The Center for Population Research of the National Institute of Child Health and Human Development (NICHD) held a pre-application information forum for investigators planning to submit applications in response to RFA HD-00-013, "Clinical Trials Network for Female Pelvic Floor Disorders." This meeting provided prospective applicants with an opportunity to receive answers to their questions about the intent and requirements of the RFA.
The complete text of the RFA "Clinical Trials Network for Female Pelvic Floor Disorders" is available at http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-00-013.html.
Potential applicants to the RFA were not required to attend this information forum.
For further information, to submit questions, and to register, please contact:
Anne M. Weber, M.D., M.S.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B-13C, MSC 7510
Bethesda, MD 20892-7510
Telephone: 301-435-6972
Fax: 301-480-1972
Email: webera@mail.nih.gov
The following is a summary of the questions and answers discussed during the forum:
QUESTION 1A:
Should the Data Coordinating Center proposal also include a concept protocol?
ANSWER:
Yes.
QUESTION 2A:
What percentage of the 25 page limit is the concept protocol expected to require? How much detail (or how many pages) do you expect in the concept protocol?
ANSWER:
For Clinical Site applications, the concept protocol should be provided in the Research Plan section of the PHS-398. We recommend that you follow the general instructions provided for the PHS-398 application form. In general, the concept protocol should follow the format of the Research Plan, including Specific Aims (1 page), Background and Significance (2-3 pages), Preliminary Studies (6-8 pages), and Research Design and Methods. As stated in the RFA, under Special Requirements (page 5), "Applicants should outline the rationale and background of the proposed study, study design and protocol, eligibility criteria, and initial sample size and power analyses." Applicants should provide as much detail as page limits permit.
In addition to the concept protocol, applications for the Data Coordinating Center should include description of a plan for data collection from the Clinical Sites, data management, quality control, processing, analysis, and reporting. The concept protocol and overall data management plan should be provided in the Research Plan portion of the PHS-398 application and are, together, subject to the 25 page limit. Applicants for the Data Coordinating Center should judge how much space to allocate to the concept protocol as well as the Network-wide plan for handling data, providing as much detail as page limits permit.
QUESTION 3A:
Should the concept protocol from the Data Coordinating Center be more focused on data management and statistical analysis, or do you expect similar responses from both the Clinical Site and the Data Coordinating Center applicants?
ANSWER:
As indicated in the RFA, under Review Criteria for the Evaluation of Data Coordinating Center Applications (page 15), the concept protocol will be reviewed by the same criteria for both the Clinical Site applications and the Data Coordinating Center applications. In addition, the Data Coordinating Center applications should include "proposed plans for data collection, management, editing, processing, analysis, and reporting" and "the approach to developing a cooperative relationship among the Clinical Sites and exercising appropriate leadership in matters of study design, data acquisition, data management, data quality, and data analysis." Peer reviewers will be reminded that the DCC applications were required to combine the data plan and the concept protocol within the 25 page limit. See also Question 1A for additional information on applications for the Data Coordinating Center.
QUESTION 4A:
Can a study related to urinary incontinence be proposed as the concept protocol?
ANSWER:
Yes.
QUESTION 5A:
Should the concept protocol be limited to urinary incontinence, pelvic organ prolapse or fecal incontinence?
ANSWER:
The concept protocol must address some aspect of female pelvic floor disorders. As stated in the RFA, under Background (page 2), "The term 'pelvic floor disorders' refers to a group of clinical conditions that includes pelvic organ prolapse, urinary incontinence, fecal incontinence, and other sensory and emptying abnormalities of the lower urinary and gastrointestinal tracts."
Therefore, the concept protocol is not necessarily limited to urinary incontinence, pelvic organ prolapse, or fecal incontinence, since the term "pelvic floor disorders" is defined more broadly than that. The concept protocol could focus on one of the pelvic floor disorders or some combination (for example, urinary incontinence and pelvic organ prolapse).
In choosing the topic for the concept protocol, applicants should keep in mind that the concept protocol in each application will be reviewed for evidence that: (page 15) (1) the applicant possesses the knowledge necessary to contribute meaningfully to the final designs, including understanding of the scientific, ethical, and practical issues underlying the proposed study; (2) the applicant demonstrates knowledge of the potential problems associated with the conduct of the proposed study, and identifies solutions or alternatives; and (3) justification of the proposed sample size is provided.
QUESTION 6A:
Are there specific clinical trials NICHD is looking for?
ANSWER:
No. For the purposes of the concept protocol, four topics are suggested in the RFA (under Special Requirements, page 5).
QUESTION 7A:
Should the concept protocol include one or many proposed studies?
ANSWER:
One and only one concept protocol is required per application.
QUESTION 8A:
If an institution is planning to submit applications for both a Clinical Site and the Data Coordinating Center, can the same concept protocol be used for both?
ANSWER:
Yes.
QUESTION 1B:
How many protocols are expected to run concurrently at any particular site?
ANSWER:
That will be determined by the Steering Committee of the Network, in conjunction with the Clinical Trials Advisory Board.
QUESTION 2B:
What percentage of the total effort of this RFA is anticipated to research urinary incontinence since NIH-funded Continence Centers already exist to answer some of the questions related to this aspect of pelvic floor dysfunction?
ANSWER:
That will be decided by the Steering Committee of the Network, in conjunction with the Clinical Trials Advisory Board.
QUESTION 3B:
The RFA states that the network will "maximize the number of studies possible with minimal data collection." How many new protocols are expected to be fielded in the last six months of the first year, and in each of the subsequent years?
ANSWER:
That will be determined by the Steering Committee of the Network, in conjunction with the Clinical Trials Advisory Board.
QUESTION 4B:
Similarly, how much data collection (for instance, the number of data variables, or number of pages of data forms per subject), on average, is anticipated for each protocol?
ANSWER:
That will not be known until the final protocols are developed by the Steering Committee of the Network.
QUESTION 5B:
Will there be any single site protocols? If so, will statistical analysis for these be performed by the Data Coordinating Center?
ANSWER:
It is not expected that there will be single site protocols. The Data Coordinating Center will provide statistical support for all protocols performed through the Network.
QUESTION 6B:
How many clinical trials are likely to be funded? How many patients are likely to be included in each trial?
ANSWER:
That will not be known until the final protocols are developed by the Steering Committee of the Network.
QUESTION 7B:
Will there be a central laboratory repository?
ANSWER:
That will not be known until the final protocols are developed by the Steering Committee of the Network.
QUESTION 8B:
Will there be a central resource for interpretation of diagnostic testing (e.g., ultrasound, MRI, defecography, video urodynamics)?
ANSWER:
That will not be known until the final protocols are developed by the Steering Committee of the Network.
QUESTION 9B:
How much emphasis will be placed on quality of life and sexual function as an outcome?
ANSWER:
That will be determined by the Steering Committee of the Network.
QUESTION 10B:
Do the clinical sites have the option not to participate in certain trials or will they be required to participate in all studies chosen?
ANSWER:
As stated in the RFA, under Collaborative Responsibilities (page 8), "Awardees will be required to accept and implement the common protocols and procedures approved by the Steering Committee." The Steering Committee is composed of the Principal Investigators (one from each Clinical Site), the Principal Investigator of the Data Coordinating Center, and the NICHD Project Scientist. Decisions about which protocols to pursue for the Network will be made within the Steering Committee; once the Steering Committee approves an individual protocol, all Clinical Sites are required to participate.
QUESTION 11B:
Can a center publish on its own data if the research focus and outcomes are different from those chosen by the Network?
ANSWER:
As stated in the RFA, under Awardee Rights and Responsibilities (page 7), "Awardees will retain custody of and primary rights to data from their Clinical Site developed under the award, subject to current Government policies regarding rights of access." Therefore, a Clinical Site may publish data from their site (separate from Network publications) for secondary outcomes other than those specified by the Steering Committee. It is expected that all publications initiated by the Data Coordinating Center will be Network publications.
QUESTION 12B:
How will the final study protocols be selected?
ANSWER:
In the first phase of the study, the Steering Committee, in conjunction with the Clinical Trials Advisory Board, will review and identify issues of importance in pelvic floor disorders. While these groups will not have access to the original applications submitted in response to this RFA, it is expected that investigators at the funded sites (as members of the Steering Committee) will include their concept protocol to be considered as one of the final protocols selected. Protocols in unfunded applications will not be available to the Steering Committee or the Clinical Trials Advisory Board.
Specific budget instructions for Clinical Sites and the Data Coordinating Center are included in the RFA. As noted in the RFA, since the project proposed in the application may not be adopted by the Network, the application budget should be viewed as a reasonable estimate for the purpose of review. Budget requests should be estimated as accurately as possible.
Do not use the modular grant application format for the budget. Applications that use the modular format will be judged non-responsive to the RFA and will be returned to the applicant without review.
For the purposes of estimating the budget in applications for Clinical Sites, assume that your proposed study will be carried out by the Network and that your site will be responsible for enrolling a proportion of subjects in that protocol. Based on anticipated enrollment from the pool of eligible subjects at your institution, estimate costs of performing that portion of the protocol at your site.
For the purposes of estimating the budget in applications for the Data Coordinating Center, assume that three new protocols for randomized clinical trials will be initiated during the second phase of the study (the second six months of Year 01, and Years 02-05). Assume that the three studies plan to enroll 200 subjects in each study, with the collection of 1000 data points on each subject in each study.
For applications for the Data Coordinating Center, the travel budget also should include travel for the number of personnel needed to carry out training of the Clinical Sites’ study coordinators and data entry clerks. Assume centralized training for one to two days to be held in the Washington, DC area annually during Years 01-05.
QUESTION 1C:
The section on travel for the Data Coordinating Center does not mention the yearly 1-2 day centralized training meetings. Shouldn't the Data Coordinating Center also budget for its travel to these meetings?
ANSWER:
Yes. For applications for the Data Coordinating Center, the travel budget should also include travel for the number of personnel needed to carry out training of the Clinical Sites' study coordinators and data entry clerks. Assume centralized training for one to two days to be held in the Washington, DC area annually during Years 01-05.
QUESTION 2C:
The RFA indicates direct costs of up to $600,000 per year for the Data Coordinating Center. Would this limit be adjusted for yearly inflation (3%?) after the first year?
ANSWER:
No.
QUESTION 3C:
Can testing (such as urodynamics or ultrasound) be included as part of the budget for a Clinical Site?
ANSWER:
Yes.
QUESTION 4C:
Should the Clinical Sites budget for computers for direct data entry or should these resources be included in the Data Coordinating Center's budget? Will the Data Coordinating Center need to purchase computers or other equipment for the sites? If so, would this need to be budgeted within the upper limit of $600,000 in direct costs or would this be an add-on?
ANSWER:
The Clinical Sites should budget for personnel (such as a data entry clerk) and equipment (such as computers) for direct data entry at each site. The Data Coordinating Center should budget for centralized data management, including requirements for personnel and equipment. Clinical Sites may request up to $200,000 direct costs per year; the Data Coordinating Center may request up to $600,000 direct costs per year.
QUESTION 1D:
Can a single individual serve as a Clinical Site Principal Investigator and a co-investigator on the Data Coordinating Center?
ANSWER:
Yes, a single individual can serve as a Clinical Site Principal Investigator and a co-investigator for the Data Coordinating Center. Assuming no Other Support, an individual's combined effort for both applications cannot exceed 100%. (With Other Support, effort on the two applications must be adjusted according so the total, including current commitments, does not exceed 100%.) As stated in the RFA, under Eligibility Requirements (page 1), "The application for the Data Coordinating Center must include a specific plan for maintaining the independent operation of each unit (for example, confidentiality of study-wide data)."
QUESTION 2D:
How is a "urogynecologist" defined?
ANSWER:
There are no specific requirements for a urogynecologist or a urologist, other than that stated in the RFA (Minimum Requirements for Clinical Site Applicants, page 5): "demonstrated training and experience in the diagnosis and treatment of pelvic floor disorders in women." Formal fellowship training is not specifically required.
QUESTION 3D:
Can someone other than a urologist or urogynecologist serve as the Principal Investigator for a Clinical Site?
ANSWER:
As stated in the RFA, under Minimum Requirements for Clinical Site Applicants (page 5), "The clinical investigators at each Clinical Site must include a urogynecologist and a urologist with demonstrated training and experience in the diagnosis and treatment of pelvic floor disorders in women. It is expected that either a urologist or a urogynecologist will serve as the Principal Investigator for a Clinical Site."
Therefore, the RFA does not specifically state that someone other than a urologist or urogynecologist cannot be the Principal Investigator. However, an application proposing someone other than a urologist or a urogynecologist as PI would have to adequately justify that choice. Given the requirements of the Network and the instructions of the RFA, this may be a disadvantage in the review process.
QUESTION 4D:
I am planning to submit a concept protocol related to fecal incontinence in my application for a Clinical Site. Should I still include a urologist as a co-investigator?
ANSWER:
Yes. The clinical investigators at each Clinical Site must include a urogynecologist and a urologist with demonstrated training and experience in the diagnosis and treatment of pelvic floor disorders in women. In general, the application should include all investigators who would be qualified to participate in protocols on any aspect of female pelvic floor disorders that are selected by the Network, even if they would not be directly involved in the concept protocol proposed in the application. As stated in the RFA (Application Instructions, page 10), key personnel in Clinical Site applications " ... should include physician staff representing several areas of expertise, either based in the participating department or available as collaborators. These areas could include obstetrics, gastroenterology, colorectal surgery, radiology, and physical therapy." Other areas of expertise should be included as appropriate to an individual institution.
QUESTION 5D:
What degree of medical expertise (qualifications, level of effort) do you expect the Data Coordinating Center to possess?
ANSWER:
There are no specific requirements for the level of medical expertise available to the Data Coordinating Center. As indicated in the RFA, under Review Criteria for the Evaluation of Data Coordinating Center Applications (page 15), the application should provide evidence that "the applicant possesses the knowledge necessary to contribute meaningfully to the final designs, including understanding of the scientific, ethical, and practical issues underlying the proposed study." This would include understanding of the clinical issues related to female pelvic floor disorders.
QUESTION 1E:
We were just notified of an award for participation in a different multicenter network. We have an excellent collaboration and large volume of stress incontinence and prolapse. Are groups funded for one network NOT encouraged for this RFA?
ANSWER:
Being a member of one network would not be a disadvantage for applications competing under the Clinical Trials Network for Female Pelvic Floor Disorders RFA. Indeed, this could be used to your advantage to demonstrate previous successful competition and experience in multicenter collaborations.
QUESTION 2E:
I have six sites (and could easily recruit more) who have agreed to work with me on a multicenter trial of non-surgical treatment for female urinary incontinence. Can I submit a proposal as such with a comprehensive budget and letters from each site in support of the proposal? Is there any chance it could be funded as such? If not, would that still be an appropriate way of demonstrating the organization and planning needed to participate in the group?
ANSWER:
An individual application for a Clinical Site may consist of several sites, but the overall budget must still come under the dollar limit as stipulated in the RFA (direct costs of $200,000). It should also be remembered that direct and indirect costs on a subcontract become part of the direct costs of the parent grant application.
An alternative strategy is for each site to submit its own application, but it will be reviewed independently of all the other applications and must stand on its own merit. One other suggestion was that if you or one of your collaborators was able to compete successfully with the original grant application, it may be possible to bring on additional clinical sites as satellites to the award with outside funding.
In answer to the second part of the question, describing past or current research collaborations would be an appropriate way to demonstrate the organization and planning to participate in the Network, as far as ability to work collaboratively with other sites, etc.
QUESTION 3E:
What are the relative roles of the Data Coordinating Center compared to the Clinical Trials Advisory Board and Steering Committees in determining types of, and performing analyses for, randomized controlled trials? Who will be responsible for developing the data analysis plan or plans? (I assume that the data coordinating center will be conducting analyses.) How much input in designing the initial analysis plans will the Clinical Trials Advisory Board be expected to have? How much input into the initial plans will the Steering Committee have? Will these governing bodies be advisory in this respect or will they direct how analyses should be done?
ANSWER:
The Steering Committee (or subcommittees created by the Steering Committee, as appropriate to each protocol) will be primarily responsible for developing the plan for data analysis for each protocol.
The Clinical Trials Advisory Board will advise the Steering Committee in identifying and setting priorities for research topics, and evaluating the overall hypotheses and scope of planned Network protocols. It is not expected that the Clinical Trials Advisory Board will have a major role in determining data analyses.
The Data Coordinating Center is responsible for conducting data analyses. Through its Principal Investigator on the Steering Committee, the Data Coordinating Center will contribute to the development of data analysis plans for all protocols performed in the Network.
QUESTION 4E:
If a clinical site is moving to a new hospital that will open long before any patient recruitment is planned, but which will not be open at the time of application, can the site include only the description of the new facility if such a situation is clearly explained in the application?
ANSWER:
Yes, although this may be seen as a weakness by reviewers. A strong record of patient volume among the investigative team at the original institution would be helpful. The description of the new facility should include a description of research and clinical personnel, characteristics of the patient population, and how this may differ from the original institution.
QUESTION 5E:
What organization will handle logistics for meetings of the Steering Committee, Clinical Trials Advisory Board, and Data Safety and Monitoring Committee?
ANSWER:
NICHD.
QUESTION 6E:
Will minutes of the meetings be required? If so, what organization will be responsible for producing and distributing these?
ANSWER:
NICHD.
QUESTION 7E:
What organization will handle drug acquisition and distribution?ANSWER:
The Data Coordinating Center.
QUESTION 8E:
Will any studies be subject to FDA regulations? If so, what organization will be responsible for obtaining regulatory documentation from the sites? What organization will obtain and hold any required INDs?
ANSWER:
It is possible that some studies in the Network will be subject to FDA regulations. In that case, NICHD will hold all regulatory documentation.
QUESTION 9E:
Please clarify the separate roles of the Project Scientist and the Program Officer.
ANSWER:
The specific responsibilities of the Project Scientist and the Program Officer are listed in the RFA under NICHD Staff Responsibilities (page 7). In general, the Project Scientist's role is to contribute scientifically to the Network, while the Program Officer's role is more administrative, carrying out normal NIH program stewardship functions.