Frequently Asked Questions, NINDS Parkinson’s Disease Biomarkers Program (PDBP)

The following are brief answers to some frequently asked questions (FAQs) regarding RFA NS-12-010 (U18) (Exploratory Laboratory and Analysis Projects in Parkinson’s disease Biomarkers), and RFA NS-12-011 (Studies in Parkinson’s Disease Biomarkers Discovery) (U01). However, they are not meant to be comprehensive and all potential applicants are urged to read the entire announcement(s) regarding program and FOA goals and review requirements.

General

What is the emphasis of this program?

The overall purpose of the NINDS PDBP, in general, is to rapidly identify and develop potential biomarkers to improve the efficiency and outcome of Phase II clinical trials and advance therapeutic development for PD. The two recently released FOAs are for discovery projects, whether laboratory based (see RFA NS-12-010) or clinical (see RFA NS-12-011) for progression markers.

What is the difference between the U18 (RFA NS-12-010) and the U01 (RFA NS-12-011)?

RFA NS-12-010 (Exploratory Laboratory and Analysis Projects in Parkinson’s Disease Biomarkers) has the expressed purpose of stimulating innovation and development of technologies and reagents that will accelerate the discovery effort in Parkinson’s disease biomarkers. No clinical studies will be supported under this announcement, though use of human biospecimens in extant collections is allowed. This uses the U18 mechanism, which requires milestones and a timeline in each proposal and will have substantial NINDS programmatic input and requirements. Funds may be available up to costs of $200K direct costs per year, for up to three years.

RFA NS-12-011 (Studies in Parkinson’s Disease Biomarkers Discovery) can be used to 1) support hypothesis driven clinical research to discover biomarkers that will improve the efficiency and outcome of Phase II clinical trials for Parkinson’s Disease (PD) and 2) support the collection of clinical data and new biological specimens that will be used for biomarker exploratory efforts under the NINDS Parkinson’s Disease Biomarkers Program (PDBP). Projects which have both goals will also be acceptable. This uses the U01 mechanism, meaning there will be substantial NINDS programmatic input and requirements. Milestones and a timeline must be included in each proposal. Budgets depend on the scope of proposed projects, and the project period can be a maximum of five years.

What is the difference between an R01 and a U01?

An R01, also known as a Research Project Grant, is awarded to an institution to allow the Principal investigator to pursue a scientific focus or objective. The U01 mechanism allows for a partnership between the NIH and the teams of researchers who will be funded through this RFA. Under the cooperative agreement mechanism, the NIH supports awardees' activities by working jointly with them to ensure fulfillment of programmatic goals; however, prime responsibility for the conduct of the research resides with the awardees. Given the unique and relatively novel nature of these RFAs, substantial NIH programmatic involvement and support will be important to enable successful completion of project goals. Milestones are goals that create go/no-go decision points in the project and must include clear and quantitative criteria for success. For these announcements, milestones and a timeline are required, and applications for which milestones are not met may be discontinued.

Will grants under these two announcements support validation studies?

The goal for these announcements is to support discovery projects. The Michael J Fox Foundation is currently supporting the Parkinson Progression Markers Initiative (PPMI) which includes a biospecimen collection which can support validation efforts; therefore, this effort will dovetail with existing efforts.

Specific Clinical and Biospecimen Questions Regarding RFA NS-12-011 (Studies in Parkinson’s Disease Biomarkers Discovery)

Do subjects ascertained under the U01 (RFA-NS-12-011) need to be ascertained longitudinally?

The majority of studies under the program are expected to be longitudinal, especially if the collection of biospecimens is the primary goal of the proposal. However, other approaches, such a cross sectional cohorts, are also acceptable especially if particularly suited to the aims of the study.

Can cross-sectional cohort studies be proposed?

Yes, cross-sectional cohorts can be proposed.

Can existing cohorts be included in an application proposal?

Yes, existing cohorts can be included. Such studies might involve the entire cohort that is participating in an ongoing clinical study (not a clinical trial), or selected subsets of the participants. If an application plans to utilize the infrastructure or resources of existing projects, letters of support detailing the feasibility, terms of collaboration and data sharing must be included.

What Clinical Data Elements are required?

In order to maximize data standardization across studies, the NINDS strongly encourages researchers to use the NINDS Common Data Elements which are available at http://www.commondataelements.ninds.nih.gov/General.aspx. The PDBP Data Management Resource (DMR) will develop web-based forms to assure ease of data entry and quality assurance. Some of these assessments may be self-administered in order to reduce subject and study burden. PDBP clinical projects will be required to include the following General and PD-specific CDEs:

General CDEs

All “core” General CDE items and forms will be required in the following domains for all subjects:

• Participant/Subject Characteristics (Demographics)
• Participant/Subject History (Medical History and Behavioral History)
• Assessments and Examinations (Physical/Neurological Exam, Vital Signs, Laboratory Tests and Biospecimens/Biomarkers)
• Treatment/Intervention Data (Prior and Concomitant Medications)
• Protocol Experience (Inclusion and Exclusion Criteria, Informed Consent and Enrollment)

PD-Specific CDEs

All “core” and the following “recommended” items and forms will be required in the domains listed below, both for PD subjects and for those at risk for PD (i.e., pre-symptomatic, gene carriers, etc.). Items that are duplicative of those in the General CDEs need not be collected twice.

• Participant/Subject Characteristics (Demographics)
• Participant/Subject History and Family History (Medical History, Family History)
• Assessments and Examinations (MDS-UPDRS, Hamilton Depression and Anxiety Rating Scales, Montreal Cognitive Assessment, Epworth Sleepiness Scale, RBD Screening Questionnaire, and University of Pennsylvania Smell Identification Test)
• Treatment/Intervention Data (PD Medication Log)
• Outcomes and End Points (PDQ-39).
• Additionally, the Schwab and England ADL Scale will be required.

In addition to the above, PDBP applicants may employ supplementary assessment and measurement tools if relevant to addressing the specific hypotheses proposed in their application. If other tools are proposed, applicants are strongly encouraged to use those suggested or provided by the NINDS CDE program.

Where will the biological specimens be curated?

The biospecimens will be banked, stored, and distributed to other researchers via the NINDS Repository.

Is CSF (once a year) mandatory for clinical studies?

Ideally, CSF will be collected yearly, but we realize this may not be possible for all studies proposed.

What are the volumes of biological specimens required?

Ideally, samples will be collected every six months (other than CSF, which ideally can be collected yearly, and DNA, which only needs to be collected once) in the following volumes:

• Plasma/Serum: minimum 6 milliliters
• Whole blood: (for DNA extraction) minimum 6 milliliters (initial visit only)
• Whole blood for other studies minimum 6 milliliters (in addition to that for DNA at initial and also other than initial visits)
• Pax-gene tube (for RNA) minimum 8 milliliters
• CSF: minimum 10 milliliters (local analyses to include cell count, total protein, glucose, submitted to DMR)

Data Management

Who is managing the Data Management Resource (DMR)?

The Data Management Resource will be managed by NINDS as a contract mechanism or IT purchase.

How should planned projects consider integration with the DMR?

The study site must identify at the time of application, key personnel whose responsibility will be to ensure and facilitate data quality, transfer, sharing, and biological specimen submission to the DMR and NINDS repository respectively. For those with existing studies already utilizing a data management core or resource, data will not be required to be entered twice or transferred, but, must be federated with the DMR. Deposition of all data into the PDBP DMR should occur in real time.

Applications proposing efforts that are duplicative of DMR functions or responsibilities will not be funded in part or at all. Activities that are the sole purview of the DMR include: 1) development of standardized electronic data forms, data formats and software for use across multiple cohorts and projects; 2) development of software to support subject scheduling, site tracking, and facilitation and coordination of de-identified clinical and biospecimen data collection across multiple new and existing cohorts and projects through an easy to use web-based entry system for submitters; 3) quality assurance checks of data entry and collection; 4) development of a user-friendly query system for users to evaluate availability of data and biospecimens within and across PD biomarker projects; 5) development of aggregate data report formats that are user-friendly and supported by well documented data dictionaries; 6) training for both data submitters and data users; 7) coordination of data and biospecimen summary reports and postings in collaboration with the NINDS Repository; and 8) public outreach for data submission and data use. Development of all electronic data entry forms and quality assurance checks of de-identified data will be done by the DMR.

Budget

Does a PI need special approval for a submission over $500K?

No, special approval is not needed for these under these particular RFAs.

Do kits for collection of samples, or the costs for shipping of samples need to be included in the budget? 

No, the tubes for collection of biospecimen and the shipping containers will be funded via the NINDS repository. However, costs for collection of the sample and any on-site processing of the sample must be covered by the proposal.

Does Data Management need to be included in the budget? Will these funding opportunities support a unique database for a project and can that be included in the proposal? 

A Data management resource is being developed for this program and so does not need to be included in the budget as described in the FOAs. However, note that it is essential that the proposal include key personnel whose role will be to integrate data from their study into the DMR.