Background:

 

Q. Which groups are currently awarded in the network and what are they studying?

A. You can find a tab labeled PGRN at PharmGKB.  That site links to descriptions prepared in late 2003 of the research groups’ plans, the members of the groups, and the groups’ websites (note that the network has agreed that all data presented on their individual websites will appear simultaneously and publicly at PharmGKB).

 

Q. How can I gain access to PharmGKB?

A. PharmGKB offers credentialed access to all with legitimate scientific purposes.  Go to the registration page to sign-up and describe your research goals.  Turn-around time of about 24-48 hours is required before a password is issued.  All registrants’ access to data can be monitored per the agreement reached with Stanford University regarding HIPAA compliance; this is described in disclaimers at the PharmGKB site.

 

Q. What types of data will PharmGKB accept?

A. PharmGKB presently accepts genotype submissions compliant with XML schema, phenotype submissions via EXCEL spreadsheets, literature annotations by the community submission project, microarray data (MIAME-compliant format preferred), and pathways under an established process to form a committee of peers.  See the PharmGKB submit tab.

 

Q. What kinds of goals statements are on record from the PGRN and NIH from the current funding cycle?

A. In June 2003, as a result of an iterative process of assessing priorities, the NIH and the PGRN member groups agreed on a series of goals.  The goals statement resulting from that process is posted publicly.

 

Governance, Advising:

 

Q. How is the network currently governed?

A. The network is governed by a Steering Committee, comprised as outlined in the funding RFA, per the Terms and Conditions.  Each PGRN group sends a voting member (the PI) to meetings along with an observer. The Steering Committee has a Chair and a Vice-Chair.  All funding NIH institutes also have voting representation on the Steering Committee.  The Chair has assembled a Coordinating Committee of a sub-set of members that assists in planning and vetting the issues as they arise.   The PGRN committees meet by monthly conference calls.  The Steering Committee meets twice a year in person.

 

Q. Are there subcommittees or working groups in the PGRN? 

A. The network originally had a series of standing policy subcommittees (Human Subjects, Intellectual Property, Communications, Knowledge Base), set up in response to concerns raised by the initial scientific review group.  The work products of those subcommittees are the PGRN policy statements.  In mid-course of the funding cycle, the network evolved to have a scientifically-based series of task forces.  Those task forces are more ad hoc in nature and meet until the task at hand is completed.  Recent task forces have dealt with recommendations on shared sample sets, use of local websites, and putting together a statistics/analysis workshop for the PGRN.

 

Q. Where are the network’s policy statements found?

A. They are posted publicly at PharmGKB as PGRN Policies.  These are the policies to which all network members have agreed to adhere.

 

Q. What is the ESP?

A. The ESP (External Scientific Panel) is a standing body that was established in 2003 at the recommendation of NIH consultants.  The membership of the group and charge to the ESP is posted.  This group is advisory to the network.  In their recent meetings, ESP recommendations have included advice about making genotype submissions to PharmGKB easier, the use of local websites in support of PharmGKB, incorporating statistics upfront in the design of pharmacogenetics studies, developing phenotype ontologies and standard vocabularies, including data analysis capabilities at PharmGKB, and outreach to the scientific community.

 

Planning an application:

 

Q. What is the NIH mainly looking for in responses to this RFA?

A. NIH is looking for applications that will demonstrably aid this network in fulfilling its four main goals:  1.) further developing the knowledge base, 2.) advancing the research field, 3.) producing and sharing resources and reagents, and 4.) enhancing communication among scientists both within and outside of the network.

 

Q. How should the application be organized?

A. It should not be organized like a P01.  Rather, it should be organized like a comprehensive, integrated program that has components.  For example, past experience has shown that a variation discovery core + functional assays core + clinical samples detection core is an organization that works (called a “genotype-to-phenotype” group).  In contrast, a clinical studies core + variant analysis core + statistical associations core has also worked (called a “phenotype-to-genotype” group).  This is obviously an over-simplification, and careful study of the funded groups and their deposits into PharmGKB can help the potential new applicant.

 

Q. Why are multiple budget formats required in the application?

A. Budgets must be prepared for each research component/core to aid the reviewers in reaching a scientific assessment, and also for each awardee institution to facilitate the funding process.  These pages do not count against the 50 page research plan limit.

 

Q. What can new applicants do to demonstrate their interest in this initiative?

A. New applicants should put careful and critical thought into the design of studies that will generate high quality data sets to populate a database, consider rigorous statistical and mechanistic correlations that can be made between genotypes and phenotypes for pharmacogenetics, and actively explore PharmGKB and actually make deposits of data and community (literature) annotations.  Discussion with present network members is also encouraged.  

 

Q. How large should the budget request be?  Could an R01-scale application be submitted? 

A. The RFA announced an upper limit of $2 million per year in direct costs (F & A costs of subcontracts, which normally become direct costs to the host institution, may be excluded).  However, the applicant should carefully consider the justified needs of a proposed program; past awards have ranged from $0.5 to $2.0 million per year.  In contrast, an R01-scale application would not be considered responsive.  NIH accepts unsolicited R01s in the pharmacogenetics area.

 

Q. I prefer to submit an unsolicited R01-scale application for the regular receipt dates; will there be chance to interact with the PGRN?

A. Yes.  PharmGKB is intended to be a research tool for all investigators.  Anyone may deposit data, and use of the knowledge base is encouraged in the broader scientific community.  The PGRN has held four open, annual meetings thus far with published post-meeting reports, and more discussions at open forums will be encouraged in the future.  Research tools and resources produced by the network will be disseminated as broadly as practically possible.

 

Research areas of applications:

 

Q. Do the disease focus areas have to align with the supporting institutes of NIH?

A. The participating NIH institutes and office (NIGMS, NHLBI, NCI, NHGRI, NIEHS, NIDA, NLM, and ORWH) have focused goals and are accountable for funding research in their areas.  Keep in mind that some areas of study (e.g., metabolism and transport, signaling pathways, the immune response) cross several institutes’ interests, and likewise some focused interests (the environment, women’s health) are cross-cutting in a different way.  Co-funding occurred in the past and may be possible in the future.  Check the published statements of interest in the RFA and consult with institute staff.

 

Q. Can one study the genetics of a disease?

A. Yes, to understand drug actions it is often necessary to understand the basis of disease. However, an application must propose to study drug actions in addition to the disease itself; to fail to do so would cause an application to be considered unresponsive to this RFA.  The Pharmacogenetics Research Network has defined pharmacogenetics research to be comprised of study of the actions of drugs + genes + diseases. 

 

Q. Could a model organism or animal be studied?

A. Yes, and in some cases this may be the best way to study a problem.  The model organism or animal model experiments must be presented in the application as the best way to study the genetic contributions to drug actions in humans.  Furthermore, PharmGKB accepts non-human-derived data in all categories except “Clinical Outcome”.

 

Q. Are clinical trials eligible under this RFA?

A. This initiative supports fundamental research studies, both basic and clinical.  Therefore, a focus on the discovery and analysis of the contributions of genetic variation and correlation with clinical observations of drug effects is recommended.  In some cases, de novo clinical studies will be required, and these must be carefully justified to the reviewers.  In other instances, well-phenotyped samples may be obtained by interacting with ongoing clinical trials supported elsewhere (with clear approvals for this interaction indicated by letters of support accompanying the application).  Please contact staff in the appropriate institute for further guidance.  All data obtained must be made available in a timely manner for deposition into PharmGKB, according to established network policies.  

 

Review of the applications:

 

Q. Where will the applications be reviewed?

A. The applications will be reviewed at CSR, the NIH Center for Scientific Review, because this is a trans-NIH initiative.

 

Q. Are there “tailored” review criteria?

A. Yes, and these criteria should be considered with the understanding that reviewers will be instructed to factor the criteria into their scores.  See the ADDITIONAL REVIEW CRITERIA in the RFA.

 

Q. Will the research groups and database groups be reviewed together at the same study section?

A. CSR anticipates reviewing the research groups and the comprehensive database groups separately, to provide a neutral and complete evaluation of all applications.  Therefore, applicants should ensure that all relationships are completely described, and documented with letters of support for any collaborations that will extend beyond simply making database deposits.  Smaller database groups that are tightly connected with specialized research missions will likely be reviewed with the research groups; only comprehensive database groups that describe PharmGKB in its totality are planned for review separately, per CSR staff’s judgment and experience.

 

Q. Will there be site visits?

A. No, site visits are not planned, due to constraints on CSR’s staff time and limited travel funds.

 

Special issues:

 

Q. What letters of support should be included?

A. Per the SPECIAL REQUIREMENTS section in the RFA, applicants should submit a group letter specifically referring to the network policies, indicating that they have been read by all group members, and that they all agree to adhere to these network guidelines.

 

Q. Should I talk to the IRB at my institution at the application preparation stage?

A. This RFA, as others at the NIH, adheres to Just-in-Time principles, which means that IRB approval is only required immediately prior to an award being made.  However, because deposits of data are crucial to this initiative, it would be prudent to have preliminary discussions with the involved IRB(s). Note that the PGRN-recommended model informed consent language  specifically refers to PharmGKB.  Individual situations will have to be considered at your institution(s); for example, sharing data on the web may be considered comparable to electronic journal publication.  Preliminary discussions with an IRB reflected in the application will demonstrate the serious intentions of an applicant.

 

Q. Are there limitations on intellectual property?

A. There are no limitations applied by NIH; normal grantee institutional rights as a result of the Bayh-Dole Act are preserved.  However, the PGRN has recommended that provisional patent strategies are consistent with the prompt dissemination of potentially valuable functional genetic information.  An institutional plan for handling intellectual property is required in the application.  A timeline for data deposits (note the review criteria “meaningful data deposits planned in a timely manner”) should also be described in the application.

 

Q. How should applications proposing to study identified racial and ethnic groups approach the issues?

A. All clinical research supported by NIH continues to have the requirement that patients and/or volunteers must be recruited from diverse backgrounds.  As the research focus on identified subgroups increases, the investigators’ responsibilities increase.  NIGMS has convened several meetings of the Populations Advisory Group in this area, and the reports and recommendations are publicly available.  Brochures are available (at no cost) to communicate the purpose of pharmacogenetics research and the value of participating in genetics research studies; see the “thumbnail” pictures at the NIGMS website.   The responsibilities for outreach efforts grow proportionately by degree to which individual groups, and ultimately the research results, are labeled by their ethnicity, race, gender, or geographic origins, and the PGRN applicants should strive to attain high standards of practice.  The greatest requirements exist where samples are submitted to repositories; please see the topic of Consultation with Communities and call an NIGMS staff member to discuss your plans.