Publications by authors named "John Farley"

119 Publications

Cancer mortality in a population-based cohort of American Indians - The strong heart study.

Cancer Epidemiol 2021 Oct 19;74:101978. Epub 2021 Jul 19.

MedStar Health Research Institute, 6525 Belcrest Road, Suite 700, Hyattsville, MD, 20782, USA; Georgetown, Howard Universities Center for Clinical and Translational Research, Washington, DC, 2000, USA. Electronic address:

Background: Cancer mortality among American Indian (AI) people varies widely, but factors associated with cancer mortality are infrequently assessed.

Methods: Cancer deaths were identified from death certificate data for 3516 participants of the Strong Heart Study, a population-based cohort study of AI adults ages 45-74 years in Arizona, Oklahoma, and North and South Dakota. Cancer mortality was calculated by age, sex and region. Cox proportional hazards model was used to assess independent associations between baseline factors in 1989 and cancer death by 2010.

Results: After a median follow-up of 15.3 years, the cancer death rate per 1000 person-years was 6.33 (95 % CI 5.67-7.04). Cancer mortality was highest among men in North/South Dakota (8.18; 95 % CI 6.46-10.23) and lowest among women in Arizona (4.57; 95 % CI 2.87-6.92). Factors independently associated with increased cancer mortality included age, current or former smoking, waist circumference, albuminuria, urinary cadmium, and prior cancer history. Factors associated with decreased cancer mortality included Oklahoma compared to Dakota residence, higher body mass index and total cholesterol. Sex was not associated with cancer mortality. Lung cancer was the leading cause of cancer mortality overall (1.56/1000 person-years), but no lung cancer deaths occurred among Arizona participants. Mortality from unspecified cancer was relatively high (0.48/100 person-years; 95 % CI 0.32-0.71).

Conclusions: Regional variation in AI cancer mortality persisted despite adjustment for individual risk factors. Mortality from unspecified cancer was high. Better understanding of regional differences in cancer mortality, and better classification of cancer deaths, will help healthcare programs address cancer in AI communities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canep.2021.101978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455435PMC
October 2021

Regulatory approval for anti-infectives in children.

Lancet Child Adolesc Health 2021 06;5(6):e26

Division of Anti-Infectives, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-4642(21)00137-1DOI Listing
June 2021

Disparities in pap smear screening follow up: A catalyst for collective action vs. collective despair.

Gynecol Oncol 2021 02;160(2):361-363

Department of Obstetrics and Gynecology, Dignity Health Medical Group, Division Head for Gynecologic Oncology, UA Cancer Center at Dignity Health St. Joseph's, Gynecologic Oncology, UA College of Medicine, Creighton University School of Medicine at St. Joseph's Hospital and Medical, 500 West Thomas Road Suite 660, Phoenix, AZ 85255, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2021.01.004DOI Listing
February 2021

Unwittingly biased: A note to gynecologic cancer providers.

Gynecol Oncol 2021 03 20;160(3):646-648. Epub 2021 Jan 20.

Department of Psychology, University of Arizona, Tucson, AZ, United States of America.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2021.01.009DOI Listing
March 2021

US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®).

Clin Infect Dis 2021 06;72(12):e1103-e1111

Division of Anti-Infectives, Office of Infectious Diseases, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA), Silver Spring, Maryland, USA.

In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration: NCT02321800.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1799DOI Listing
June 2021

Correction to: The Integrated Review: FDA Modernizes the Review of New Drug Marketing Applications.

Ther Innov Regul Sci 2021 May;55(3):473

Director, Special Programs, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s43441-020-00251-yDOI Listing
May 2021

FDA Approval of Remdesivir - A Step in the Right Direction.

N Engl J Med 2020 Dec 2;383(27):2598-2600. Epub 2020 Dec 2.

From the Division of Biometrics IV, Office of Biostatistics (D.R.), the Division of Antivirals, Office of Infectious Diseases (K.C.-T.), and the Office of Infectious Diseases (J.F., A.S.), Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMp2032369DOI Listing
December 2020

The Integrated Review: FDA Modernizes the Review of New Drug Marketing Applications.

Ther Innov Regul Sci 2021 05 24;55(3):467-472. Epub 2020 Nov 24.

Special Programs, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.

New Drug Applications and Biologics Licensing Applications submitted to the US Food and Drug Administration (FDA) are reviewed by an interdisciplinary team of regulatory scientists that includes medical officers, clinical pharmacologists, toxicologists, statisticians, and drug labeling experts. Upon review of an applicant's submitted evidence from nonclinical studies, clinical trials, and manufacturing capabilities, the review team evaluates the benefits and risks of the drug and makes a scientifically-informed decision. As part of a multi-year, multi-phase New Drugs Regulatory Program Modernization effort, the FDA has recently redesigned how it reviews and documents its decisions with regard to marketing applications. This article describes the origins and rationale of the new Integrated Assessment process and Integrated Review document, summarizes how these differ from the FDA's traditional review of marketing applications, and discusses what industry can expect from a modernized drug review.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s43441-020-00240-1DOI Listing
May 2021

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

Clin Infect Dis 2021 08;73(3):e602-e608

Office of Infectious Diseases, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1712DOI Listing
August 2021

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

Antimicrob Agents Chemother 2020 12 16;65(1). Epub 2020 Dec 16.

Office of Infectious Diseases, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.

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 and 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.01983-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927847PMC
December 2020

Bevacizumab plus fosbretabulin in recurrent ovarian cancer: Overall survival and exploratory analyses of a randomized phase II NRG oncology/gynecologic oncology group study.

Gynecol Oncol 2020 10 26;159(1):79-87. Epub 2020 Jul 26.

Arizona Oncology (US Oncology Network), University of Arizona College of Medicine-Phoenix, Creighton University School of Medicine, St. Joseph's Hospital, Phoenix, AZ, United States. Electronic address:

Objective: To explore the relationship between tumor size and response to combined anti-vascular targeted therapy using the anti-angiogenesis inhibitor, bevacizumab, and the tubulin-binding vascular disrupting agent, fosbretabulin.

Methods: An exploratory, post-hoc analysis of the randomized phase II trial, Gynecologic Oncology Group-0186I, was performed. One hundred and seven patients with recurrent ovarian carcinoma, treated with up to 3 prior regimens, were randomized to bevacizumab 15 mg/kg body weight with or without intravenous fosbretabulin 60 mg/m body surface area every 21 days until progression or unacceptable toxicity. The primary analysis favored the combination (HR 0.69; 95% CI, 0.47-1.00; p = .049) [Monk BJ, et al. J Clin Oncol 2016;34:2279-86]. The Cox proportional hazards model was used to estimate the treatment effect in various subpopulations.

Results: With extended follow-up, the median PFS for bevacizumab plus fosbretabulin was 7.6  months as compared to 4.8  months with bevacizumab alone (HR 0.74; 90% CI, 0.54-1.02). Overall survival was similar in the experimental and control arms (25.2 vs 24.4 mos, respectively, HR 0.85; 90% CI, 0.59-1.22; p = .461). Eighty-one patients had measurable disease and median tumor size was 5.7  cm. In the ≤5.7  cm subgroup, the HR for progression or death was 0.77 (90% CI 0.45-1.31). Patients with tumors >5.7  cm (n = 40) had a HR for progression or death of 0.55; 90% CI, 0.32-0.96; p = .075).

Conclusions: Although no significant survival benefit was observed, the trend showing a reduced HR for progression or death with increasing tumor size when fosbretabulin is added to bevacizumab compared to bevacizumab alone warrants further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2020.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789907PMC
October 2020

PROPHETIC: Prospective Identification of Pneumonia in Hospitalized Patients in the ICU.

Chest 2020 12 29;158(6):2370-2380. Epub 2020 Jun 29.

Duke University, Durham, NC; Duke Clinical Research Institute, Durham, NC.

Background: Pneumonia is the leading infection-related cause of death. The use of simple clinical criteria and contemporary epidemiology to identify patients at high risk of nosocomial pneumonia should enhance prevention efforts and facilitate development of new treatments in clinical trials.

Research Question: What are the clinical criteria and contemporary epidemiology trends that are helpful in the identification of patients at high risk of nosocomial pneumonia?

Study Design And Methods: Within the ICUs of 28 US hospitals, we conducted a prospective cohort study among adults who had been hospitalized >48 hours and were considered high risk for pneumonia (defined as treatment with invasive or noninvasive ventilatory support or high levels of supplemental oxygen). We estimated the proportion of high-risk patients who experienced the development of nosocomial pneumonia. Using multivariable logistic regression, we identified patient characteristics and treatment exposures that are associated with increased risk of pneumonia development during the ICU admission.

Results: Between February 6, 2016, and October 7, 2016, 4,613 high-risk patients were enrolled. Among 1,464 high-risk patients (32%) who were treated for possible nosocomial pneumonia, 537 (37%) met the study pneumonia definition. Among high-risk patients, a multivariable logistic model was developed to identify key patient characteristics and treatment exposures that are associated with increased risk of nosocomial pneumonia development (c-statistic, 0.709; 95% CI, 0.686-0.731). Key factors associated with increased odds of nosocomial pneumonia included an admission diagnosis of trauma or cerebrovascular accident, receipt of enteral nutrition, documented aspiration risk, and receipt of systemic antibacterials within the preceding 90 days.

Interpretation: Treatment for nosocomial pneumonia is common among patients in the ICU who are receiving high levels of respiratory support, yet more than one-half of patients who are treated do not fulfill standard diagnostic criteria for pneumonia. Application of simple clinical criteria may improve the feasibility of clinical trials of pneumonia prevention and treatment by facilitating prospective identification of patients at highest risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2020.06.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722207PMC
December 2020

Concordance of early and late endpoints for community-acquired bacterial pneumonia trials.

Clin Infect Dis 2020 Jun 25. Epub 2020 Jun 25.

Office of Infectious Diseases, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD.

Background: While there are ongoing regulatory convergence efforts, differences remain in primary endpoints recommended for community-acquired bacterial pneumonia (CABP) trials. The US Food and Drug Administration 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 six recent CABP trials submitted to the FDA (n=4,645 participants) to evaluate concordance between early and late endpoint outcomes. We used multivariate logistic regression to identify factors associated with discordance.

Results: Early and late endpoint outcomes were concordant for 85.6% of participants. The proportions of early endpoint responders that ultimately failed and early endpoint non-responders that ultimately succeeded were similar (6.0% vs 8.4%, respectively). Early endpoint response was highly predictive of late endpoint success (positive predictive value 92.9%). Multivariate logistic regression identified early endpoint responders/late endpoint 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 endpoint responders/late endpoint failures were receipt of non-study antibacterial drug therapy and loss to follow-up.

Conclusion: Early and late endpoint outcomes were highly concordant. These data may be useful in the continuing efforts to reach international regulatory convergence on CABP clinical trial design recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa860DOI Listing
June 2020

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

Clin Infect Dis 2020 Jun 25. Epub 2020 Jun 25.

Economics Staff, Office of Economics and Analysis, Office of the Commissioner, Food and Drug Administration, Silver Spring, MD.

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 - 2009, primarily led by small pharmaceutical company involvement. As of December 31, 2019, the number of active INDs has declined to an 11-year low, and the number of antibacterial INDs initiated with the FDA from 2010-2019 was lower than any of the previous three decades. Antibacterial drug development programs initiated in the 1980s and 1990s had high success rates, with over 40% of INDs obtaining marketing approval, in a median time of about six years from IND receipt to approval. For drug development programs initiated between 2000 and 2009, we find 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 December 31, 2019 come from already established drug classes, most in early stages of development, and few are sponsored by large pharmaceutical companies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa859DOI Listing
June 2020

Promoting health equity in the era of COVID-19.

Gynecol Oncol 2020 07 19;158(1):25-31. Epub 2020 May 19.

Weill Cornell School of Medicine, New York, NY, United States of America. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2020.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236740PMC
July 2020

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

JAMA Netw Open 2020 05 1;3(5):e205435. Epub 2020 May 1.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.5435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244987PMC
May 2020

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

Clin Infect Dis 2021 04;72(8):1422-1428

Office of Infectious Diseases, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa246DOI Listing
April 2021

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

Antimicrob Agents Chemother 2020 04 21;64(5). Epub 2020 Apr 21.

U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, Office of Infectious Diseases, Silver Spring, Maryland, USA.

Animal models of bacterial infection have been widely used to explore the 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.02242-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179594PMC
April 2020

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

JAMA Netw Open 2018 12 7;1(8):e185816. Epub 2018 Dec 7.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2018.5816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324354PMC
December 2018

Pediatric Antibacterial and Antifungal Trials From 2007 to 2017.

Pediatrics 2018 09;142(3)

Divisions of Infectious Diseases and

Background And Objectives: The impact of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) on pediatric antibacterial or antifungal drug trials is unknown. Our objective was to identify and characterize trials conducted under the BPCA and/or the PREA.

Methods: Pediatric antibacterial and antifungal drug trials with industry or US federal funding registered in clinicaltrials.gov from 2007 to 2017 were identified. Those conducted under BPCA and/or PREA were identified through US Food and Drug Administration and National Institute of Child Health and Human Development databases.

Results: Of 17 495 pediatric trials registered on clinicaltrials.gov between October 2007 and September 2017, 122 systemic antibacterial or antifungal drug trials with industry or US federal funding were identified. Of these 122 trials, 98 (80%) involved antibacterials only, 23 (19%) antifungals only, and 1 (1%) both antibacterials and antifungals. These represented <1% (122 of 17 495) of pediatric trials. Neither pediatric antibacterial nor antifungal drug trials commonly enrolled neonates 0 to 30 days old (30% [30 of 99] vs 42% [10 of 24], respectively). Pediatric antibacterial and antifungal trials were commonly industry funded (79% [78 of 99] and 83% [20 of 24], respectively). In total, 65% (79 of 122) of pediatric antibacterial and/or antifungal drug trials were conducted under BPCA and/or PREA. Researchers in trials conducted under BPCA and/or PREA, relative to non-BPCA and/or PREA trials, more often collected pharmacokinetic data (70% [55 of 79] vs 26% [11 of 43]).

Conclusions: Although the majority of pediatric antibacterial and/or antifungal drug trials were conducted under BPCA and/or PREA, the overall number was low. Greater effort is needed to stimulate such trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2017-1849DOI Listing
September 2018

Phase II study of single-agent cabozantinib in patients with recurrent clear cell ovarian, primary peritoneal or fallopian tube cancer (NRG-GY001).

Gynecol Oncol 2018 07 5;150(1):9-13. Epub 2018 May 5.

Department of Gynecologic Oncology & Reproductive Medicine, Unit 1362, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States. Electronic address:

Objective: To evaluate the efficacy and tolerability of cabozantinib in recurrent clear cell ovarian, primary peritoneal or fallopian tube cancer.

Methods: Patients with recurrent ovarian, fallopian or primary peritoneal tumors with at least 50% clear cell histomorphology, measurable disease, one or two prior regimens and ECOG performance status 0-2 received cabozantinib 60 mg orally once daily continuously, in 4-week cycles until disease progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) at six months and complete or partial tumor response (as assessed by RECIST 1.1). Secondary endpoints included toxicity, PFS, and overall survival (OS).

Results: Over 19 months, 13 patients were accrued. Fifty-four percent of patients were ≥60 years of age. Performance statuses of 0 and 1 comprised 8 and 5 patients. No objective tumor responses were seen. Three (23% [95% CI: 5%, 54%]) of 13 patients had PFS ≥6 months, including one patient who received cabozantinib for 23 cycles and was still on treatment as of the data cut-off date. Median PFS and OS were 3.6 and 8.1 months, respectively. There was one patient with a grade 5 event: a thromboembolic event considered possibly related to study therapy; patient's cause of death was determined to be due to disease and protocol treatment. Four other patients had thromboembolic events (two grade 3 and one each grade 1 and grade 2). Other grade 3 or higher events reported in two or more patients were nausea, vomiting, fatigue, dyspnea, and dehydration.

Conclusions: Cabozantinib demonstrated minimal activity in the second- and third-line treatments of clear cell ovarian, fallopian tube or primary peritoneal carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2018.04.572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365003PMC
July 2018

Perceived barriers to pediatrician and family practitioner participation in pediatric clinical trials: Findings from the Clinical Trials Transformation Initiative.

Contemp Clin Trials Commun 2018 Mar 26;9:7-12. Epub 2017 Nov 26.

Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27705, USA.

Despite legislation to stimulate pediatric drug development through clinical trials, enrolling children in trials continues to be challenging. Non-investigator (those who have never served as a clinical trial investigator) providers are essential to recruitment of pediatric patients, but little is known regarding the specific barriers that limit pediatric providers from participating in and referring their patients to clinical trials. We conducted an online survey of pediatric providers from a wide variety of practice types across the United States to evaluate their attitudes and awareness of pediatric clinical trials. Using a 4-point Likert scale, providers described their perception of potential barriers to their practice serving as a site for pediatric clinical trials. Of the 136 providers surveyed, 52/136 (38%) had previously referred a pediatric patient to a trial, and only 17/136 (12%) had ever been an investigator for a pediatric trial. Lack of awareness of existing pediatric trials was a major barrier to patient referral by providers, in addition to consideration of trial risks, distance to the site, and time needed to discuss trial participation with parents. Overall, providers perceived greater challenges related to parental concerns and parent or child logistical barriers than study implementation and ethics or regulatory barriers as barriers to their practice serving as a trial site. Providers who had previously been an investigator for a pediatric trial were less likely to be concerned with potential barriers than non-investigators. Understanding the barriers that limit pediatric providers from collaboration or inhibit their participation is key to designing effective interventions to optimize pediatric trial participation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.conctc.2017.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898553PMC
March 2018

An evaluation of progression free survival and overall survival of ovarian cancer patients with clear cell carcinoma versus serous carcinoma treated with platinum therapy: An NRG Oncology/Gynecologic Oncology Group experience.

Gynecol Oncol 2017 11 12;147(2):243-249. Epub 2017 Aug 12.

Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States. Electronic address:

Purpose: We examined disparities in prognosis between patients with ovarian clear cell carcinoma (OCCC) and serous epithelial ovarian cancer (SOC).

Methods: We reviewed data from FIGO stage I-IV epithelial ovarian cancer patients who participated in 12 prospective randomized GOG protocols. Proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS) by cell type (clear cell versus serous).

Results: There were 10,803 patients enrolled, 9531 were eligible, evaluable and treated with platinum, of whom 544 (6%) had OCCC, 7054 (74%) had SOC, and 1933 (20%) had other histologies and are not included further. In early stage (I-II) patients, PFS was significantly better in OCCC than in SOC patients. For late stage (III, IV) patients, OCCC had worse PFS and OS compared to SOC, OS HR=1.66 (1.43, 1.91; p<0.001). After adjusting for age and stratifying by protocol and treatment arm, stage, performance status, and race, OCCC had a significantly decreased OS, HR=1.53 (1.33, 1.76; p<0.001). In early stage cases, there was a significantly decreased treatment effect on PFS for consolidative therapy with weekly Paclitaxel versus observation in OCCC compared to SOC (p=0.048).

Conclusions: This is one of the largest analyses to date of OCCC treated on multiple cooperative group trials. OCCC histology is more common than SOC in early stage disease. When adjusted for prognostic factors, in early stage patients, PFS was better for OCCC than for SOC; however, in late-stage patients, OCCC was significantly associated with decreased OS. Finally, treatment effect was influenced by histology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2017.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697899PMC
November 2017

A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus).

Br J Cancer 2017 Jun 6;117(1):33-40. Epub 2017 Jun 6.

Western Regional Medical Center, Cancer Treatment Centers of America, 14200 W Celebrate Life Way, Goodyear, AZ 85338, USA.

Background: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy.

Methods: Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted.

Results: Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.

Conclusions: Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/bjc.2017.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520208PMC
June 2017

Bivalent rLP2086 (Trumenba®): Development of a well-characterized vaccine through commercialization.

Vaccine 2018 05 19;36(22):3180-3189. Epub 2017 Apr 19.

Worldwide Safety and Regulatory Global CMC, 100 Route 206 North, Peapack, NJ 07977, USA. Electronic address:

The phrase "Process is the Product" is often applied to biologics, including multicomponent vaccines composed of complex components that evade complete characterization. Vaccine production processes must be defined and locked early in the development cycle to ensure consistent quality of the vaccine throughout scale-up, clinical studies, and commercialization. This approach of front-loading the development work helped facilitate the accelerated approval of the Biologic License Application for the well-characterized vaccine bivalent rLP2086 (Trumenba®, Pfizer Inc) in 2014 under Breakthrough Therapy Designation. Bivalent rLP2086 contains two rLP2086 antigens and is licensed for the prevention of meningococcal meningitis disease caused by Neisseria meningitidis serogroup B in individuals 10-25years of age in the United States. This paper discusses the development of the manufacturing process of the two antigens for the purpose of making it amenable to any manufacturing facility. For the journey to commercialization, the operating model used to manage this highly accelerated program led to a framework that ensured "right the first time" execution, robust process characterization, and proactive process monitoring. This framework enabled quick problem identification and proactive resolutions, resulting in a robust control strategy for the commercial process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2017.03.100DOI Listing
May 2018

Obtaining tissue diagnosis in lung cancer patients with poor performance status and its influence on treatment and survival.

Respir Med 2017 03 13;124:30-35. Epub 2017 Jan 13.

Department of Respiratory Medicine, Stobhill Hospital/Glasgow Royal Infirmary, Glasgow, UK.

Introduction: 25% of patients with lung cancer have performance status 3 or 4. A pragmatic approach to investigative procedures is often adopted based on the risks and benefits in these patients and whether tissue diagnosis is necessary for anticipated future treatment. This cohort study investigated factors influencing a clinician's decision to pursue a tissue diagnosis in patients with lung cancer and performance status 3 and 4 and to examine the association of tissue diagnosis with subsequent management and survival.

Methods: All patients with lung cancer diagnosed in North Glasgow from 2009 to 2012 were prospectively recorded in a registry. We investigated the relationships between achieving a tissue diagnosis, treatment and survival.

Results: Of 2493 patients diagnosed with lung cancer, 490 patients (20%) were PS 3 and 122 patients (5%) were PS 4. Tissue diagnosis was attempted in 60% and 35% patients with PS 3 and PS 4 respectively. Younger age, better performance status and having stage 4 disease were independently associated with a diagnostic procedure being performed. Only 5% of patients with poor performance status received treatment conventionally requiring a tissue diagnosis. Age, stage and performance status were independent predictors of mortality. Achieving a tissue diagnosis was not associated with mortality. Receiving treatment requiring tissue diagnosis is associated with survival benefit.

Conclusions: The majority of patients with poor fitness undergo a diagnostic procedure which does not influence further treatment or affect survival. However, the cohort of patients who do undergo therapy determined by tissue diagnosis have improved survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmed.2017.01.002DOI Listing
March 2017

Racial disparities in cervical cancer: Worse than we thought.

Cancer 2017 05 23;123(6):915-916. Epub 2017 Jan 23.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, Phoenix, Arizona.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.30501DOI Listing
May 2017

Safety and efficacy of salvage nano-particle albumin bound paclitaxel in recurrent cervical cancer: a feasibility study.

Gynecol Oncol Res Pract 2016 14;3. Epub 2016 Apr 14.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arizona Cancer Center at Dignity Health St. Joseph's Hospital and Medical Center, 500 West Thomas Road, Suite 660, Phoenix, AZ 85013 USA.

Background: After platinum and taxane chemotherapy, with or without bevacizumab, active regimens for advanced or recurrent cervical cancer are lacking. Our objective was to review a single institution experience in treating recurrent, refractory cervical cancer with nano-particle albumin bound (NAB) paclitaxel with or without bevacizumab.

Methods: This retrospective case series was conducted in accordance with the regulations set forth by the Institutional Review Board at St. Joseph's Hospital and Medical center. The chemotherapy log at the outpatient infusion center at the University of Arizona Cancer Center was reviewed to identify all advanced cervical cancer patients treated with NAB-paclitaxel from November 2011 until February 2015. The following data points were extracted from patient charts: demographic information, number of cycles, progression free survival (PFS), overall survival (OS), dose reductions and dose-limiting toxicities. In addition the average number of treatment cycles and age at recurrence were calculated.

Results: A total of 12 subjects were identified as receiving treatment with NAB-paclitaxel. Mean age at time of recurrence was 47.2 years (36-55). Nine subjects had squamous cell histology and three subjects had adenocarcinoma histology. All subjects had failed treatment with platinum and taxane, or platinum and topotecan chemotherapy. Two subjects were lost to follow up. The Median number of cycles of NAB-paclitaxel was 6.5 (2-19). The total number of cycles of NAB-paclitaxel in the study population was 65. Seven subjects were treated in combination with bevacizumab. Of these, three subjects are still alive and one subject is currently receiving active treatment with NAB-paclitaxel. The median PFS and OS for all subjects that met mortality endpoint was 4.8 months and 8.9 months (n = 7), respectively. One subject discontinued NAB-paclitaxel secondary to peripheral neuropathy, and one subject developed a vesicovaginal fistula while obtaining combination NAB-paclitaxel and bevacizumab therapy.

Conclusions: NAB-paclitaxel with or without bevacizumab is tolerable and potentially active in treating recurrent cervical cancer after failing platinum-taxane or topotecan chemotherapy. This small case series deserves confirmation through prospective clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40661-016-0025-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880945PMC
May 2016

Adverse Events Associated with Fosfomycin Use: Review of the Literature and Analyses of the FDA Adverse Event Reporting System Database.

Infect Dis Ther 2015 Dec 5;4(4):433-58. Epub 2015 Oct 5.

US Food and Drug Administration, Silver Spring, MD, USA.

Introduction: The growing problem of antibacterial resistance resulted in an increased interest in fosfomycin, especially its parenteral formulation. We reviewed fosfomycin safety profile using the Food and Drug Administration Adverse Event (AE) Reporting System (FAERS) and published literature.

Methods: We conducted a FAERS search and disproportionality analysis of all fosfomycin-associated AEs. We also conducted a FAERS search for AEs implicating fosfomycin as the primary suspect and a search of reports of fosfomycin-associated bone marrow toxicity. We then review the literature for publications reporting AEs associated with fosfomycin by conducting PubMed searches.

Results: The disproportionality analysis of all FAERS reports of fosfomycin-associated AEs produced a higher than expected frequency of agranulocytosis, liver injury, severe skin reactions, and pseudomembranous colitis. Subsequent search for AEs where fosfomycin was the primary suspect and the literature review did not suggest a higher association of fosfomycin with these AEs. The search of bone marrow toxicity reports did not demonstrate an association between aplastic anemia and fosfomycin. The literature review selected 23 trials of parenteral administration of fosfomycin in 1242 patients including 8 comparative and 15 non-comparative trials. For oral fosfomycin, only prospective comparative trials (n = 28) in 2743 patients were included. The most frequent AEs associated with parenteral fosfomycin included rash, peripheral phlebitis, hypokalemia, and gastrointestinal disorders. Serious AEs such as aplastic anemia, anaphylaxis, and liver toxicities were reported infrequently. Gastrointestinal disorders were the most common AEs associated with oral fosfomycin.

Conclusion: The identified AEs were consistent with the safety profile of fosfomycin. No new safety signals related to either parenteral or oral fosfomycin were identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40121-015-0092-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675770PMC
December 2015
-->