Streamlining Safety Data Collection in Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Trials: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team.

BACKGROUND: Resistant bacteria are one of the leading causes of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). HABP/VABP trials are complex and difficult to conduct due to the large number of medical procedures, adverse events, and concomitant medications involved. Differences in the legislative frameworks between different regions of the world may also lead to excessive data collection. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development (ABDD) by streamlining clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. METHODS: In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with current data collection processes. Experts defined "data collection" as the act of capturing and reporting certain data on the case report form as opposed to recording of data as part of routine clinical care. The ABDD Project Team developed strategies for streamlining safety data collection in HABP/VABP trials using a Quality by Design approach. RESULTS: Current safety data collection processes in HABP/VABP trials often include extraneous information. More targeted strategies for safety data collection in HABP/VABP trials will rely on optimal protocol design and prespecification of which safety data are essential to satisfy regulatory reporting requirements. CONCLUSIONS: A consensus and a cultural change in clinical trial design and conduct, which involve recognition of the need for more efficient data collection, are urgently needed to advance ABDD and to improve HABP/VABP trials in particular.

Improving Conduct and Feasibility of Clinical Trials to Evaluate Antibacterial Drugs to Treat Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team.

BACKGROUND: The etiology of hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is often multidrug-resistant infections. The evaluation of new antibacterial drugs for efficacy in this population is important, as many antibacterial drugs have demonstrated limitations when studied in this population. HABP/VABP trials are expensive and challenging to conduct due to protocol complexity and low patient enrollment, among other factors. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development by streamlining HABP/VABP clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. METHODS: In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with HABP/VABP protocol complexity. The Project Team developed potential solutions to streamline HABP/VABP trials using a Quality by Design approach. RESULTS: CTTI recommendations focus on 4 key areas to improve HABP/VABP trials: informed consent processes/practices, protocol design, choice of an institutional review board (IRB), and trial outcomes. Informed consent processes should include legally authorized representatives. Protocol design decisions should focus on eligibility criteria, prestudy antibacterial therapy considerations, use of new diagnostics, and sample size. CTTI recommends that sponsors use a central IRB and discuss trial endpoints with regulators, including defining a clinical failure and evaluating the impact of concomitant antibacterial drugs. CONCLUSIONS: Streamlining HABP/VABP trials by addressing key protocol elements can improve trial startup and patient recruitment/retention, reduce trial complexity and costs, and ensure patient safety while advancing antibacterial drug development.

Parents' perceived obstacles to pediatric clinical trial participation: Findings from the clinical trials transformation initiative.

Enrollment of children into pediatric clinical trials remains challenging. More effective strategies to improve recruitment of children into trials are needed. This study used in-depth qualitative interviews with parents who were approached to enroll their children in a clinical trial in order to gain an understanding of the barriers to pediatric clinical trial participation. Twenty-four parents whose children had been offered the opportunity to participate in a clinical trial were interviewed: 19 whose children had participated in at least 1 clinical trial and 5 who had declined participation in any trial. Each study aspect, from the initial explanation of the study to the end of the study, can affect the willingness of parents to consent to the proposed study and future studies. Establishing trust, appropriate timing, a transparent discussion of risks and benefits oriented to the layperson, and providing motivation for children to participate were key factors that impacted parents' decisions. In order for clinical trial accrual to be successful, parents' priorities and considerations must be a central focus, beginning with initial trial design. The recommendations from the parents who participated in this study can be used to support budget allocations that ensure adequate training of study staff and improved staffing on nights and weekends. Studies of parent responses in outpatient settings and additional inpatient settings will provide valuable information on the consent process from the child's and parent's perspectives. Further studies are needed to explore whether implementation of such strategies will result in improved recruitment for pediatric clinical trials.

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

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.

Patient and physician attitudes regarding risk and benefit in streamlined development programmes for antibacterial drugs: a qualitative analysis.

OBJECTIVES: To explore patient, caregiver and physician perceptions and attitudes regarding the balance of benefit and risk in using antibacterial drugs developed through streamlined development processes. DESIGN: Semistructured focus groups and in-depth interviews were conducted to elicit perceptions and attitudes about the use of antibacterial drugs to treat multidrug-resistant infections. Participants were given background information about antibiotic resistance, streamlined drug development programmes and FDA drug approval processes. Audio recordings of focus groups/interviews were reviewed and quotes excerpted and categorised to identify key themes. PARTICIPANTS: Two primary stakeholder groups were engaged: one comprising caregivers, healthy persons and patients who had recovered from or were at risk of resistant infection (N=67; 11 focus groups); and one comprising physicians who treat resistant infections (N=23). RESULTS: Responses from focus groups/interviews indicated widespread awareness among patients/caregivers and physicians of the seriousness of the problem of antibacterial resistance. Both groups were willing to accept a degree of uncertainty regarding the balance of risk and benefit in a new therapy where a serious unmet need exists, but also expressed a desire for rigorous monitoring and rapid, transparent reporting of safety/effectiveness data. Both groups wanted to ensure that >1 physician had input on whether to treat patients with antibiotics developed through a streamlined process. Some patients/caregivers unfamiliar with exigencies of critical care suggested a relatively large multidisciplinary team, while physicians believed individual expert consultations would be preferable. Both groups agreed that careful oversight and stewardship of antibacterial drugs are needed to ensure patient safety, preserve efficacy and prevent abuse. CONCLUSIONS: Groups comprising patients/caregivers and physicians were aware of serious issues posed by resistant infections and the lack of effective antibacterial drug therapies and shared a consensus that streamlined development programmes represent a necessary response to the resistance crisis, but one that requires enhanced safeguards and risk communication.

Unintentional transfer of vaccinia virus associated with smallpox vaccines: ACAM2000(®) compared with Dryvax(®).

BACKGROUND: Routine vaccination against smallpox (variola) ceased in the US in 1976. However, in 2002 limited coverage for military personnel and some healthcare workers was reinstituted. In March 2008, ACAM2000® replaced Dryvax® as the vaccine used in the United States against smallpox. Unintentional transfer of vaccinia virus from a vaccination site by autoinoculation or contact transmission, can have significant public health implications. We summarize unintentional virus transfer AEs associated with ACAM2000® since March 2008 and compare with Dryvax®. RESULTS: We identified 309 reports for ACAM2000® with skin or ocular involvement, of which 93 were autoinoculation cases and 20 were contact transmission cases. The rate for reported cases of autoinoculation was 20.6 per 100,000 vaccinations and for contact transmission was 4.4 per 100,000 vaccinations. Eighteen contact transmission cases could be attributed to contact during a sporting activity (45%) or intimate contact (45%). Of the 113 unintentional transfer cases, 6 met the case definition for ocular vaccinia. The most common locations for all autoinoculation and contact cases were arm/elbow/shoulder (35/113; 31%) and face (24/113; 21%). Methods We reviewed 753 reports associated with smallpox in the Vaccine Adverse Event Reporting System and CDC Poxvirus consultation log, reported from March 2008 to August 2010. Reports were classified into categories based upon standard case definitions. CONCLUSION: Overall, unintentional transfer events for ACAM2000® and Dryvax® are similar. We recommend continued efforts to prevent transfer events and continuing education for healthcare providers focused on recognition of vaccinia lesions, proper sample collection, and laboratory testing to confirm diagnosis.

Severe combined immunodeficiency (SCID) and rotavirus vaccination: reports to the Vaccine Adverse Events Reporting System (VAERS).

BACKGROUND: Rotavirus vaccines are the only live vaccines recommended for infants in the US. Postmarketing reports have described severe gastroenteritis with vaccine viral shedding in infants who received rotavirus vaccine and were later diagnosed with SCID. The US Food and Drug Administration recently approved labeling changes for RotaTeq and Rotarix contraindicating administration to individuals with a history of SCID. We queried VAERS to characterize reports of SCID after rotavirus vaccination. METHODS: VAERS inclusion criteria included current US-licensed rotavirus vaccines, report dates from February 3, 2006 to January 15, 2010, and queries for the MedDRA preferred term "combined immunodeficiency" as well as any text containing the terms, "SCID" or "combined immunodeficiency." RESULTS: We identified nine reports of SCID and rotavirus vaccination in infants between 3 and 9 months of age. All but one case presented with diarrhea among other symptoms. All infants were hospitalized and had workups leading to the SCID diagnosis. Stool rotavirus testing was positive in all cases and the virus was identified as the vaccine strain in six cases. Prolonged viral shedding was documented in five cases. No deaths were reported. CONCLUSION: The aforementioned labeling changes were warranted given the risk posed by live rotavirus vaccine to individuals with SCID, as illustrated by these VAERS cases. Although congenital, SCID was not diagnosed in these infants until after rotavirus vaccination. Earlier identification of SCID (e.g., from expanded newborn screening or heightened clinical vigilance) could prevent inadvertent live rotavirus vaccine administration and also potentially result in earlier life-saving stem cell transplants.

Kawasaki disease after vaccination: reports to the vaccine adverse event reporting system 1990-2007.

BACKGROUND: Kawasaki disease (KD) is a multisystemic vasculitis primarily affecting children<5 years. A review of RotaTeq (rotavirus vaccine live) clinical trial data revealed higher, though not statistically significantly, KD rates among RotaTeq vaccines than placebo recipients. In June 2007, the RotaTeq label was revised accordingly. OBJECTIVES: To describe and assess KD reported to Vaccine Adverse Event Reporting System (VAERS) for all US licensed vaccines. METHODS: We reviewed all KD reports received by VAERS from 1990 through mid-October 2007. Cases were characterized by age, gender, onset interval, and vaccine type. Proportional reporting ratio (PRR) was used to evaluate KD reporting for each vaccine compared with all others. Reporting rates were calculated using number of doses distributed as denominator. RESULTS: Through October 14, 2007, 107 KD reports were received by VAERS: 26 were categorized as classic cases, 19 atypical, 52 possible, and 10 were noncases. Of the 97 cases, 91% were children<5 years. There was no clustering of onset intervals after day 1 postvaccination. Before the RotaTeq label revision, the KD PRR was elevated only for Pediarix (DTaP, hepB, and IPV combined) but the KD reporting rate for Pediarix (0.59/100,000 person-years) was much lower than the background incidence rate (9-19/100,000 person-years) for children<5 years in the United States. After the revision, reporting of KD for RotaTeq was stimulated but the reporting rate for RotaTeq (1.47/100,000 person-years) was still much lower than the background rate. CONCLUSIONS: Our review does not suggest an elevated KD risk for RotaTeq or other vaccines. Continued postmarketing monitoring for KD is ongoing.