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Genetics Workgroup (GWG)

Frequently asked questions about Access To the NIDA Center for Genetic Studies Repository and Data Sharing Using the CTN as a Platform

Q1. What is the NIDA Center for Genetic Studies (NCGS)?

A1. The NIDA Center for Genetics Studies (NCGS) is a NIDA-funded scientific resource for informing the human molecular genetics of drug addiction. The NCGS stores clinical data, diagnostic data, pedigree information, and biomaterials (including DNA, plasma, cryopreserved lymphocytes, and/or cell lines) from human subjects participating in studies that form the NIDA Genetics Consortium (NGC). The resource is for all investigators who have fulfilled the requirements for membership and agree to become members of the NGC. For more information about the NGC, please see FAQs about the NGC. For information about each study in the NGC, please see http://zork.wustl.edu. Click the NIDA icon, select public information, and then click on study information.

Q2. What is the NIDA Center for Genetic Studies (NGC)?

A2. In September 1998, NIDA issued a Request for Applications (RFA) entitled "RFA DA-99-003: Genetics of Drug Addiction Vulnerability" to identify human chromosomal regions containing genes that confer susceptibility to drug abuse and addiction and related behaviors. The principal investigators of the studies funded under this RFA formed the initial membership of the NGC, and other investigators have subsequently joined. The NGC investigators represent multiple institutions, use diverse approaches and study designs, and are required to meet twice yearly to discuss issues related to the collection and analyses of data from human genetic studies on drug addiction.

The overarching goals of the NGC are to identify genetic factors involved in drug addiction and addiction vulnerability, and to create a database on the human molecular genetics of drug addiction for sharing among members and the broader scientific community. Toward this end, NGC members collect anonymized data on family structure, age, sex, clinical status, and diagnoses, as well as blood samples from which DNA and cryopreserved lymphocytes are derived. These data, plus all data derived from genotyping and other genetic analyses of these clinical data and biomaterials, are stored in the NIDA Center for Genetic Studies (NCGS). To learn more about the NCGS, please see FAQs about the NCGS

Q3. What is the CTN?

A3. The National Drug Abuse Treatment Clinical Trials Network (CTN) is a unique alliance of community-based drug abuse treatment programs (community treatment programs - CTPs) and investigators in research centers and universities (regional research and training centers- RRTCs) located across the nation and organized into distinct functional units called Nodes. The Clinical Trials Network's (CTN) multi-site clinical trials provide a valuable resource for accessing diverse patient populations, modalities, and clinical treatment sites. The filtered data set (i.e., without the information that can be used to identify individuals) is housed at a repository contracted by NIDA. These data are kept confidential to the extent permitted by Federal law and no information is disclosed except to NIDA, or pursuant to NIDA's explicit direction as a result of publications. No individual study site analyses or publications on main outcome measures are permitted prior to publication of the main study findings, however ancillary data may be published prior to main study. Once the acceptance for publication of the main findings from the final dataset occurs, the timely release and sharing of final research data from CTN studies for use by other researchers can occur.

Q4. What are the services of the NCGS?

A4. The NCGS creates high-quality DNA, plasma, and cryopreserved lymphocytes (CPLs) on all samples submitted by NGC members. If samples do not have sufficient lymphocytes for cryopreservation, the sample will be made into an Epstein-Barr virus transformed cell line (from which DNA is extracted and stored). If DNA quantities become low, the CPLs are thawed and transformed into cell lines. The NCGS also provides a mechanism by which all databases containing clinical information and biomaterials (DNA) can be widely searched or distributed to qualified investigators in the scientific community. The services of the NCGS for shipping blood, producing cell lines, and storing clinical data are free to members of the NGC. Requests to access stored DNA samples (at 10 µg aliquots) may require a nominal fee depending on NGC membership status and the number of prior requests. Please refer to the fee structure below.

FAQs: Requesting Approval For Submitting Samples To The Repository

Q5. How may CTN investigators gain access to submit and store data and biologic materials at the NCGS?

A5. Ideally, the concept for a genetics protocol should be discussed in the very early stages of the parent protocol development so that there is more opportunity for genetics issues to be resolved (i.e. statistical power for low effect sizes, population stratification, etc). Once a concept has been established, the process proceeds in two stages (See attached flow diagram for process). Stage I is the genetics protocol concept approval process and Stage II is the dataset request.

The process may take 2-3 months. Investigators must submit a concept to the Executive Committee for initial comment and approval for proceeding to obtain funding. The proposal should include a detailed budget (for CTN costs), and documentation that the CTN Lead Investigator of the parent study has discussed the plan and is in concurrence with the proposal. In the event that the NGC Repository is unable to accept submission of samples due to budgetary limitations, the budget should also include a contingency to pay for the samples to be submitted to the Repository. If there are sufficient funds, this item in the budget will be administratively deleted, and the NIDA Center for Genetic Studies will pay for those costs. The PI must then obtain funding through regular mechanisms (eg. R01 or other grant mechanism, or administrative supplement). Once funding has been secured, submit the request to the NGC Steering Committee, where it will be sent for review to the NIDA Genetic Data Access Request Committee to request sample and data storage. Requests should consist of one original plus one copy of the following:

1. Cover Letter. A cover letter containing the name, mailing address, e-mail address, fax number, and telephone number of the applicant principal investigator. This letter should be written on the letterhead of the sponsoring institution at which the research is or will be conducted.
2. Biographical Sketches. The biographical sketches of the applicant principal investigator and all co-investigators (NIH format).
3. Resources and Environment (NIH format).
4. Full Disclosure of Funding. Declaration of all sources of public and private funding, periods of support, active/pending status, and relationships with any public or private agency conducting work related to the proposed research. In lieu of the above information, the "Other Support" pages from an NIH format application may be attached.
5. Study Description. A description of the study design that includes the following sections:
   1. Abstract. Summarize the study in no longer than one-half page.
   2. Specific Aims. Clearly state the hypotheses to be tested.
   3. Background and Significance. Justify that the hypotheses are of interest to the scientific community and that the resources of the NCGS are essential to the study.
   4. Method. Provide a clear description, justification, and timetable of the research to be conducted including the DNA (number and amount) and data requirements, the markers to be used and the general methods of analysis. In addition, present evidence of a clear understanding of the limitations, strengths, and feasibility of using the dataset to address the proposed study aim(s).
   5. Statistical Analysis. Indicate which analytical techniques will be applied, including, when relevant, power calculations to justify the amount of DNA requested.
   6. Statement of Public Health Good. Identify the public health benefits and risks of the proposed research, and describe how the findings from the proposed research would be used to promote public health.
   7. Dissemination of Research Findings. Clearly specify the plans to disseminate findings from the proposed research.
6. Human Subject Approval. Applicants should provide documentation of IRB review and either approval of the proposed project or exemption of the proposed project from the need for further IRB review, according to the requirements of the Department of Health & Human Services Office for Human Research Protections (OHRP). Although IRB approval will not be required at the time the Access Request is submitted, neither data nor DNA can be released until evidence of IRB approval has been received. Applicants should indicate to their IRB that all data and materials in the repository were stripped of all personal identifiers before they were submitted to the repository, such that no identifying information is associated with the samples.

Following review by the NGC Access Committee, a decision will be sent from the NGC Steering Committee to the CTN Executive Committee (EC) and the PI. If approved, submission of samples may begin once the data sharing plans and consent forms have been reviewed and approved by the NGC Steering Committee. Stage II must follow to ensure that the appropriate dataset for the genetics study will be created (See Attachment).

Q6. What is the SOP for the review process?

A6. The following is the procedure for obtaining approval for a genetics sub-study for a planned CTN protocol:

1. Genetics sub-study PI submits proposal to Lead Investigator early on in the conceptual design of the clinical trial. The LI with the development team reviews for feasibility in context of the parent study and assurance that the genetic sub-study will not interfere with completing the parent protocol (i.e. it does not impose undue burden on subjects, staff, etc.; it will not interfere with enrollment, etc).
2. PI sends full proposal (see Q5) and letter of support from LI to the Executive Committee (EC) for review of feasibility and resources in the CTN and in context of comments and recommendations from LI makes approval/disapproval recommendation from the CTN perspective. EC can request additional information before the final determination is made. EC sends proposal and review comments to the NIDA Genetics Consortium Steering Committee/NIDA Access Committee for review (*This is done only if PI requests that samples collected are stored in the NIDA Genetics Repository).
3. NIDA Access Committee reviews for scientific merit and for feasibility and resources in the NGC and makes final approval/disapproval for samples to be placed in the Repository. The NIDA Access Committee review and decision will be sent to the EC and PI.

Full approval for studies with samples going to the Repository requires both EC and NGC concurrence. Studies with samples collected and stored elsewhere require EC approval only.

FAQs: Requesting Approval For Access To Collected CTN Samples In The Repository

Q7. How may CTN investigators who are non-lead PIs or non-CTN investigators gain access to CTN data and biologic materials at the NCGS Repository?

A7. This is a Stage III request (See Diagram). Investigators must submit a NIDA Genetic Data Access Request to the NGC Steering Committee, where it will be sent for review to the NIDA Genetic Data Access Request Committee to request sample and data storage. Requests should consist of one original plus one copy of all of the information requested in the previous question (Q5.) and include the following:

1. A completed Distribution Agreement. See the following web page: http://www.nida.nih.gov/about/organization/genetics/DistPol.html
2. A completed List of Requested DNA and Associated Data. See the bottom of the following web page: http://www.nida.nih.gov/about/organization/genetics/GeneticDistPol.html

Following review by the NIDA Access Committee, a decision will be sent to the NGC Steering Committee. The NGC Steering Committee will inform the requesting PI of the decision and copy the EC.

Q8. Where should NIDA Genetic Data Access Requests be sent?

A8. Requests should be sent to:

Joni L. Rutter, PhD
Chair, NIDA Genetic Data Access Request Committee
NIH/NIDA
Genetics and Molecular Neurobiology Research Branch
Division of Neuroscience and Behavioral Research
6001 Executive Blvd.
Rm 5227, MSC 9555
Bethesda, MD 20892-9555
Rockville, Maryland 20852 (for courier/overnight mail service)
Phone: 301-443-1887
Fax: 301-594-6043
E-Mail: jrutter@mail.nih.gov

Q9. What is the NIDA Genetic Data Access Request Committee?

A9. The NIDA Genetic Data Access Request Committee, selected by NIDA staff, is a panel composed of one bioethicist and four other individuals with expertise in one or more areas including human genetics, genetics of complex traits, statistical analysis, molecular genetics and drug addiction research. NIH Program and Review staff members are excluded from membership on the Committee. The Committee will determine 1) whether or not an investigator is qualified to access the data stored at the NCGS, and 2) priority in which access is granted in cases where funding may not be available to all investigators requesting access.

The following criteria will be used to determine access:

1. Experience and qualifications of the applicant principal investigator and co-investigator(s)
2. Adequacy of the research environment(s)
3. Ethical considerations
4. Applicant principal investigator's familiarity with the characteristics, limitations, and strengths of the dataset
5. Adequacy of proposed research design, statistical methods, and timetable of proposed project
6. Adequacy of the applicant principal investigator's funding resources to support the proposed study
7. Benefit to public health

Q10. What happens after Access Requests are reviewed?

A10. After the Access Request has been reviewed, the NGC Steering Committee will inform the PI of the decision along with subsequent instructions on how to proceed.

Q11. When is the soonest that I can access CTN samples that have been sent to the Repository?

A11a. If you are a member of an active CTN node and you have submitted an access request that has been approved, you can access samples from the Repository as soon as the data are locked. The locking of a database is when all data points are considered to be valid and final. The database is considered final when all cleaning is completed, and no further changes to the database are expected. Only completed studies with a locked database are eligible for data sharing. It is the responsibility of the Lead Investigator of the original study to verify data lock, to carefully review the research project protocol and agree to release the requested data set for the study. No individual study site analyses or publications are permitted prior to publication of the main study findings. Once the acceptance for publication of the main findings from the final dataset occurs, the timely release and sharing of final research data from CTN studies for use by other researchers can occur.

A11b. If you are not a member of a CTN node, but have been approved for access, you can access the samples as soon as the main study findings have been published. Prompt and timely presentation and publication in the scientific literature of findings resulting from research undertaken in the CTN is required. It is expected that the Lead Investigator will have an initial outcome paper completed and submitted to an appropriate peer-reviewed scientific journal within 180 days of data lock for the protocol. Once this occurs, NIH (and therefore NIDA) expects the timely release and sharing of data to be no later than the acceptance for publication of the main findings from the final dataset. Any CTN investigator, as well as those outside the CTN structure, will no longer need to follow the procedures outlined in this document but can request the final dataset from NIDA. Procedures for such requests are under development.

NIH's data sharing policy may be found at the following Web site: http://grants1.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html

Other FAQs:

Q12. How can I find out what studies are participating in the NGC and contributing clinical data and biomaterials to the NCGS?

A12. This information can be found at the NCGS website, which is maintained at Washington University (http://zork.wustl.edu/). Click on the NIDA icon, select public information, and then click on study information.

Q13. The CTN uses nested informed consents in which research participants agreed to different levels of access to data stored at the NCGS. Is this true and how does this affect access to data stored at the NCGS?

A13. NIDA and the NCGS must abide by and implement the wishes of research participants as indicated in their nested informed consents. These nested consent forms vary from study to study, but typically include three levels of consent. These levels of consent may restrict access to data to the scope of the original study, to addiction and related medical disorders, or to any genetics study. NIDA will provide the access status of the samples on the NCGS website (http://zork.wustl.edu/).

Q14. How soon can qualified scientists from around the world gain access to CTN data stored at the NCGS?

A14. In general, access can occur if one of the following conditions are met: either18 months after the ending date of the parent protocol period (the proprietary period), upon initial publication of the sample set, or upon early release as defined by the investigator. For information on availability of samples, the NCGS website (http://zork.wustl.edu/).

Q15. To gain access to CTN data stored at the NCGS, must the Recipient have IRB approval?

A15. Yes. As stated above, applicants should provide documentation of IRB review and either approval of the proposed project or exemption of the proposed project from the need for further IRB review. The IRB approval will not be required at the time the Access Request is submitted. However, no data can be released from the NCGS until evidence of IRB approval has been received.

Q16. Must the Recipient follow the conditions for use of Biomaterials, Clinical Data, and Genetic Analysis Data as approved by the Institutional Review Board (IRB) of their own institution and the IRB of the NIDA contractor and subcontractor that operate the NCGS?

A16. The Recipient must follow the conditions for use of Biomaterials, Clinical Data, and Genetic Analysis as approved by the Institutional Review Board of their own institution and of the IRB of the NIDA contractor and subcontractor that operate the NCGS in accordance with the United States Department of Health and Human Services regulation at 45 CFR Part 46. Some IRBs may waive IRB approval for studies concerned with secondary analysis of data.

Q17. How soon must the Recipient provide NIDA with any Genetic Analysis Data derived from CTN data stored at the NCGS and received under the conditions of the Distribution Agreement?

A17. The Recipient agrees to provide NIDA, through the NCGS, with any and all Genetic Analysis Data derived from CTN data stored at the NCGS and received under the conditions of the Distribution Agreement within 18 months after receipt of such data or upon publication of the research, whichever comes first. http://www.nida.nih.gov/about/organization/genetics/DistPol.html

Q18. When must the Recipient destroy Biomaterials, Clinical Data, and Genetic Analysis Data received from the NCGS?

A18. The Recipient must notify NIDA and provide written certification of the destruction of Biomaterials, Clinical Data, and Genetic Analysis Data received from the NCGS in accordance with any applicable laws and/or accepted safety procedures upon completion of the project or within 3 years after receipt of clinical data and DNA.

Q19. What happens if the Recipient fails to comply with the terms in the distribution agreement?

A19. Failure to comply with any of the terms may result in disqualification of the Recipient from receiving additional Biomaterial, Clinical Data, and Genetic Analysis from NIDA, as provided by the NCGS. This disqualification may be posted on the NIDA web site and in the NIH Guide.

Q20. Who is liable for demands, damages, expenses, and losses arising out of the Recipient's use for any purpose of Biomaterials, Clinical Data, and Genetic Analysis Data received from the NCGS?

A20. The Recipient is liable. Under the Distribution Agreement the Recipient agrees to hold the United States Government, its contractor and subcontractor that operate the NCGS, Submitters, and other Recipients providing Genetic Analysis Data to the NCGS harmless and to indemnify all such parties for all liabilities, demands, damages, expenses, and losses arising out of the Recipient's use for any purpose of Biomaterials, Clinical Data, and Genetic Analysis Data received from the NCGS.

Q21. Is the Recipient forbidden from any effort to discover the identity of anonymized subjects from Clinical Data and DNA received from the NCGS?

A21. Yes. Under the Distribution Agreement the Recipient will not make any effort to discover the identity of anonymized subjects from Clinical Data and DNA received from the NCGS.

Q22. What safeguards are in place to prevent disclosure of subject identities whose biomaterials and clinical data are sent and stored at the NCGS?

A22. Several safeguards are in place to protect subject confidentiality. First, biomaterials and clinical data sent to the NCGS are stripped of all subject identifiers and given a code by the Principal Investigator sending the samples. The NCGS then provides a new identifier number for the sample and informs the Principal Investigator of the new identifier number that corresponds to the code given by the Principal Investigator. Any samples containing subject identifiers submitted to the NCGS are returned immediately to the investigator.

Second, a Certificate of Confidentiality also covers the NCGS. This protects the NCGS from court orders and subpoena to release information from the NCGS in most cases.

Third, the NCGS must operate in accordance with the United States Department of Health and Human Services regulation at 45 CFR Part 46 concerning human subjects and its local institutional review board.

Fourth, anyone given access to clinical data and DNA is forbidden to attempt to discover the identity of the research participants from DNA and biomaterials obtained from the NCGS. This is stipulated as a term and condition in the Distribution Agreement.

Q23. What assurance to the investigator and their subjects is there that NIDA will handle the clinical data and biological materials (DNA) as indicated in the data-sharing plan?

A23. The data-sharing plan becomes part of the notice of grant award (NGA). The NGA is a contractual agreement between the investigator's institution and NIDA. The NGA cannot be changed except by mutual agreement between the investigator's institution and NIDA. NIDA is also legally bound to follow the United States Department of Health and Human Services policy regarding protection of human subjects.

Q24. Has there ever been a breach of confidentiality by the NCGS?

A24. No. There has never been a breach of identity of research participants in over 20,000 samples for all projects collected as of Jan 1, 2005.

Data Sharing FAQs

Q25. Are data sharing plans expected for all human genetic studies of addiction funded by NIDA - CTN? (If I am not approved for membership, am I still required to comply to the sharing policies outlined in this FAQ)?

A25. Yes. These sharing plans must describe how data and resources generated by NIDA-funded research will be made available to other qualified individuals in a timely manner. If membership is not approved, NIDA will help guide the investigator to other potential resources or ways in which compliance to NIDA sharing policies can be maintained.

Q26. Are there any special expectations about data sharing for other human genetic studies of addiction vulnerability such as twin studies and adoption studies that try to characterize traits or phenotypes that are heritable?

A26. No. However, in the spirit of NIH policy on sharing data (NOT-OD-02-035) and sharing research resources (Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999: http://ott.od.nih.gov/NewPages/Rtguide_final.html) data generated by public funds should be made available in a timely manner.

Q27. What is an appropriate data sharing plan for a CTN genetics study?

A27. An appropriate data sharing plan includes all elements of the NGC Model Data Sharing Plan. *

NIDA Genetics Consortium Model Data Sharing Plan

1. Whole blood samples from each subject will be sent to the NIDA Center for Genetic Studies (NCGS), which will extract DNA and plasma and cryopreserve the lymphocytes. If the lymphocyte cell count is low, the NCGS will attempt to create a cell line immediately.
2. The NCGS will distribute DNA and plasma only to the principal investigator until the materials are available for sharing. If the principal investigator pays for and receives a copy of a cell line, they may prepare and distribute DNA from these cell lines for himself/herself and his/her collaborators. However, resolving any discrepancies associated with DNA samples that were not prepared by the NCGS will be the responsibility of the principal investigator and at the principal investigator's expense.
3. The data provided for each subject will be:
   1. Subject ID #
   2. Family ID #
   3. Site ID #
   4. Parental ID #s
   5. Sex
   6. Death status
   7. Ethnicity or geographic origin of ancestry
   8. Age and/or year of birth
   9. Twin status
   10. DSM-IIIR diagnoses
   11. DSM-IV diagnoses
   12. Instrument used to establish diagnoses
   13. Answers to all of the questions in the structured interview or, minimally, the answers to those questions from which the addiction diagnoses were established.
   14. Other descriptive information collected about the drug abuse/addiction phenotypes, such as age of onset, quantity and frequency of peak lifetime use of addictive substances, etc.
   15. Genotyping data, including the DNA marker names, description of SNPs (single nucleotide polymorphisms) or allele sizes in base pairs and corresponding frequencies, and relative map distances.
4. Data will be verified and regular updates will be provided to the NCGS throughout the project.
5. Verified genotyping data will be submitted to the NCGS at the time that the data will be made available for sharing.
6. The approved informed consent(s) for this study are consistent with this sharing plan. Annual updates and modifications will be sent as approved by the IRB.
7. A statement in the data sharing plan acknowledging that the PI has read and agrees to the term set forth in the FAQ documents.
8. A statement describing a timetable specifying when various elements of the database (e.g., diagnostic assessments or genetic data) and DNA will be available for distribution. In general, 18 months after the termination of the grant period, including extensions, or immediately upon first publication of the data, whichever comes first, the NCGS will distribute DNA and data to qualified investigators who have been approved by the NIDA Genetic Data Access Request Committee [FAQs about the NCGS] and who have signed the Distribution Agreement.
9. The NCGS will not provide pedigree structures online; instead, a printed copy of the pedigrees will be sent to approved investigators at the time that the investigator is given access to the materials and database.
10. The PI will participate in NGC meetings, which are held 2 times per year. Cost for travel to the NGC is included in the PI's grant award.
11. Most services of the NCGS shall be free to investigators belonging to the NGC. Services include providing the mailers and tubes needed to ship the blood to the Repository. The NCGS also provides access to all databases containing clinical information so that biological materials (DNA) can be widely searched or distributed to qualified investigators in the scientific community. A nominal fee may be required depending on membership status and materials requested. For information about the fee structure, see FAQs about the NCGS.

• Minor modifications will be considered by your program official and the NGC Steering Committee.

Q28. Do these expectations about the dissemination of data and biological materials apply to all applications studying molecular genetics of addiction in humans?

A28. Yes. These expectations about dissemination of data and biological materials apply to all NIDA-funded research on the molecular genetics of addiction in humans.

Q29. Does NIDA need to approve my consent form?

A29. Yes. NIDA requires that your consent form be approved prior to submitting it to the local IRB.

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