiella pneumoniae among Asian cIAI isolates (17.8% vs 9.0%, P = .0057), a higher proportion of cephalosporin resistance in South American Enterobacteriaceae cUTI isolates (26.8% vs 15.7%, P = .044), and a lower proportion of Staphylococcus aureus in Eastern European ABSSSI isolates (43.7% vs 61.9%, P < .0001). CONCLUSIONS: Geographic trends in recruitment for recent antibacterial clinical trials differ by indication. Regional similarities in demographic characteristics and microbiology across regions lessen concerns regarding generalizability due to shifting enrollment trends.

An Analysis of Antibacterial Drug Development Trends in the United States, 1980-2019.

We present a longitudinal analysis of investigational new drug applications (INDs) for new, systemic antibacterial drugs under active development between 1980 and 2019, evaluating the characteristics of these investigational drugs and the outcomes of these drug development programs. The number of INDs in active development declined by two-thirds, from 39 active INDs at its peak in 1987 to a low 13 in 2001, with decreased development of new cephalosporin, quinolone, and macrolide drugs and reduced participation from large pharmaceutical firms. Antibacterial drug development activity rebounded substantially from 2002 to 2009, primarily led by involvement of small pharmaceutical companies. As of 31 December 2019, the number of active INDs has declined to an 11-year low, and the number of antibacterial INDs initiated with the US Food and Drug Administration during 2010-2019 was lower than any of the previous 3 decades. Antibacterial drug development programs initiated in the 1980s and 1990s had high success rates, with >40% of INDs obtaining marketing approval, in a median time of about 6 years from IND receipt to approval. For drug development programs initiated between 2000 and 2009, we found that IND-to-approval rates reduced to 23%, with median development times for approved antibacterial drugs increasing to 8.2 years. The majority of INDs in development as of 31 December 2019 come from already established drug classes, most in early stages of development, and few are sponsored by large pharmaceutical companies.

Assessing Animal Models of Bacterial Pneumonia Used in Investigational New Drug Applications for the Treatment of Bacterial Pneumonia.

Animal models of bacterial infection have been widely used to explore the in vivo activity of antibacterial drugs. These data are often submitted to the U.S. Food and Drug Administration to support human use in an investigational new drug application (IND). To better understand the range and scientific use of animal models in regulatory submissions, a database was created surveying recent pneumonia models submitted as part of IND application packages. The IND studies were compared to animal models of bacterial pneumonia published in the scientific literature over the same period of time. In this review, we analyze the key experimental design elements, such as animal species, immune status, pathogens selected, and route of administration, and study endpoints.

FDA Public Workshop Summary: Advancing Animal Models for Antibacterial Drug Development.

The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled "Advancing Animal Models for Antibacterial Drug Development" on 5 March 2020. The workshop mainly focused on models of pneumonia caused by Pseudomonas aeruginosa and Acinetobacter baumannii The program included discussions from academic investigators, industry, and U.S. government scientists. The potential use of mouse, rabbit, and pig models for antibacterial drug development was presented and discussed.

Consensus on Language for Advance Informed Consent in Health Care-Associated Pneumonia Clinical Trials Using a Delphi Process.

Importance: Information to be included in advance informed consent forms for health care-associated pneumonia treatment trials remains to be determined. Objective: To identify and determine how to describe information to be included in an advance informed consent form for an early-enrollment noninferiority hospital-acquired and/or ventilator-associated bacterial pneumonia (HABP/VABP) clinical trial. Design, Setting, and Participants: A Delphi consensus process with stakeholders in HABP/VABP clinical trials was conducted using qualitative semistructured telephone interviews from June to August 2016, followed by 2 online surveys, the first from April to May 2017, and the second from September to October 2017. All stakeholders who participated in the interview were invited to participate in the first survey. Stakeholders who participated in the first survey were invited to participate in the second survey. Stakeholders were patients at risk of pneumonia, caregivers, representatives of institutional review boards, investigators, and study coordinators. Main Outcomes and Measures: Description and consensus of information to be included in advance informed consent forms for early enrollment in noninferiority HABP/VABP clinical trials. Results: Suggestions from 52 stakeholders about what key informed consent concepts to include and how to explain them were used to create 3 categories to be included in an advance consent form: (1) reassurances on patient health and treatment, (2) rationale for advance consent and early enrollment, and (3) an explanation of noninferiority. At the end of the Delphi process, at least 80% consensus was reached among the 40 stakeholders who participated in the second online survey on each of the statements to include in the proposed consent text. Throughout the process, however, describing and reaching consensus on statements about noninferiority was more problematic than the other categories. Conclusions and Relevance: The stakeholders endorsed consent language to be used in combination with a strategy for enrolling patients at highest risk for pneumonia before infection onset. Data-driven consent language may help potential participants make informed decisions about their involvement in clinical research and improve enrollment rates, which are necessary to evaluate new treatments and improve patient care. The proposed consent language may be adapted for other trials using an early enrollment strategy and for noninferiority trials.

Assessment of the Perceived Acceptability of an Early Enrollment Strategy Using Advance Consent in Health Care-Associated Pneumonia.

Importance: Better treatment options are needed in life-threatening infections, including health care-associated pneumonia. Enrolling patients in antibacterial clinical trials before diagnosis may circumvent existing time-to-enrollment constraints. However, the acceptability of an early enrollment strategy using advance consent is unknown. Objective: To assess the perceived acceptability of an early enrollment strategy for enrolling patients in an antibacterial clinical trial before a pneumonia diagnosis. Design, Setting, and Participants: This qualitative, descriptive study used semistructured telephone interviews. Framed within a planned noninferiority pneumonia antibiotic trial, an early enrollment strategy was described and perceptions were assessed. Using this strategy, patients give consent to enroll before developing pneumonia, to be monitored by study staff, and to be randomly assigned a study antibiotic if pneumonia develops. All interviews were audiorecorded, transcribed verbatim, and analyzed using applied thematic analysis. Fifty-two key stakeholders from across the United States, including 18 patients at risk of pneumonia, 12 caregivers, 10 representatives of institutional review boards, 7 investigators, and 5 study coordinators, were interviewed from June 20 to August 19, 2016. Main Outcomes and Measures: Perceived acceptability of the early enrollment strategy. Results: Among the 52 stakeholders interviewed (ages 29-75 years; 14 women), patients and caregivers expressed no concerns about patients being approached about participation before developing pneumonia; however, some patients may experience anxiety on learning about their risk for pneumonia. No concerns with study staff accessing patients' medical records were expressed. The clarity of consent information was important for understanding the study rather than having the condition under investigation. Among patients, caregivers, and institutional review board representatives, preferences varied regarding opt-out and precedent autonomy procedures. Nearly all patients would be willing to join a trial using the early enrollment strategy and caregivers would be willing to provide proxy consent. Institutional review board representatives were supportive of the strategy and made recommendations for the study protocol, primarily around informed consent. Investigators and study coordinators believed the strategy would not be burdensome and offered suggestions to ensure its feasibility. Conclusion and Relevance: Results of the study suggest that the early enrollment strategy is acceptable. Future research should evaluate whether the strategy improves enrollment rates in registrational pneumonia trials and in trials of other acute infection syndromes with narrow enrollment windows and/or patients with transient decisional incapacity.

Caregiver psychosocial characteristics and children's adherence to antiretroviral therapy.

Although parents and caregivers may have primary responsibility for their children's medication- taking, surprisingly few studies have examined caregiver psychosocial correlates of children's adherence to antiretroviral therapy (ART). This cross-sectional, descriptive study examined the relationship between caregiver psychosocial characteristics and medication adherence among children with HIV. Fifty-four caregivers of children with HIV completed a demographic questionnaire, the Parenting Stress Index, the Brief Symptom Inventory, the Family Support Scale, and the Support Functions Scale. Adherence to ART was measured with children's 6-month pharmacy refill histories. Children and caregivers were primarily African American, urban, and poor (63% reported <$15,000 annual household income). Univariate analyses showed that an adherent classification (>/= 80% refill rate) was associated with shorter duration of highly active antiretroviral therapy (HAART) treatment, nondisclosure of the HIV diagnosis to the child, lower caregiver income level, having a nonbiologically related caregiver, and less caregiver psychiatric distress. In a multivariate logistic regression, duration of child's HAART treatment, child HIV disclosure status, caregiver income, and caregiver psychiatric distress accounted for 63% of the variance in adherence. Findings highlight the complexity of children's adherence to ART and the need for multicenter studies with greater sample sizes to explore in more detail the effects of caregiver psychological distress and child HIV disclosure status on adherence as well as the ways in which regimen fatigue and adherence fluctuate over time.

Cognitive, academic, and behavioral correlates of medication adherence in children and adolescents with perinatally acquired HIV infection.

OBJECTIVE: Medication adherence is critical to the success of antiretroviral therapies for children and youth with perinatally acquired HIV. Factors that influence successful transition of medication responsibility from caregivers to youth are poorly understood. The purpose of this study was to evaluate the relationship of medication adherence with demographic, cognitive, academic, and behavioral characteristics. METHODS: Randomly selected youth, N = 151, aged 8 to 18 years, completed cognitive and academic measures, and they and their caregivers completed questionnaires assessing behavior and emotional well-being. An announced pill count and questionnaires completed by youth and their caregivers were used to evaluate adherence. RESULTS: Of 151 participants, 100 completed all adherence measures. Adherence rates varied by assessment method. Nonadherence (<90%) by pill count was associated with older child age, greater youth responsibility for medications, and other demographic and medication regimen variables. Verbal impairment predicted better self-reported adherence and reading problems predicted better self- and caregiver-reported adherence. Youth-reported locus of control was associated with pill count nonadherence, and poor relationships with parents were associated with youth-reported nonadherence. CONCLUSIONS: Consideration of youth cognitive or academic status may be helpful in evaluating medication adherence in patients with perinatally acquired HIV infection, particularly when using self- or caregiver reports to assess adherence. Vigilance for adherence problems is indicated when youth are older, responsible for medications, report poor caregiver relationships, and/or sense a lack of control over their lives.

Assessing medication adherence of perinatally HIV-infected children using caregiver interviews.

Medication adherence is critical for children's HIV treatment success, but obtaining accurate assessments is challenging when complex measurement technologies are not feasible. Our goal was to evaluate a multidimensional adherence interview designed to improve on existing adherence measures. Data from caregivers (N = 126) of perinatally infected children were analyzed to determine the ability of the revised interview guide to detect potential treatment nonadherence. Questions related to viral load (VL) on a bivariate level included proportion of doses taken in the previous 3 days and 6 months, caregivers' knowledge of prescribed dosing frequencies, and caregivers' reports of problems associated with medication administration. VL was not associated with 3-day recall of missed doses. In multivariate analyses, only caregiver knowledge of prescribed dosing frequencies was uniquely associated with VL. Our modified interview appears to successfully identify family struggles with adherence and to have the capacity to help clinicians address medication adherence challenges.

Assessment of adherence to antiretroviral therapy in perinatally HIV-infected children and youth using self-report measures and pill count.

BACKGROUND: Parent/caregiver or child/youth self-report and pill counts are commonly used methods for assessing adherence to antiretroviral therapy among children and youth with HIV. The purpose of this study was to compare these different methods with one another and with viral load. METHODS: Randomly selected parent/caregiver and child/youth dyads were interviewed using several adherence self-report measures and an announced pill count was performed. Adherence assessment methods were compared with one another and their relative validity was assessed by comparison with the child's viral load close to the time of the interview or pill count, adjusting for primary caregiver, child age, and child disclosure of the diagnosis. RESULTS: There were 151 evaluable participants. Adherence rate by pill count was >or=90% in 52% of participants, was significantly associated with log(RNA) viral load (p = .032), and had significant agreement with viral load <400 copies/mL. However, pill count data were incomplete for 26% of participants. With similar proportions considered adherent, a variety of self-report adherence assessment methods also were associated with log(RNA) viral load including: "no dose missed within the past 1 month" (p = .054 child/youth interview, p = .004 parent/caregiver interview), and no barrier to adherence identified (p = .085 child/youth interview, p = .015 parent/caregiver interview). Within-rater and inter-rater agreement was high among self-report methods. Three day recall of missed doses was not associated with viral load. CONCLUSION: Findings demonstrate the validity of adherence assessment strategies that allow the parent/caregiver or child/youth to report on adherence over a longer period of time and to identify adherence barriers. Adherence assessed by announced pill count was robustly associated with viral load, but there was incomplete data for many participants.

Brief report: assessing adherence to pediatric antiretroviral regimens using the 24-hour recall interview.

OBJECTIVE: Examine the 24-hr Recall Interview (24RI) for assessing children's antiretroviral medication adherence. METHODS: Caregivers of 54 children with HIV (aged 2-12 years) completed a clinical adherence interview and the 24RI by telephone. Children's viral load and 3-month pharmacy records were obtained. RESULTS: Thirty-seven percent of children missed > or = 1 dose of medicine over 3 days. In 22% of the samples, adherence varied across medications. The 24RI adherence scores (Frequency, Interval, and Dietary Adherence) were moderately reliable across the three interviews. Pharmacy refill rates were significantly related to viral load, and 24RI barriers were marginally significantly related to viral load. CONCLUSIONS: The 24RI, with its systematic, cued recall, and decreased focus on adherence, may reduce socially desirable responding compared to other self-report methods, and reporting adherence barriers may indicate adherence difficulty. However, the validity of the 24RI must be improved to make it a useful measure to include in an adherence assessment battery.