CTSA U54 (RM-06-002) Application – Dan Byrne’s additions (revised 12/21/05)
Timeframe:
Feb 27, 2006 – Letter of Intent
March 27, 2006 – Application due
Sept 2006- Funding
Outline of the grant:
I) Overall Integrated Approach and Governance
25 pages
G. Bernard/D. Robertson
II. Program Functions
1) Development of Novel Clinical and Translational Methodologies
15 pages
Group
2) Pilot and Collaborative Translational and Clinical Studies
15 pages
G. Bernard/D. Robertson
3) Biomedical Informatics
15 pages
D. Masys/P. Harris
4) Design, Biostatistics and Clinical Research Ethics
15 pages
F. Harrell/D. Byrne
a) support provided
b) resources available
c) approaches to prioritize research topics or projects
d) educational topics
e) chargeback systems
F. Harrell/J. Manning
f) integration of clinical research ethics
L. Churchill
5) Participant and Clinical Interactions Resources (PCIR)
15 pages
D. Robertson/L. Lane
6) Community Engagement
15 pages
TBD
7) Translational Technologies and Resources
15 pages
TBD
8) Research Education, Training and Career Development
25 pages
N. Brown/others
9) Public health Implementation and Evaluation
10 pages
B. Dittus
10) Research Initiation and Conduct Administrative Support
10 pages
J. Pulley
11) Other program function (?)
10 pages
TBD
12) Other program function (?)
10 pages
TBD
III. Evaluation and Tracking
20 pages
G. Bernard/D. Robertson/R. Chalkley/team
IV. Implementation Phase and Milestones
10 pages
L. Lane/G. Perez/T. Yarbrough/team
V. Tables
50 pages
L. Lane/G. Perez/T. Yarbrough/team
Current draft of section II-4
Design, Biostatistics and Clinical Research Ethics
15 pages, F. Harrell/D. Byrne
Overall Vision, Approach, and Goals (1 page)
Although Vanderbilt is widely regarded as a leader in clinical research, the CTSA will provide valuable resources to enable research that is more efficient and addresses specific concerns of the American public. These resources will also provide support for research and improvements in advanced experimental designs, such as adaptive designs, which can significantly raise the level of clinical research ethics.
Like many General Clinical Research Centers (GCRCs), Vanderbilt’s GCRC has traditionally been hindered by an outdated model with a disproportionately small amount of biostatistical support. Over the past decade, this has grown into a rate-limiting step in the research process. To correct this problem, we propose a Clinical & Translational Biostatistical Core of 5 FTEs of biostatistical support and 1 FTE of administrative assistant support. We will recruit 4 additional, experienced, applied biostatisticians, who will have faculty appointments in the Department of Biostatistics but will focus their efforts on functioning as catalysts in clinical and translational research in the capacity of study design planning, research into efficient designs and analysis, analysis, consultation, and teaching.
This additional support will enable the biostatisticians to apply modern, efficient study designs that will not only improve the efficiency of the research but also create an environment in which the research is conducted at the highest ethical level possible – in that the question is answered while placing the fewest participate at risk. This support will also allow us to implement and teach advanced statistical methods using modern statistical software.
A major problem in modern medical research is that often the research is not reproducible and the results are often overstated. The Department of Biostatistics is a leader in the area of reproducible research and reproducible reporting. Another common problem regarding biostatistics in clinical research is poor communication and inadequate teaching of biostatistics. Vanderbilt has been a leader at improving the quality of teaching of biostatistics and has several innovations, such as a project to measure and improve long-term retention of statistical skills. The CTSA will support a major expansion of the teaching activities to help fellows and investigators learn modern methods of analysis. The Department of Biostatistics is currently developing an innovative Masters and PhD training program in biostatistics that will emphasize experimental design, and state-of-the-art statistical analysis and software. Since this program is not limited by tradition or resistance of current faculty, it will fit ideally into the innovative CTSA model.
Vanderbilt has a novel Biostatistical Collaboration plan in which biostatisticians develop long-term relationships with investigators in a discipline and become co-investigators. The biostatisticians in the CTBC will complement this arrangement and provide continuity to the translational research teams as they move the discoveries from bench to bedside and then to the community. For more on the Department of Biostatistics at Vanderbilt see:
Background/Situation Assessment (2 pages)
Vanderbilt has a long history of translational research. In fact, the building in which the GCRC currently resides was specifically designed to foster collaboration between basic scientist, clinical scientists, medical students, and clinicians. In many respects, Vanderbilt has been moving in the direction described in the CTSA request for some time. This funding will help increase the rate of this transformation.
Currently, there are numerous barriers for translational research, including:
Physical
Financial, budgets
Different goals
Different languages
Current GCRC guidelines
Current funding of NIH grants
Cultural
Administrative
Artificial
We proposed the following solutions to dissolve these barriers:
Establish a match-making mechanism (Clinical & Translational Think Tank) to include a basic scientist as a co-investigator on every GCRC protocol.
Encourage clinical investigators and basic scientists to collaborate and co-author
papers with one another.
Invite basic scientist as speakers and attendees at clinical grand rounds.
Develop interdisciplinary translational research teams.
Support continuous quality improvement projects addressing novel ways to
reduce these barriers.
Existing Services, Programs, and Resources (3-4 pages)
Vanderbilt’s GCRC Biostatistics Clinic.
Biostatistics Clinic is an innovative educational service that Vanderbilt’s GCRC biostatisticians provide to clinical researchers and fellows. The Clinic has been offered every Thursday from noon until 1 PM for the past two years. The purpose is to provide a free, drop-in forum in which investigators, their fellows, or medical students can bring data for statistical analysis or questions about analysis, study design, graphics, etc. A free lunch is offered to encourage attendance.
Each week between 10 and 15 people attend. The GCRC biostatisticians lead the clinic by demonstrating how to analyze the data using statistical software projected on a large screen in the GCRC conference room. Participants learn practical skills regarding how to set up a spreadsheet for analysis, how to screen data for errors, how to perform descriptive and inferential analyses, and how to conduct modern, state-of-the-art modeling. These clinics are also valuable in teaching fellows how to convert the analysis into graphs, tables, and text suitable for publication in a medical journal.
On a typical week 2-3 participants will bring data or questions. The biostatistician uses the examples to teach practical aspects of data analysis and also demonstrate how to avoid common problems. These sessions provide a method of raising the level of statistical skills so that investigators add more modern statistical tools to their toolbox without having to enroll in a graduate course.
Biostatistics Clinic has been so successful that the Department of Biostatistics at Vanderbilt has embraced the ideas and offers similar clinics during the noon hour on the other 4 weekdays. See the following web site for details:
[The following will be described in more detail in the next draft.]
GCRC Research Skills Workshop
Research efficacy.
Efficacy of teaching.
GCRC Data Analysis and Publication Seminar Series.
Continuing Education.
Development of Novel Programs and Functions (4-6 pages)
The 6 Key Novel Programs are:
1- Clinical & Translational Biostatistics Core
2- Clinical & Translational Research Teams
3- Think Tank for Clinical & Translational Research.
4- Publication Core
5- Research Nurse Training Program
6- Advanced Degree Program in Biostatistics.
1-Clinical &Translational Biostatistics Core (CTBC)
[Use subheadings for each novel approach that will transform scientific innovation into health gains for the nation.]
The CTSA will solve the rate-limiting step in the current GCRC structure by expanding the biostatistical support. We will develop a new Clinical & Translational Biostatistical Core with 5 FTEs of biostatistical support. The GCRC currently has 1 FTE (2 biostatisticians at 0.5 FTE support). Four full-time, experienced applied biostatisticians will be recruited.
This support will be used to provide additional biostatistical training and in-depth analysis and study design consultation to investigators and the expanded network of translational research teams. The current underfunding of biostatistical support creates several problems. Without proper biostatistical assistance many protocols are never translated into publications and many are published in less prestigious journals than the importance of the findings indicate. In addition, many protocols could produce more than one publication, if there was sufficient biostatistical support.
Experienced biostatisticians understand that minimizing bias and strengthening study design are much more important than complex statistical methods. This expanded support will provide resources and time to invest in planning research. It will also allow the biostatisticians time to develop study designs and analysis plans for studies of unique populations or very small numbers of subjects.
These biostatisticians will study what works and what does not work by comparing protocols that are published with those that are not published (cold protocols) and evaluating the impact of these publications on the practice of medicine in the community. Resources will be devoted to measure return on investment and assessing productivity. Biostatisticians will study, teach, and implement more efficient study designs. One task will involve review of approved protocols over the past 5-10 years to assess the success and obstacles. The accuracy of sample size estimates will be analyzed. This information will provide value in planning future projects. Thus, there will be a feedback loop to apply what is learned about clinical research efficiency.
The CTSA will also provide biostatistical support to basic researchers. Many basic researchers continue to use primitive, and often inappropriate, statistical methods wasting valuable information from their experiments. While advanced statistics have not been required for success in publishing in the basic sciences, this is changing rapidly. The editor of Nature Medicine (ref x) recently wrote an editorial describing steps he was taking to raise the level of statistical sophistication. This came after a review of papers published in his journal found an alarming number of statistical flaws.
The CTBC will develop a high-tech data analysis conference rooms for a multidisciplinary team of investigators to analyze and visual research data with state-of-the-art graphical, statistical, and informatics tools. This room will also be used for “extreme collaboration” in which the biostatistician analyze data during the meeting with investigators to provide for efficient analysis. This avoids the common problem of long delays at each point in the analysis when the biostatistician or investigator have questions that must be answered. These rooms will resemble a “situation room” will multiple large screens and a central conference table to provide real-time answers to questions.
The CTBC would also provide 1 FTE of administrative assistant support. This will allow the biostatisticians to be productive by having an assistant help with routine tasks.
The biostatisticians from the CTBC will also provide support to Vanderbilt’s Institutional Review Board on a rotating basis. The purpose of this assignment will be to continuously raise the level of sophistication of investigators with respect to efficient study designs and analyses to ensure the highest level of ethical research.
[Justification for the 5 FTEs will be added here]
The CTBC will establish a standing DSMB (0.5 FTE) in the Center. This will give
investigators ready access to such a panel when the GAC deems it necessary. It will ensure proper and ethical conduct of clinical trials. Statisticians can play a role in this effort.
With the added resource (5 FTEs) in biostatistics, it would make it possible for statisticians to developed novel statistical methods, e.g. adaptive study design, for studies with non-conventional design and analyses. That would enhance professional development for statisticians in the Center, as well as helping investigators.
The biostatisticians will research methods of increasing the pace at which scientific discoveries are translated into practical solutions that benefit patients. The value of various endpoints, for example tumor size vs. survival time, will be evaluated. The goal will be increase the advances in the development process, the study designs, and analysis to keep pace with the advances in science.
Novel Approach 10 – Research and apply the most efficient statistical tools. Clinical research questions can often be answered more efficiently, with fewer patients by applying statistical tools that they may not initially consider. The additional biostatistical support will help investigators in this area. For example, many investigators fail to use survival analysis in research evaluating time to event, when the event is something other than death. Yet, these methods provide such increased efficiency that the question can often be answer with a fraction of the patients required for methods that do not consider censoring.
Novel Approach 11 – Integrate the biostatistical core, bioinformatics, and bench-to-bedside laboratories to promote study design innovation.
Novel Approach 12 – Train investigators and research nurses how to create clean, complete, and accurate spreadsheets and databases for optimal analysis. Clinical and translational research could be greatly improved by training those who enter data how to format the data set for statistical analysis. Much time is wasted by having to clean and reformat data that was entered improperly. This will require integration with the bioinformatics core and training at the appropriate point.
Budget money to pay a recruiter to find experienced applied biostatisticians who are excellent communicators.
2-Clinical &Translational Research Teams (CTRT)
Although the GCRCs have been highly effective at helping investigators address specific clinical research problems, the rules and structure imposed on GCRCs have not encouraged research with broader aims. The CTSA will allow us to restructure and expand resources to address problems that are important to taxpayers and require this broader perspective.
For example, taxpayers are concerned about the medication errors that occur during hospitalization. An important component of our CTSA will be Translational Research Teams designed to address such problems. In the first year, we will develop 5-10 such teams. One team will study ways to reduce medication errors and adverse drug events in the Vanderbilt Hospital. The CTSA award will allow us to form a team of pharmacists, clinical pharmacologists, biostatisticians, informatics specialists, continuous quality improvement experts, safety experts, and hospital administrators. This translational research team (CTRT) will develop improve methods of tracking these events and assess patterns and trends. The team will develop interventions to avoid ADE and track the effectiveness of these interventions. Vanderbilt has already invested extensively in this project, however, the CTSA and TRT will ensure that there are sufficient resources for success.
See Figure 1.
Table 1. Thematic Areas for Clinical & Translational Research Teams.
Reducing Medication Errors and Adverse Reactions.
Improving Safety and Ethics in Clinical Research
Assessing Alternative Medicine and Treatments.
Issues in diseases with limited treatment options.
DNA databank
Assessing long-term safety of most commonly used prescription medications.
In addition, there will be teams focusing on the following leading health indicators:
Physical Activity
Overweight and Obesity
Tobacco Use
Substance Abuse
Responsible Sexual Behavior
Mental Health
Injury and Violence
Environmental Quality
Immunization
Access to Health Care.
We will devote sufficient funding to address the translational research needs of the community. For example, pharmaceutical firms often stop researching a treatment once approved. Translational research would provide long-term safety information on the most commonly used drugs.
In addition, many Americans use alternative medicines or treatments that are untested or tested under biased conditions. Fair, unbiased research on the most commonly used alternative medicines would be an important application of translational research.
[The following are suggestions for additions to this section.]
Novel creative programs. Innovative and creative research programs.
Limiting Risk to Study Participants:
[Reference H. Murff’s work here.]
Informed consent – testing whether participants actually understand.
Good example of translational research is reducing ADE. Also, good example of the need to improve the quality of data and speed of converting the data into useful information. Need for dashboard, control charts, etc. Need to invest in biomedical informatics in this area and cross-train in biostatistics and quality improvement methods.
Develop an admission predictive modeling computer system to alter the hospital staff to the probability of complications and ADE. Improving the hospital quality indicators will require coordinated efforts and applied translational research.
Develop and study prevention strategies.
Pilot translational projects.
“catalyze the development of a new discipline of clinical and translational science.”
Clinical Research Ethics
How we will bridge these areas with other CTSA activities.
“encourage the development of novel methods and approaches to clinical and translational research”
“partnerships in the CTSA are strongly encouraged between schools of medicine, dentistry, nursing, pharmacology, osteopathy, public health, engineering, and other clinically related institutions and clinical research entities.”
One of the Clinical & Translational Research Teams will be devoted to preparing for efficient research of the next epidemic or sudden major health problem facing our country. Approximately 5% of the CTSA budget will be reserved for this project.