text:
Childhood maltreatment increases the risk of subsequent depression, anxiety and alcohol abuse, but the rate of resilient victims is unknown. Here, we investigated the rate of victims that do not suffer from clinical levels of these problems after severe maltreatment in a population-based sample of 10980 adult participants.
Compared to men, women reported more severe emotional and sexual abuse, as well as more severe emotional neglect. For both genders, severe emotional abuse (OR = 3.80 [2.22, 6.52]); severe physical abuse (OR = 3.97 [1.72, 9.16]); severe emotional neglect (OR = 3.36 [1.73, 6.54]); and severe physical neglect (OR = 11.90 [2.66, 53.22]) were associated with depression and anxiety while only severe physical abuse (OR = 3.40 [1.28, 9.03]) was associated with alcohol abuse.
Looking at men and women separately, severe emotional abuse (OR = 6.05 [1.62, 22.60] in men; OR = 3.74 [2.06, 6.81] in women) and severe physical abuse (OR = 6.05 [1.62, 22.60] in men; OR = 3.03 [0.99, 9.33] in women) were associated with clinical levels of depression and anxiety. In addition, in women, severe sexual abuse (OR = 2.40 [1.10, 5.21]), emotional neglect (OR = 4.78 [2.40, 9.56]), and severe physical neglect (OR = 9.86 [1.99, 48.93]) were associated with clinical levels of depression and anxiety.
Severe emotional abuse in men (OR = 3.86 [0.96, 15.48]) and severe physical abuse in women (OR = 5.18 [1.48, 18.12]) were associated with alcohol abuse. Concerning resilience, the majority of severely maltreated participants did not report clinically significant levels of depression or anxiety (72%), or alcohol abuse (93%) in adulthood. Although the majority of severely abused or neglected individuals did not show clinical levels of depression, anxiety or alcohol use, severe childhood maltreatment increased the risk for showing clinical levels of psychopathology in adulthood.
Severe child maltreatment is conventionally defined within child protection practice as severe physical, emotional, sexual abuse and/or severe physical and emotional neglect by adults [1]. Severity can be defined on the basis of the type of maltreatment, its frequency, if the child was subjected to multiple forms of maltreatment, if a weapon had been used, if the maltreatment resulted in an injury, and if the abuse was considered severe by the victim. For sexual abuse, even a single experience is often considered to be severe [1].
Childhood maltreatment and its psychosocial consequences
There are annually over one million victims of childhood maltreatment in the USA alone and childhood maltreatment has a large public health impact [2]. Several studies show that childhood physical, emotional, and sexual abuse are all related to an increased risk of depression and anxiety disorders in adulthood [3–9]. Other studies have found that the severity of abuse and neglect is associated with increased depression and anxiety symptoms in adulthood [10–12]. This means that as a general rule, the more severe the abuse and neglect, the more likely the abused individuals are to show symptoms of depression and anxiety.
There is also a robust relationship between childhood maltreatment and later alcohol abuse [13–16]. For example, Young-Wolff et al. [17] found that men who had experienced childhood maltreatment were 1.7 times more likely to suffer from alcohol abuse in adulthood than men who did not report experiences of childhood maltreatment. Similar findings have been made when investigating the consequences of abuse and neglect in women (e.g., [18]). Findings from a study by Schwandt et al. [19] suggested that the severity of emotional and physical abuse plays a prominent role in the development of alcohol abuse. In line with these results suggesting a role of the severity of childhood abuse on later substance misuse, Hyman et al. [20] found that the severity of abuse was predictive of cocaine use after having been discharged from an inpatient treatment for cocaine addiction. This was true for women but not for men. Kendler et al. [21] showed that women who had experienced child sexual abuse reported higher incidences of alcohol abuse. Twin studies have also shown that childhood sexual abuse increases the risk of alcohol abuse and addiction later in life [21–24]. To summarize, there is a strong, robust relationship between childhood maltreatment and mental disorders in adulthood. These associations include associations between childhood experiences of physical abuse, emotional abuse, and neglect, respectively, and mental disorders such as depression and anxiety disorders, and alcohol abuse [25–26]. Moreover, multi-type maltreatment in childhood is associated with greater impairment in adulthood, and this association also includes a range of psychological and behavioral problems, such as depression, anxiety, and alcohol abuse [27].
However, not all victims of childhood maltreatment develop symptoms of substance abuse or psychopathology in adulthood. Meta-analyses suggest that many (but not all) children who have experienced abuse succeed in overcoming some of the possible negative outcomes [28]. For example, Klika and Herrenkohl [28] found that some individuals who have experiences of abuse in childhood do not suffer long-term negative sequelae. Collishaw et al. [29] reported that despite serious experiences of childhood sexual or physical abuse, some individuals did not develop psychiatric problems during adulthood. Moreover, Hamilton et al. [30] reported that emotional neglect did not significantly predict increases in depressive or anxiety symptoms later in life. It has been estimated that 12–22% of maltreated individuals are functioning well despite experiencing childhood maltreatment [31].
The current study
Several studies have focused on only experiencing one type of maltreatment (e.g., sexual abuse) or one type of outcome (e.g., depression). Moreover, most previous studies have relied on either convenience samples or samples from health care services, and especially samples of the latter kind might bias the results and show less resilience than is actually the case.
In the present study, we used a large, population-based sample of Finnish men and women. The types of maltreatment included emotional, physical, and sexual abuse as well as emotional and physical neglect. Thus, the aims of the present study were to:
1. Investigate gender differences in severe experiences of different types of childhood abuse;
2. Compare if and how individuals reporting severe experiences of different types of childhood abuse differ from individuals who did not report experiencing childhood abuse, in terms of presence of clinically significant symptoms of depression and anxiety in adulthood; and
3. Compare if and how individuals reporting severe experiences of different types of childhood abuse differ from individuals who did not report experiencing childhood abuse in terms of presence of alcohol abuse symptoms in adulthood.
Descriptive results
The proportion of participants with severe experiences of emotional abuse was 0.6% (n = 64). The corresponding proportion for severe experiences of physical abuse was 0.2% (n = 26) while the proportions for severe experiences of sexual abuse was 0.4% (n = 43). For severe experiences of emotional neglect, the proportion was 0.4% (n = 44) and for severe experiences of physical neglect 0.1% (n = 7). With regard to gender differences in the different types of severe experiences of abuse, Table 2 shows that there were statistically significant differences between men and women in the proportion of individuals with severe experiences of emotional abuse, sexual abuse and emotional neglect. All of these were more prevalent in women. There were no statistical differences between men and women in terms of having severe experiences of physical abuse and physical neglect.
We then investigated whether the proportion of individuals having clinical levels of depression and anxiety was higher in individuals with severe experiences of abuse and neglect compared to individuals with less severe (or no) experiences of abuse and neglect. Table 3 shows that, for both genders, severe experiences of emotional and physical abuse and emotional and physical neglect increased the likelihood of suffering from clinical depression or anxiety compared to less severe experiences of the said forms of childhood maltreatment.
In men, severe abuse experiences were significantly associated with increases in the prevalence of clinical depression or anxiety when it came to experiences of severe emotional and physical abuse and physical neglect. No association was observed for severe sexual abuse and severe emotional neglect. For women, severe experiences of all childhood maltreatment types increased the likelihood of suffering from clinical depression or anxiety compared to other lower experiences of maltreatment.
Next, we explored the proportions of both men and women who were resilient to severe experiences of childhood maltreatment with regards to not suffering from clinical levels of depression or anxiety in adulthood. Depending on the abuse type, 55.6% to 100% of men with experiences of severe abuse did not show clinically significant levels of depression or anxiety. For women, 50% to 80.5% did not show clinically significant levels of depression or anxiety.
The present study investigated five types of maltreatment: emotional, physical and sexual abuse, and physical and emotional neglect; and their relationships to depression, anxiety and alcohol abuse. The study used a population-based sample of 10980 participants and used validated measures of experiences of childhood maltreatment, current depression and anxiety, and current alcohol abuse.
More particularly, our aim was to investigate gender differences in victims of severe childhood maltreatment, as well as to compare if and how individuals reporting severe experiences of different types of childhood abuse differ from individuals without such severe experiences in terms of presence of clinically significant symptoms of depression, anxiety and alcohol abuse in adulthood.
The present study found that women reported more childhood experiences of severe emotional, sexual abuse and emotional neglect than men. Our findings are inconsistent with the results of those of previous studies indicating that men reported more childhood experiences of abuse than women [3, 38]. However, our results are consistent with findings suggesting that women are more sensitive than men to the effects of experiences abuse in childhood [29].
Compared to another Finnish population based sample, the frequencies of severe abuse were relatively low in our sample. This could be due to samples being obtained at different times, as abuse in Finland has been decreasing [39], or that in the present study the complete CTQ was used: in the study by Albrecht's et al. [33], only one item per factor was used. The decrease in measurement reliability that follows from removing 80% of the original items might have inflated the estimates in Albrecht's study [33].
More specifically, our results revealed that, in men, severe experiences of emotional and physical abuse as well as physical neglect were significantly associated with increases in the prevalence of depression and anxiety symptoms. For women, there was an association between all types of severe childhood maltreatment (emotional, physical and sexual abuse, and physical and emotional neglect) with depression and anxiety symptoms in adulthood.
These results were consistent with previous literature indicating that physical abuse and/or emotional abuse are related to depression and anxiety disorders [4–5, 40–41]. These findings also corroborate findings from meta-analyses and extend previous reports of severe experiences of abuse or neglect being associated with greater risk of developing depressive and anxiety disorders in adulthood [26].
When we examined each type of maltreatment for associations with alcohol abuse, the results showed that severe emotional abuse was associated with alcohol abuse in men. For women, severe physical abuse emerged as a predictor for problematic alcohol use. This is consistent with research suggesting that childhood experiences of emotional and physical abuse were found to be the primary predictor of alcohol abuse [19, 42].
It is intriguing, however, that there appears to be a gender difference in response to abuse type, with men having a considerably more severe response to emotional abuse in terms of propensity to develop alcoholism later in life. For example, an explanation for why women appear to suffer greater consequences in terms of abusing alcohol later in life could be that boys are more likely to engage in rough-and-tumble play and play fights [43], and are thus desensitized to physical abuse to a higher extent than women. It is also, however, possible that measurement invariance could explain the perceived gender differences.
Our current findings suggest that, fortunately, more than half of the participants who have severe experiences of abuse and neglect in childhood seem to succeed in overcoming some of the possible consequences with regards to depression and anxiety symptoms and alcohol abuse in adulthood. While the present study did not investigate mediators of resilience, many studies have considered successful psychosocial adjustment as a mediator of psychological resilience following adverse events [44–45]. It should also be mentioned that some individuals likely have heritable factors that have been shown to protect against adverse effects of maltreatment, by means of gene–environment interaction (i.e., the concept that individuals respond differently to environmental stressors depending on their genotype) [46].
Limitations of the research
Despite the strengths of the present study, it is also characterized by some limitations worth mentioning. First, memories are usually influenced by later experiences, and since the questionnaire was about events that happened during childhood, the obtained information might be somewhat biased. Second, we did not consider the possible overlap between experiences of maltreatment types. Because experiencing one type of abuse or form of neglect is associated with experiencing also another type of abuse or form of neglect [10, 47], it is possible that also severe forms of abuse and neglect are correlated across types or maltreatment. This could, for example, mean that several of the individuals with clinical cases of depression and anxiety or alcohol abuse, not only had experienced one form of severe abuse, but several. Should this be the case, the additive effect of multiple types of abuse could influence the results.
In the present study, it is possible that the true prevalence of anxiety, depressive symptoms or alcohol abuse has been underestimated, as we have only one cross-sectional assessment of the above mentioned indicators (i.e., some individuals may have experienced clinically significant symptoms before study participation, or may experience symptoms in the future, but did not do so at the time of assessment). A longitudinal assessment of adulthood symptoms would thus arguable have been more appropriate than a single, cross-sectional measure.
Also, some of our results and group comparisons were based on very few individuals. This might both influence the estimated prevalence of depression and anxiety or problematic alcohol use and undermines the statistical power to detect differences. Finally, we only included three known consequences of experiencing childhood maltreatment: Depression and anxiety and problematic alcohol use. It is possible that individuals showing resilience on these possible consequences of maltreatment are not resilient with respect to other negative outcomes, such as social functioning or health-risk behavior.
To our knowledge, this is the first study that has looked at the effects of severe experiences of abuse in childhood on depression and anxiety symptoms and alcohol abuse in adulthood in a relatively large sample.
We found that a majority of individuals with severe experiences of childhood maltreatment did not meet the criteria for clinical of levels depression and anxiety or clinical significant levels of alcohol abuse. Although this is a positive message, it is important to remember that experiences of child maltreatment increase the risk of psychosocial problems in adulthood and several of the victims of severe maltreatment included in our study may have had increased, but non-clinical significant levels of depression, anxiety, and alcohol abuse.
Source: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177252


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Participating Organization(s)
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Funding Opportunity Title
Pediatric Phase 1/Pilot Consortium (Limited Competition UM1)
Activity Code
UM1 Multi-Component Research Project Cooperative Agreements
Announcement Type
Reissue of RFA-CA-07-502
Related Notices
Funding Opportunity Announcement (FOA) Number
Companion FOA
Only one application from eligible institution is allowed as defined in Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)
FOA Purpose
The purpose of this Funding opportunity Announcement (FOA) is to continue the NCI's program for Pediatric Phase 1/Pilot Consortium. The function of the Consortium is to conduct Phase 1 and pilot studies in children with cancer so that new agents can be introduced into the pediatric oncology setting in a timely manner. The Consortium's ability to quickly conduct "first in children" studies is critical to NCI's overall clinical research program for children with cancer. To accomplish the objectives of the FOA, a strong multi-institutional, multi-disciplinary research team is needed that can rapidly and efficiently design and conduct Phase 1 and pilot clinical trials and that is experienced in doing so within the ethical constraints applicable to research involving children. The ultimate purpose for supporting the Pediatric Phase 1/Pilot Consortium is to improve therapy outcomes for children with cancer. The Consortium applicants must plan to serve this goal through the safe and efficient introduction of promising new agents and treatment regimens into the pediatric clinical setting through the conduct of well-designed Phase 1 and pilot studies. In addition, Consortium applicants must plan to incorporate pharmacokinetic and pharmacodynamic endpoints (to include imaging and translational laboratory studies) as appropriate into Phase 1 and pilot studies to facilitate future development of the new treatment approaches. The Consortium covered by this FOA is designed to be a complementary program to the Children Oncology Group (COG), another NCI-sponsored program that is mainly focused on Phase 2 and Phase 3 pediatric clinical trials. The Consortium is expected to collaborate with COG Disease Committees in the development of its pilot studies of new treatment approaches for children with specific types of cancer.
Posted Date
January 5, 2012
Letter of Intent Due Date
February 20, 2012
Application Due Date(s)
March 20, 2012
AIDS Application Due Date(s)
Not Applicable
Scientific Merit Review
Advisory Council Review
Earliest Start Date(s)
September 1, 2012
Expiration Date
March 21, 2012
Due Dates for E.O. 12372
Not Applicable
Required Application Instructions
It is critical that applicants follow the instructions in the PHS398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.
Part 1. Overview Information
Part 2. Full Text of Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
The purpose of this Limited Competition Funding Opportunity Announcement (FOA) is to continue the NCI's program for conducting Phase 1 and pilot studies in children with cancer. The goal of the program is to facilitate a quick conduct of "first in children" studies of new therapeutic agents so that new treatments can be introduced into the pediatric oncology setting in a timely manner.
The eligibility to apply in response to this FOA is limited to the current Consortium awardees. To accomplish the objectives of the FOA, applicants must have a strong multi-institutional, multi-disciplinary research team. The team must have appropriate experience and ability to rapidly design and efficiently conduct Phase 1 and pilot clinical trials, all within the ethical constraints applicable to research involving children. The Pediatric Phase 1/Pilot Consortium covered by this FOA is designed as a complementary program to the Children Oncology Group (COG), another NCI-sponsored program that is mainly focused on Phase 2 and Phase 3 pediatric clinical trials.
The specific objectives for the Consortium in the coming 5-year funding period will be:
The NCI is the primary source of support for early phase evaluations of new agents and new treatment approaches for children with cancer. The support that NCI has provided for early phase clinical trials has resulted in children with cancer having access to a broad range of new anti-cancer agents and has contributed to the identification of curative treatments for approximately 80% of children with cancer. Nonetheless, as many as 20% of children with cancer succumb to their disease, and a significant number of survivors experience significant short- and long-term toxicities. Additionally, the rate of decline in childhood cancer mortality rates slowed in the late 1990s, a trend most noticeable for pediatric solid tumors. There remains a critical need for safely introducing new agents and new treatment approaches for children with cancer so that children can benefit from advances in cancer biology and drug development. The reissuance of the Pediatric Phase 1/Pilot Consortium FOA represents a continuation of NCI's historic commitment to childhood cancer research as well as a forward-looking program for extending targeted therapeutics into the pediatric population as validated targets are identified for specific childhood cancers.
This FOA builds upon experience gained during the two earlier funding periods of the Phase 1/Pilot Consortium. The continuation of the Consortium program is grounded in basic principles guiding the conduct of pediatric Phase 1 clinical trials, as listed below. Consortium applicants responding to this FOA are expected to follow these general principles in their plans for the new funding period.
The proposed COG Phase 1/Pilot Consortium must include the following components that meet the requirements specified below:
Note on Process for Initiating and Funding of Patient Studies and the Biology/Pharmacokinetic Studies:
The Consortium is expected to establish procedures for initiating and funding auxiliary studies along with the main clinical Phase 1/Pilot studies. The Consortium applicants must provide plans to establish a process for soliciting and reviewing applications from researchers to perform pharmacokinetic and correlative studies.
For this purpose, the Consortium must have two dedicated budget items:
The Consortium applicants are also encouraged to seek additional funds for auxiliary studies from other sources to supplement those expected in the Consortium award.
PROGRAM EVALUATION. The program of Pediatric Phase 1/Pilot Studies will be subject to external evaluation near the end of the funding period (to be coordinated by the NCI Program Staff). Such evaluation is part of NIH efforts to optimize the efficiency of the funded research. The evaluation process will involve monitoring and assessing the progress of the Pediatric Phase 1/Pilot Studies program toward achieving its goals. This aspect includes evaluating the quality, value, and the quality and scientific impact of the research conducted by the Consortium. For the efficient evaluation of the Program, cooperation of the Consortium awardee will be important and expected.
CRN GOVERNANCE. The Pediatric Phase 1/Pilot Studies Consortium will be governed by the Steering Committee. Details on the composition and functions of the Consortium Steering Committee are provided in Section VI.2.A. Cooperative Agreement Terms and Conditions of Award.
Funding Instrument
Cooperative Agreement
Application Types Allowed
The OER Glossary and the PHS398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards
NCI intends to commit up to approximately $3.47 million in FY 2012 to fund one award.
Award Budget
Application budget (total costs) must not exceed $3.47 million.
Award Project Period
Five years.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.
The eligibility to apply in response to this FOA is limited to the current recipient of the Children's Oncology Group Phase 1/Pilot Consortium award.
Not Applicable.
Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.
All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.
All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
For institutions/organizations proposing multiple PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS398 Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Eligible applicant institution may submit only one application.
NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.
Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.
It is critical that applicants follow the instructions in the PHS398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
Malcolm A. Smith, MD, PhD
National Cancer Institute
Telephone: 301-496-2522
Email: email@example.com
Applications must be prepared using the PHS 398 research
grant application forms and instructions for preparing a research grant
application. Submit a signed, typewritten original of the application,
including the checklist, and three signed photocopies in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
At the time of submission, two additional paper copies of
the application and all copies of the appendix files must be sent to:
Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
Email: email@example.com
All page limitations described in the PHS398 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:
This FOA uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).
Follow the current PHS 398 instructions to provide a detailed budget (direct costs) for the entire application for the first 12-month period (Form page 4) and the entire proposed project period (Form page 5).
Use additional Form Pages 4 and 5 to provide detailed separate budget information (first year and cumulative budgets for the entire project period) for the individual application components. This information must include:
Important Note on Budget:
The budget for the Consortium should include (in addition to support for scientific leadership, administrative and regulatory activities, data management and analysis, meeting support and travel, etc.) the following items:
All instructions in the PHS398 Application Guide must be followed, with the following additional instructions:
For the Consortium application submitted in response to this FOA, the PHS398 Research Strategy Section must consist of the following sub-sections (modify Table of Content accordingly):
A. Overview, Progress, and Scientific Leadership: 12 pages
B. Clinical Research Program: 12 pages
C. Member Institutions: 12 pages
D. Statistics and Data Management Core: 6 pages
E. Pharmacokinetic/Biology Component: 6 pages
F. Imaging Core: 6 pages
Other sections of the PHS398 Research Plan (398 application instructions Part I, Section 5.5) remain unmodified and must be completed following standard instructions.
In this section address the following aspects:
1) Brief overview of Consortium formation and evolution
2) Progress accomplished during the current funding period, including:
Note 1: Do not include in the Progress those elements that are required for the standard clinically-oriented sections of the Research Plan (Secions 4 and 6-9). Those Sections must be completed exactly as per PHS398 Inclusions.
Note 2: A list of publications, manuscripts accepted for publication, patents, and other printed materials should NOT be included under Progress but should be listed as per standard PHS398 instructions in Section 5 of Research Plan "Bibliography and References Cited/Progress Report Publication List".
3. Scientific Leadership, including:
Note 3: If multiple PD(s)/PI(s) are proposed, the standard Section 12 of PHS 398 Research Plan "Multiple PD(s)/PI(s) Leadership Plan" must also be completed as per PHS 398 instructions.
Note 4: To fulfill the objectives of the FOA, individuals designated as PD(s)/PI(s) will need to engage meaningfully in Consortium activities. It is expected that an overall Consortium PD/PI will commit at least 2.4 person months effort and all other PD(s)/PI(s) (if designated) at least 1.8 person months effort to the Consortium. These commitments are expected to be maintained through the entire funding period.
In this section, identify the Program Leader(s) and Specific Aims. It is expected the overall consortium PD(s)/PI(s) will serve as Director(s) of the Clinical Research Program. In addition, address the following aspects:
In this section, address the following aspects:
In this section, identify the Core Leader(s) and address the following aspects:
In this section, identify the Core Leader(s) and address the following aspects:
In this section, identify the Core Leader(s) and address the following aspects:
Resource Sharing Plan
Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS398 Application Guide:
Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS398 Application Guide, with the following modifications as described in the preceding Sections 1 – 7:
Part I. Overview Information contains information about Key Dates.
Information on the process of receipt and determining if
your application is considered "on-time" is described in detail in the PHS398
Application Guide.
Applicants may track the status of the application in the eRA Commons, NIH's electronic system for grants administration.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost
principles, and other considerations described in the NIH
Grants Policy Statement..
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Application must be received on or before the due dates in Part I. Overview Information. If an application is received after that date, it will not be reviewed.
Upon receipt, application will be evaluated for completeness by the Center for Scientific Review and responsiveness by the NCI. Application that is incomplete and/or nonresponsive will not be reviewed.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.
Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.
For this particular announcement, note the following:
The overarching goal of this FOA is to bring novel anticancer agents into pediatric oncology through Phase 1 and pilot clinical trials. In this context, the important aspects are whether the applicants have assembled a team of investigators capable of conducting state-of-the-art Phase 1 and pilot studies in children with cancer, and whether they will be able to work as a coherent research team to efficiently and expeditiously conduct early phase clinical trials. These aspects are expected to be assessed in part based on past performance/accomplishments and the extent to which the Consortium has set a standard for drug development efforts in global pediatric oncology. The assessment should also be based on the proposed research approach and direction for the coming funding period and on the documentation of its ability to accomplish the required specific objectives stated in this FOA.
Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the COG Phase 1/Pilot Consortium to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the COG Phase 1/Pilot Consortium proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a program that by its nature is not innovative may be essential to advance a field.
Does the Consortium address an important problem or a critical barrier to progress in the field? If the aims of the Consortium are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Specific for this FOA: How likely is the prospect that the Consortium, as proposed, will introduce appropriate novel anticancer agents into pediatric oncology in a timely, safe, and efficient manner?
Are the PD/PIs, collaborators, and other researchers well suited to the Consortium? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Specific for this FOA: How complete and comprehensive are the expertise of the PD(s)/PI(s) and the entire team of investigators assembled by the applicants in terms of their ability to conduct state-of-the-art Phase 1 and pilot studies in children with cancer? Will these investigators be able to work as a coherent research team to efficiently and expeditiously conduct early phase clinical trials? Are the proposed leadership structure and decision-making processes and interactions among the Consortium leadership and its various components optimal for the Consortium goals?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Specific for this FOA: Within the confines of the ethical constraints applicable to Phase 1 trials in children, do the applicants propose novel or improved ways and/or methods to enhance or better serve the goals of the Consortium?
Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the Consortium? Are potential problems, alternative strategies, and benchmarks for success presented?
If the project is in the early stages of development, will the strategy
establish feasibility and will particularly risky aspects be managed?
Are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?
Specific for this FOA: How strong overall are the approaches proposed for individual components of the Consortium?
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.
Protections for Human Subjects
For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.
Inclusion of Women, Minorities, and Children
The committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.
Vertebrate Animals
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
Not Applicable
For Renewals, the committee will consider the progress made in the last funding period.
In particular: Has the Consortium shown appropriate progress in developing productive and highly successful early phase clinical trials program for children with cancer?
Not applicable.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.
Applications from Foreign Organizations
Not Applicable.
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Application will be assigned to the NCI. Following initial eview, application will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:
After the peer review of the application is completed, the PD(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee's business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.
Throughout these Terms and Conditions of Award, "Pediatric Phase 1/Pilot Consortium" (or "Consortium") refers to the organizational structure which is composed of the Consortium PD(s)/PI(s) and other key personnel, the Clinical Research Program, Member Institutions, the Pharmacokinetic/Biology Component, the Statistics and Data Management Core, and Imaging Core. All of Consortium investigators and participating institutions agree to collaborate on research goals of the Consortium.
The PD(s)/PI(s) will have the primary responsibility for:
All the Consortium activities and specific activities of its components must be consistent with the guidelines contained in the following documents (and any subsequent modification to them) that are hereby incorporated as parts of the terms of award. These documents describe the programmatic responsibilities for the conduct of the research supported by this cooperative agreement:
Responsibilities of Clinical Research Program:
The Clinical Research Program working with the Statistics and Data Management Core will be responsible for coordinating clinical trial protocol development, protocol submission to the NCI for review and approval, study conduct (including central data collection and analysis), quality assurance including quality control and study monitoring, protocol amendments/status changes, adherence to requirements regarding investigational drug management and federally mandated regulations and protocol and performance reporting. Specific responsibilities are listed below.
1) Organization and Standard Operating Procedures (SOPs) for Clinical Trials: The Clinical Research Program, with the guidance of the PD(s)/PI(s) and Steering Committee, is responsible for development and maintenance of an appropriate organizational infrastructure and Standard Operating Procedures for the Consortium.
2) Clinical Trial Protocol Development: Clinical Research Program is responsible for all aspects of developing Phase 11 clinical trials and Pilot studies, including: defining study objectives and approaches (including details of experimental design), planning study implementation, data analyses and interpretations, and publication of study results. These responsibilities include preparation and implementation of procedures for development and submission of Consortium clinical trial protocols to the CTEP Protocol and Information Office (PIO) in a timely fashion for review and approval by NCI.
3) Study Monitoring: The Consortium must follow the general guidelines for study monitoring for CTEP-sponsored trials as described at http://ctep.info.nih.gov/monitoring/section2.html#2.2.2. The Consortium is responsible for assuring accurate and timely monitoring of the progress of each study, and therefore must have standard procedures for timely data collection and data management consistent with the intensive data requirements and the need for rapid reporting necessary for Phase 1 and pilot studies. Procedures for study monitoring are expected to address at a minimum the following aspects:
4) Data Management Policies and Practices: The responsibilities of the Statistics and Data Management Core for data management related to study monitoring include:
5) Quality Control/Quality Assurance (QC/QA) of Consortium Clinical Trials: The Consortium is responsible for establishing and implementing mechanisms to assure the accuracy and reliability of the Consortium clinical trials data. Key items that should be addressed in this regards include:
a) Evaluation of the performance of Member Institutions in terms of:
b) Procedures for placing Member Institutions on probation for inadequate performance and for removing such institutions from the Consortium if performance is not adequate during the probationary period or at any time that the institution (or participating site) does not meet Consortium standards for institutional performance.
c) Training functions that address data collection, data management, and overall data quality. These aspects include, but are not limited to, the following elements:
d) Procedures for central review of the reliability of the key elements defining the outcome of clinical trials, including such aspects as: claims of therapeutic responses; adequacy of imaging studies, sufficiency of the submitted data to verify protocol compliance in terms of dose administration and dosage modification, etc.
e) On-site Auditing of Consortium Member Institutions: The Consortium's on-site monitoring program is expected to be coordinated with the CTEP Clinical Trials Monitoring Branch (CTMB) and the Clinical Trials Monitoring Service (CTMS). On-site auditing of Consortium Member Institutions will occur approximately annually, with the timing of audits to be based in part on Member Institution accrual. The on-site audit will address issues of data verification, protocol compliance, compliance with regulatory requirements for the protection of human subjects and investigational agent accountability. The Clinical Research Program, together with Statistics and Data Management Core, will be responsible for providing the CTMS with the accrual and the protocol-specified data needed to conduct institutional audits. Any serious problems with data verification or compliance with Federal regulations must be reported to CTMB immediately. In the event that the NCI determines that a Consortium Member Institution failed to adequately comply with NCI guidelines for conduct of clinical trials, the accrual of new patients to Consortium protocols at the affected institution shall be suspended immediately upon notice of the NCI determination. The suspension will remain in effect until the Consortium conducts the required audit and the audit report or remedial action is accepted by the NCI. The Clinical Research Program will be responsible for notifying any affected participating institution of the suspension. During the suspension period, no funds from this award may be provided to the participating institution for new accruals, and no charges to the award for new accruals will be permitted.
Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
The PD(s)/PI(s) assumes responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the Consortium research in accordance with terms and conditions of the award.
The Consortium will be subject to periodic external evaluation (coordinated by the NCI). The CRN awardee and member institutions will be expected to participate in such evaluations.
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
A designated NCI Program Director, acting as a Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards. The NCI Project Scientist will be the main NCI contact for all facets of the scientific interaction with the awardees and will provide advice to the awardee on specific scientific and/or analytic issues in addition to programmatic issues. As needed, additional NCI scientific staff members with relevant expertise may also become substantially involved in the Consortium activities as Projects Scientists or Coordinators. NCI Program Staff Responsibilities will include:
1) Monitoring Consortium progress. Actions necessary for monitoring may include, but are not limited to, the following: regular communications with the PD(s)/PI(s)and staff, periodic site visits for discussions with awardee research teams, response audits to confirm activity reported from a Consortium clinical trial, observation of field data collection and management techniques, fiscal review, review of clinical trial reports submitted by the Consortium to NCI, review of the Consortium's annual progress report, and attendance at Consortium meetings. The NCI retains, as an option, the right to conduct periodic external reviews of progress.
2) Scientific Liaison: Serving as a resource with respect to other ongoing NCI activities that may be relevant to the Consortium research efforts to identify promising new leads, to facilitate compatibility with other NCI research projects, and to avoid unnecessary duplication of effort.
3) CTEP Assistance in Clinical Trial Protocol Development: The clinical trial protocol must be a detailed written plan of a clinical experiment mutually acceptable to the Consortium and to the CTEP Protocol Review Committee (PRC). The PRC meets weekly and is chaired by the CTEP Associate Director. Communication at the various stages of protocol development is encouraged as necessary to promote protocol development and implementation.
Submission of clinical trial protocols should be preceded by a written Letter of Intent (LOI) from the Consortium declaring interest in conducting a particular study. The PRC will formally review the LOI. Following review, the NCI Project Scientist will provide the Consortium with a summary evaluation. This evaluation will address such issues as: (a) the existence and nature of concurrent clinical trials in the area of research, pointing out possible duplication of effort; (b) information including relevant pharmacokinetic and pharmacodynamic data concerning investigational agents; (c) availability of investigational agents; (d) the PRC's assessment of the scientific rationale and value of the proposed study, its design, and statistical requirements; (e) appropriate inclusion of NCI Standard Protocol Language for CRADAs and CTAs in the protocol; and (f) the implementation of the study, if indicated. The LOI mechanism is designed to allow for the rapid preliminary review of study concept, facilitate agreement on study priority and design, and expedite the development and implementation of optimized clinical trial protocol (for further details of these mechanisms, see the DCTD Investigator's Handbook at http://ctep.cancer.gov/handbook/).
4) CTEP Review of Proposed Clinical Trial Protocols: All Consortium clinical trial protocols, including protocols utilizing agents not sponsored by NCI, will be reviewed by the PRC. Ad hoc reviewers external to NCI (who could be staff members of other NIH ICs and/or non-NIH scientists), will be utilized when deemed appropriate by the PRC chairperson. Following the review of the clinical trial protocol by the PRC, the NCI Project Scientist will provide the Consortium with a consensus review that describes recommended modifications and other suggestions, as appropriate (see the DCTD Investigator's Handbook, for further information regarding protocol review at CTEP). The major considerations relevant to Protocol Review by CTEP include:
If a proposed clinical trial protocol is disapproved, the specific reasons for lack of approval will be communicated in writing by the NCI Project Scientist to the Consortium as a consensus review within 30 days of protocol receipt by the NCI. NCI will not provide investigational agents or permit expenditure of NCI funds for a clinical trial protocol that it has not approved. The NCI Project Scientist will be available to assist the Consortium in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the Consortium and of the NCI.
5) CTEP Protocol Amendment Review: Any change to the protocol document subsequent to its approval by CTEP must be submitted in writing for review and approval prior to implementation. For full details of the required procedure, see The Investigator's Handbook http://ctep.cancer.gov/handbook/).
6) CTEP Involvement in Auditing of Member Institutions: The Clinical Trials Monitoring Branch (CTMB) of CTEP will coordinate with the Consortium the performance of on-site audits at Consortium Member Institutions, which are to occur at approximately 2-3 year intervals. CTMB will review audit results and the corrective plans developed by the Consortium in response to the audits.
7) CTEP Involvement in Imaging Research: The NCI Imaging Research Coordinator will advise the Consortium Steering Committee and the NCI Project Scientist with respect to ongoing NCI activities and research opportunities related to the application of imaging in drug development. He/she will participate in CTEP review of Consortium protocols with imaging components and will assist the NCI Project Scientist in the overall review of Consortium imaging research activities and accomplishments.
8) CTEP Involvement in Radiation Oncology Research: The NCI Radiation Oncology Research Coordinator will advise the Consortium Steering Committee and the NCI Project Scientist with respect to ongoing NCI activities and research opportunities related to radiation therapy for pediatric cancers. He/she will participate in CTEP review of Consortium protocols with radiation therapy components and will assist the NCI Project Scientist in the overall review of Consortium radiation oncology research activities and accomplishments.
9) CTEP Involvement in Clinical Trial Protocol Closure: Protocol closure is primarily the responsibility of the Consortium and the specific Protocol Committee. The NCI Project Scientist will also monitor clinical trial protocol progress and may request protocol closure to further patient accrual for the following reasons: (a) insufficient accrual rate; (b) accrual goal met; (c) poor protocol performance; (d) patient safety or regulatory concerns; (e) study results are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. NCI will not provide investigational agents or permit expenditures of NCI funds for a study after requesting closure (except for patients already on study).
10) Data Management and Analysis Review: NCI Biometrics Research Staff will review mechanisms established by the Consortium for data management and analysis. When deemed appropriate, NCI staff will make recommendations to ensure that data collection and management procedures are adequate for quality control and analysis and as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense. The NCI will have access to all data, although they remain the property of the awardee institution. Data must also be available for external monitoring as required by NCI's agreement with the FDA relative to the NCI's responsibility as drug sponsor.
11) Data and Safety Monitoring Plan: The NCI Program Director, assisted by the Biostatistical Research Branch (BRB) staff, will assess Consortium compliance with NCI and NIH established policies on Data and Safety Monitoring Plans. The NCI Project Scientist must review and approve the Consortium's Data and Safety Monitoring Plan. One or more CTEP staff will serve as non voting members on the Consortium's Data and Safety Monitoring Committee (DSMC), should the Data and Safety Monitoring Plan (DSMP) specify a DSMC.
12) Participation in the Activities of the Consortium Steering Committee and its Scientific Meetings: The NCI Project Scientist will be a member of the Consortium Steering Committte (see below) and will attend the Consortium meetings (twice a year) to discuss relevant scientific information, to discuss progress in the clinical trials, and to discuss the status of newly available investigational agents and other research opportunities in order to plan future activities. Other NCI staff (e.g., from the Investigational Drug Branch, Radiation Research Program, and Diagnostic Imaging Program) will attend as needed.
13) CTEP Involvement in Investigational New Drug Applications: The NCI Program Director and Project Scientist, assisted by the Chief, Regulatory Affairs Branch (RAB), CTEP, will advise investigators of specific requirements and changes in requirements concerning IND sponsorship that the FDA may mandate. Investigators performing trials under cooperative agreements will be expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents.
14) CTEP Review of Federally Mandated Regulatory Requirements: The Chief, Clinical Trial Monitoring Branch (CTMB), through the NCI Program Director and Project Scientist, will advise the Consortium regarding mechanisms to meet FDA regulatory requirements for studies involving DCTD sponsored investigational agents and OHRP requirements for the protection of human subjects by Consortium institutions.
15) Access to Data: The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. Data must also be available for external monitoring as required by NCI's Drug Master File Agreement with the FDA relative to the responsibility of the NCI as an IND agent sponsor. Data from studies of non-NCI sponsored agents must be available for external monitoring as described in the policies and procedures established by the Consortium for onsite auditing of clinical trials data. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS and NIH policies. The awardee will comply with the data access provisions of applicable CTAs and CRADAs, and when these agreements are in place the Industry Sponsor will have complete access to the data for any and all regulatory filings.
16) Access to Agents for Pre-Clinical Testing: For NCI-sponsored IND agents, NCI will facilitate transfer of material to investigators with a Materials Transfer Agreement (MTA).
17) CTEP Review of Progress: Performance of each Consortium will be reviewed at least annually by the NCI Project Scientist and other CTEP representatives based on the information provided at the twice-yearly Consortium Scientific Meetings and other meetings, as well as information in the annual progress reports and in the CDUS reports submitted to CTEP for each of the Consortium's clinical trials. Insufficient patient accrual or progress, or noncompliance with the terms of award, including these Terms and Conditions of Award, may result in a reduction of budget, withholding of support, suspension or termination of the award.
NCI staff members who are substantially involved in the Consortium activities will not attend peer review meetings of renewal and/or supplemental applications. If such participation is essential, these individuals will seek NCI waiver according to the NCI procedures for management of conflict interest.
In addition, an NCI Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the award, and will be named in the award notice. If this individual becomes substantially involved in the Consortium activities, he/she will not attend peer review meetings of renewal and/or supplemental applications or will seek NCI waiver if such participation is essential.
Areas of Joint Responsibility include the following:
The Consortium Steering Committee. The Consortium Steering Committee will consist of the following voting members:
NOTE: Each voting member representing the Consortium will have one vote (including those individuals who may have multiple responsibilities).
The NCI Project Scientist will serve as an advisory member. Other NCI staff may serve as advisory members as appropriate.
The Steering Committee will be responsible for the following tasks:
The Steering Committee may form subcommittees as needed.
The Consortium Steering Committee will meet twice per year in person and monthly via phone conference. Some of these face-to-face meetings are expected to be scheduled during the Consortium Scientific Meetings.
Biannual Consortium Scientific Meetings. The Consortium Steering Committee (with logistic assistance of the Clinical Research Program) will co-organize with NCI the twice-yearly Consortium Scientific Meetings. These meetings will generally be scheduled to coincide with COG Group meetings or with a CTEP Early Drug Development Meeting.
When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.
The annual reports are expected to include:
A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the .
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
GrantsInfo (Questions regarding application instructions and
process, finding NIH grant resources)
Telephone 301-710-0267
Email: email@example.com
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registration, tracking application status, post submission issues)
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Malcolm A. Smith, MD, PhD
National Cancer Institute
Telephone: 301-496-2522
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Leslie Hickman
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National Cancer Institute
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Frederick, MD 21701
Phone: (301) 631-3009
Fax: (301) 451-5391
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Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.
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subset: commoncrawl


text:
Hard to Focus Locally When the Action is Global
I have thrown away several attempts at today's column, being distracted by the ominous 8 pm passing of the Bush deadline for Saddam to get out of town. It is difficult to focus on our local economy when the events that will shape our destiny are unfolding on television right in front of us.
Our developing visions of a global economy may be about to come crashing down. The return of isolationism appears to be inevitable, with the ignorance and prejudice shown by vocal and often vicious attacks on foreign citizens and businesses.
I can't help but think back to when I saw my first "Ami go Home!" slogan painted on a bridge near Trier, Germany. We were the rich GIs then, when my $155 a month was significantly more than the average German wage earner brought home. We took it as jealousy, a typical attitude of the "ugly Americans." The Europeans, in general, did not support that feeling, however. I should know, I married a German girl and I lived there for more than five years. The few that wrote the slogans, however, got all the press.
That was the height of the DeGaulle power years, when the French were instructed to not speak English. Our honeymoon in France lasted only a day, as we abruptly changed plans and headed for Switzerland. A German and an American in France, the worst possible combination. Did that stop us from buying Michelin radial tires? No, they were the best tires available. American-made bias-ply tires were abominable, and today they are only found on museum pieces for authenticity.
I brought a VW 1500S notch-back sedan from Germany when I returned, shipping it myself from Antwerp. and picking it up at the old P&O docks in Miami. It had a set of the brand-new Dunlop CB57 "dog biscuit" radials that attracted attention until they finally wore out. I drove it off the dock with only a minimum of paperwork from the lone customs officer on duty.
Times change so drastically that America has just spent $50 million in the time it has taken me to write these few paragraphs. The first air strike against Iraq has taken place while I typed. We watch television and listen as networks and reporters beg for our attention. As unlikely as it seems, we watch live television broadcasts from the target city of our enemy!
We can only pray that sometime in the future, Iraqis and Americans will share the ideals and beliefs that the once deadly opponents of only a generation ago have realized bonds them more than separates them. My daughter has photos of both her grandfathers in uniform, fighting in the same war. One, in the U.S. 5th Army. 178th Field Artillery Battalion while in Sicily, the other sitting at his typewriter in his Wehrmacht uniform in Kiev, Russia.
Anyone who thinks peace and prosperity between former enemies is beyond the realm of possibility has not bothered to learn from history. Hopefully, as Americans. we will again learn to trust and understand our neighbors. We cannot live here alone. The planet is just too small.
George Mindling © 2003


text:
30 May Building site accident claims
Building sites have the highest rate of injuries among workplaces. If you have sustained an injury because your employer neglected their duty of care, then you might be eligible to make a building site accident claim.
Is my employer liable?
By their nature, building sites pose many dangers. Employers have a responsibility to adhere to Health and Safety legislation. An employer's duty of care is to ensure that where possible all reasonable precautions have been taken to avoid injuries on site. It is also important for employees to abide by the safety instructions provided by management.
Responsibilities of employers with staff on building sites
- Provide adequate training, such as manual handling and Safe Pass
- Provide a safe environment
- Provide protective safety equipment
- Store equipment safely to avoid falling objects
- Maintain machinery
- Prevent falls for those working at a height
- Identify hazards
Proving liability in workplace accidents isn't always straightforward but if your employer has breached any of these obligations, you may be entitled to compensation.
Common accidents which can lead to building site accident claims
- Injuries caused by lifting or handling awkward loads
- Slips or falls on uneven, slippery surfaces where no warning is given
- Falls from unsecured ladders, roofs, scaffolding or other heights
- Accidents involving defective machinery or equipment
- Injuries caused by falling structures or objects
- Back injury caused by lack of training
- Occupational deafness from excessive noise or ototoxic chemicals
What should I do after a building site accident?
Get medical attention
If you are injured, seek medical help immediately. Those who don't can risk exacerbating their injuries, which can work against them when making building site accident claims.
Report the incident
Even if the accident seems minor, make sure to report it to a foreman or manager as soon as possible. By law, building site accidents in which someone is injured and cannot resume normal work for more than three days must be reported to the Health and Safety Authority. If this situation arises, make sure to complete the HSA's Accident Record Form.
Document the incident
Documenting details about the accident will help if you decide to make a claim. Record:
- How the accident occurred
- Who witnessed it
- The date and time
- Take photos of the scene
- Medical reports
- Medical bills or proof of other expenses incurred
Contact a solicitor
If you have been injured on a building site and believe your employer was negligent, a personal injury solicitor can advise you on your case.
They can help you gather documents and submit your claim to the Personal Injuries Assessment Board. They will then advise you on whether to accept the Board's recommendation or take your employer to court, ensuring you receive fair compensation for your injuries.
Contact our solicitors specialising in building site accident claims today
Contact Ferrys Solicitors LLP Personal Injury and Accident Solicitors Solicitors and tell us about your case. We can help you estimate your compensation expectations. Alternatively, download our free Guide to Compensation.


text:
Japanese Enamel Box
212.308.7330, firstname.lastname@example.com
Japanese Enamel Box
Specializing in Meissen Porcelain, 19th and 20th century American and European paintings. CONTACT (P): 212.308.7330 (E): email@example.com
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Japanese enamel box with a colorful bird, late 19th – early 20th century.
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text: Damon Maher speaks out on immigrants and refugees by Friends of Damon Maher | Mar 6, 2017 | VideoDamon spoke out in support of immigrants and refugees in our county. He made a cogent and impassioned argument steeped in history and personal experience as to why all of our neighbors should be treated with fairness and dignity. Below is a video of his speech.


text:
In evaluating an advisor to provide you financial planning services you'd want to ask yourself five questions to get a better idea of their overall value.
What do we do?
We plan for the most important financial goals in a person's life such as planning for retirement, creating retirement income or managing an investment portfolio. With each client that hires us, we measure of success by either making them more than the cost to hire us or saving them more than the cost to hire us every year. Ultimately, we reduce stress in our clients' lives by being a resource for them to make informed decisions based on their preferences
Who do we work for?
There are two primary groups that we serve: Pre-Retirees and Retirees. In more general terms; Baby Boomers born between 1946 and 1964.
Pre-Retirees are typically in their peak earning years, the kids are out of the house and for the most part they are exclusively focused on Retirement. They want to retire comfortably and would like to know what it will take to achieve this milestone.
Retirees are looking to create income from their nest egg and ensure that they do not run out of money. Social Security Maximization is an important component to this overall strategy.
How do we serve clients?
The Financial Planning process is an important component to the service that we provide. This process is fairly standard, but it's important to know that when we work together we do go through a process. To learn more about the financial planning process, please click here:
Next, the CFP® model defines the six key areas of financial planning as the following:
1. Current Position: Managing cash flow and where to direct excess income
2. Adequate Protection: Evaluating which insurances are appropriate for each stage of your planning
3. Investments: Managing risk based on your preferences.
4. Taxes: Prepared by a Tax advisor and we will discuss both ways to reduce taxes now as well as in Retirement
5. Retirement: The plan will detail for us at what age and what dollar amount Retirement is affordable or what it will otherwise take to Retire comfortably
6. Estate Planning: Prepared by an Attorney to provide for the orderly distribution of your Estate to your family and heirs
What makes us different?
First, our company is independent. We are privately held and do not have any outside pressures from shareholders or a parent company influencing our recommendations. As a result our advice is objective.
Second, Chris is a CERTIFIED FINANCIAL PLANNER™ professional. To learn more about the CFP® designation, please click here:
Why do we work?
To begin, Chris loves his work. "I enjoy serving clients and vicariously participating in their success!"
Next, we make a difference for clients. As a country, we have had no formal education for financial planning in the past. This is one of the main reasons that Chris entered this business. "I got into this business so I could learn those details and internalize the information for people so when they tell me their preferences, I can filter which options might be the best fit for them."
Finally, we'd like to leave you with one thought . . . .
Some of the most precious resources that we all have are our time and our money. Please consider investing some of your time in meeting with Chris to see if we can complement what you've done so far with your planning. Ultimately, our goal is for you to enjoy more of your time NOT worrying about your money!


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Price: 60 - 179 € (Average)
Rating by guests: There are no reviews for this hotel.
Family-run Hotel Fontana is a restored 18th-century Venetian house which enjoys a central location in Venice, just behind San Zaccaria square and a few blocks from Saint Mark's square. In a quiet area just off the waterfront, this hotel is perfect for getting to know this unique city. Waterbuses stop just outside the hotel and much of the city is just walking distance away, including Rialto and its busy markets, which are a 10 minute stroll away. Saint Mark's square, with its spectacular cathedral is even closer, just 5 minutes away, as is the Bridge of Sighs. Comfortable rooms overlook the characteristic squares below and some have a private terrace with views of gothic San Zaccaria church, which is just next door. Well-run, with friendly staff and an emphasis on service and hospitality, this hotel is a great solution for an unforgettable stay in Venice.


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Myth vs. Reality of Last-Mile Delivery
Retailers have long held that the customer experience is based on enhanced in-store experience, as well as an equivalent online experience that offers seamless shopping. The study of customer experience has rightfully included strategies that include hiring knowledgeable and highly trained customer service agents and retail salespeople, placing online retail on an equal status to brick-and-mortar, and using data analytics to gain a deeper understanding of customers' wants and needs.
The rise of e-commerce, along with an expectation of free or discounted shipping and fast delivery, has changed the equation. Now what is core to the customer experience is less about products, return policies or friendly clerks, and more about how retailers are able to get those products to the customer's front door quickly and inexpensively. As a result, alongside those proven customer experience strategies is a hidden imperative that's no less important to the customer experience mission, and that is efficient last-mile delivery.
Retail Last-Mile Myths
Perhaps the most dangerous action a retailer can take is to underestimate the importance of last-mile delivery. Tom Fiorita, founder and CEO of Point Pickup, says that "the retail world has changed, and retailers must adapt quickly to survive. The e-commerce experience must be placed on an equal footing with in-store sales, and to accommodate that, partnering with the right last-mile network is key to providing an outstanding customer experience. In fact, it's key to a retailer's very survival."
Myth No. 1: Last-Mile, Same-Day Delivery is Easy
Far from it, the logistics involved in delivering parcels to customers — whether it's a book from Amazon.com or five bags of groceries from Walmart — is complex and many retailers are still figuring it out. "Companies like Walmart, Target and Amazon want to be within 20 miles of 80 percent of the U.S. population," says Fiorita. "This requires warehouses and distribution centers, as well as predictive analytics. And if they build those warehouses efficiently and stock them correctly, with predictive analytics they can keep SKUs in those buildings which are more precisely associated with where you live. Therefore, SKUs at a warehouse in Indiana would be very different from the SKUs kept in a warehouse in Connecticut.
Myth No. 2: The One-Size-Fits-All Solution
"There's an inherent problem in last-mile delivery, and that is much of the existing delivery ecosystem is disorganized and fragmented," Fiorita notes. "Systems like Uber work, but only for driving people short distances. If you're an Uber driver, your cargo is the same, but in parcel delivery, the needs are incredibly complicated, and the packages don't walk and talk. At Point Pickup, we developed a precision matching system which allows retailers to precisely match their packages to the most appropriate driver and vehicle."
Myth No. 3: Most Retailers Already Have a Defined Strategy for Last-Mile Delivery
Because existing delivery ecosystems are so disorganized, even the largest retailers have been challenged to put together a defined strategy to get parcels to customers quickly, efficiently and inexpensively. On the back end, it requires larger retailers to rethink their entire warehousing and fulfillment network, and often leverage their stores as de facto fulfillment centers. "The biggest challenge for retailers is that while there's enough delivery capacity, the majority of couriers are independent and not scalable, with most of them running less than six vehicles," says Fiorita. "These factors make it impossible for a major retailer to create and manage their own delivery system."
What's Real in Retail
Retailers are realizing that they must take their brands back, control the entire process, and use fewer drivers who are more familiar to themselves and their customers. More importantly, they're realizing that a one-size-fits-all delivery system like Uber works well when moving people from one place to another. Transporting humans, or basic commodities like fast food, requires very little predictability. The same driver or same vehicle isn't necessary, special licensing or certification isn't required, and the primary deciding factor is proximity. When you enter your pickup address in the Uber app, the driver who is closest to you will simply show up.
Uber's system works well for catching a ride to your favorite restaurant, but it falls short for parcel delivery. The market has dictated that not all delivery is equal. In the Uber world, shipping (people) is highly predictable. Products like groceries, liquor, pharmaceuticals and merchandise require a variety of different courier capabilities, certifications, operating procedures and capacity, and therefore require a more predictable delivery model and more precision in the underlying platform's matching algorithm that goes beyond the basics of whichever courier is closest.
"To accommodate same-day parcel delivery, you have to combine proximity and best performance against the best criteria of all needs, whether it's small parcel or large items, requires a two-person delivery team, HIPAA licensing, TSA licensing for airport pickups, and endless variations," notes Fiorita.
Two Choices for Retail
To maintain control over the customer delivery experience, retailers have two choices: own their own fleets and manage their own delivery network, or outsource delivery. While Amazon does accomplish the first option — and does it well — doing so is simply too cost prohibitive for almost everybody else.
For the vast majority of retailers that outsource parcel delivery, there are several considerations: achieving a satisfactory level of customer experience, accommodating more diverse requests, and maintaining their own brand. Retailers must strike a balance between the convenience of an outsourced solution and the control of running their own fleet.
"Point Pickup's MicroDriverNetworks™ model is built to utilize fewer drivers while increasing customer satisfaction by basing our algorithm on a correct, specific and repeatable driver model where delivery service is granular, defined and very specific, as opposed to a macro crowdsourced network like Uber, which just assigns the closest driver without other qualifiers," Fiorita says.
The retail industry is undergoing a major transformation, and in recent years store closings and bankruptcies have captured headlines. While the more simplistic response is to make villains of Amazon and other e-tailers, plenty of retailers are not only surviving, they're thriving in the current environment. The key to that survival is constant re-evaluation of business models, a willingness to change, and the ability to put in place new processes and technologies to serve new customer expectations. Chief among those expectations today is fast and inexpensive home delivery. An efficient last-mile delivery network which is capable of shipping quickly based on a wide variety of criteria and requirements will ensure their survival.
Dan Blacharski is founder and editor-in-chief at Ugly Dog Media, an international public relations and marketing company.
Related story: Retail Marketers Rolling Back Pure Digital Strategies
Dan Blacharski is founder and editor-in-chief at Ugly Dog Media, an international public relations and marketing company.


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Our "Conveyor Systems Services" division is a conveyor servicing and installation team which provides mechanical, electrical, maintenance and repair services for our customers.
Our service team can help you plan a full preventative maintenance schedule that can include maintaining conveyor systems and their components such as drives, tensioners, chains, belts and lubrication systems.
We are a specialist conveyor servicing and installation company and can provide you with a professional, cost effective and efficient service.
Once your conveyor systems are up and running, we can recommend service intervals, offer spare parts and undertake any modification that you may require.
Many of our customers put into place service contracts, including preferential call out agreements.
We are able to offer resources and services, allowing "you", the customer to get on with your everyday tasks, leaving the problems or challenges with ourselves to resolve within the agreed time frame.
With over 25 years' experience of conveyor systems, material handling and the design & manufacture of control systems we have the capacity to design, manufacture and install the right solution for you.
Our structure allows us the flexibility of supplying a complete service within the materials handling sector, from design through to on-site installation and system commissioning, however large or small the project.


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Eighteen international environmental and conservation organisations are calling on European Union governments to halt all exports of raw ivory when the EU's Committee on Trade in Wild Fauna and Flora meets on 10th April in Brussels.
Ivory trade has expanded in the EU, making it the world's largest exporter of so-called pre-Convention or "old" ivory. An analysis in 2014 of records in the database maintained by CITES – the UN Convention on International Trade in Endangered Species of Wild Fauna and Flora – confirms that re-exports of pre-Convention ivory, particularly raw tusks, from the EU have increased substantially since 2007, with mainland China and Hong Kong the main destinations of this old ivory.
The increase coincides with a decision in 2007 by CITES to allow China to purchase 62 tonnes of ivory, stimulating market demand. Conservationists demand that loopholes in European law allowing exports of old ivory are closed permanently by Ministerial agreement. Then they cannot be exploited to launder fresh ivory poached in Africa to feed the insatiable demand in Asia, especially China.
"We have repeatedly warned that weak European laws on ivory trading are a clear and present danger to Africa's elephants. Action in Brussels is long overdue," says Daniela Freyer of Pro Wildlife.
Earlier this month, 44 NGOs wrote to European Union Ministers asking them to suspend all exports of raw ivory.
Charlotte Nithart of Robin des Bois, who co-ordinated the NGO letter said "We are pleased that six EU Countries – Austria, France, Germany, Netherlands, Sweden and the United Kingdom – are already refusing to issue ivory export permits and have urged the other 22 member states to follow suit."
Sally Case of the David Shepherd Wildlife Foundation added "The EU must agree unanimously on 10th April to halt ivory exports and end its unenviable position at the top of the league table for exports of pre-Convention or old ivory."
A common EU position to halt exports is imperative. Without one, ivory can be taken from one EU country where export is not allowed to another EU country where export permits are still issued. Belgium is of particular concern since it allows exports of ivory to Asia.
This undermines the recent decisions by Austria, France, Germany, Netherlands, Sweden and the UK not to issue export permits. "To protect these magnificent animals there must be a complete prohibition of the trade in ivory since it is indisputable that any legal trade facilitates illegal trade", said DJ Schubert of the Animal Welfare Institute.
"Attempts to legalize ivory trade since 1989 have been a disaster. We need to learn from history and permanently shut down all ivory trade – international and domestic", added Vera Weber of the Foundation Franz Weber.
"We are calling on all EU countries that have not yet done so to adopt a common position on 10th April by halting all commercial exports of raw ivory," says Mary Rice of the Environmental Investigation Agency.
"The recent measures announced by China to restrict imports of worked ivory fail to address this key issue. In addition, the EU needs to adopt a ban on the export, import and domestic sale of both raw and worked ivory, clamp down on Internet trade, and follow the examples of other countries by destroying stocks. We will only be able to end the elephant poaching crisis when the trade fuelling it is banned permanently and demand curbed," adds Rice.
The groups calling for the action are:
Africa Network for Animal Welfare
Amboseli Trust for Elephants
Animal Welfare Institute
The David Shepherd Wildlife Foundation
David Sheldrick Wildlife Trust
Eco Activists for Governance and Law Enforcement
Elephant Action League
Environmental Investigation Agency
Fondation Franz Weber
Hong Kong for Elephants
Last Great Ape Organization
Projet d'Appui à l'Application de la Loi Faunique
Pro Wildlife
Rettet die Elefanten Afrikas e.V.
Robin des Bois
Tsavo Trust


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By Michael Knoll
Aside from various blog and forum posts regarding the Windows 10 Creators Update (Update 1703), we have seen some real-life issues arise. These are not life threatening to your Windows 10 operating system, but they can range from just plain annoying to temporarily crippling.
When our first customer reported issues after the Creators update, they couldn't see any text in Windows Explorer. I was able to get my hands on one of the two computers which encountered this issue. I was able to trace the behavior back to an incompatibility with a software which manages printing. When the software was disabled from startup, the text returned to Windows Explorer.
Another customer experienced some issues where the Settings app, notifications, Cortana, and start menu didn't work. This customer had many business line software applications, for which the path of least resistance was to reload the operating system.
Other clients have reported printers disappearing and printer drivers needing to be changed over to universal drivers.
Bottom line is this: If anyone experiences strange behavior after the latest Windows update, please reach out to us before taking any drastic actions. We will be able to get you back to normal in no time!


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Following a teaser, Esprit D'Air have now released Ignition, the third single from their comeback album Constellations.
Vocalist and guitarist Kai described how the track is about, "someone imagining themselves with a different life if they had made different choices. Whilst driving through the city, they are thinking about the choices they have made in the past. It depicts the moment of someone reflecting oneself and making an important decision.
The lyrics don't tell you what the person ends up doing, maybe they are going to leave the city, or stay there to start doing something they have never experienced. Like in real life, there will be some life-changing decisions, some that can make you feel anxious. However, there are some paths that you can only discover from having the courage to take it."
If you like the taste of Ignition, then you can purchase the album Constellations by clicking here.
The London-based band reformed in 2016 with members Kai (vocal & guitar), Ellis (bass) and Daishi (drums). They will embark on a huge UK tour in 2018. "This will be the biggest tour we have ever done," said Kai in an interview with MyM Magazine. "We will be working very hard to make it the most exciting tour yet." Tickets for the tour can be purchased via SeeTickets. Also, be sure to check out the rest of the interview in issue 65 of MyM Magazine.
You can sign up for exclusive updates by visiting Esprit D'Air's official website, as well as following them on Twitter and Facebook.