1. Session 2 IRB Training  What is the Principal Investigator’s role in Human Subject Research?  What is the role of the Investigator’s staff in Human Subject Research?

2. Who is the Principal Investigator ? Federal regulation 21CFR 56.102 defines the investigator as the individual who actually conducts a clinical investigation (i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject) or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team.

3. Who Regulates Human Subject Research? Human Subject Research is regulated by Federal and State regulations and Lifespan policies.  The two federal bodies come under HHS and they are FDA (Food and Drug Administration) and OHRP (Office of Human Research Protection).  Any federally funded research falls under OHRP and devices and drugs fall under the jurisdiction of FDA as well as OHRP.  The State of RI Regulations can be located www.rules.state.ri.us under the Rules and Regulations for Licensing of Hospitals R23-17-16www.rules.state.ri.us  Lifespan Policies

4. Responsibility of the PI  Is to know and understand these regulations and policies prior to initiating any human research.  Acknowledge and accept their role to protect the rights and welfare of the research subjects by complying with all of the regulations.

5. So what is GCP and how does it fit in?  When a principal investigator receives a Human Subjects Protection Approval letter from the Lifespan IRB, they are notified that this institution and the investigator complies with ICH GCP guidelines as they correspond to the FDA/DHHS regulations.  Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conduction, recording and reporting trials that involve the participation of human subjects. Compliance with GCP standards:  provides public assurance that the rights, safety and well being of trial subjects are being protected  clinical trial data are credible.

6. So what are the PI Responsibilities according to GCP? _ The investigator’s responsibility according to ICH GCP guidelines: _ 4.1 Investigator qualifications and agreements _ 4.2 Adequate resources _ 4.3 Medical care of trial subjects _ 4.4 Communication with IRB _ 4.5 Compliance with the protocol _ 4.6 Investigational product _ 4.7 Randomization procedures and unblinding _ 4.8 Informed consent of trial subjects _ 4.9 Records and reports _ 4.10 Progress reports _ 4.11 Safety reporting _ 4.12 Premature termination or suspension of a trial _ 4.13 Final report by the investigator

7. 4.1 Investigator’s qualifications and agreements  Is the PI qualified by education, training and experience to assume the responsibility for the proper conduct of the trial? The IRB verifies this by requesting a copy of all CV and that they are updated every 2 yrs. FDA requires Form 1572  Is the PI well versed with the use of the investigative product? Are all the co-investigator’s trained?  Does the PI maintain a list of appropriately qualified persons and the significant trial duties they have been delegated?

8. 4.2 Adequate Resources  Has the PI been able to demonstrate a potential for recruiting the required number of suitable subjects within the recruitment period?  Is their adequate qualified staff and resources to conduct the trial properly and safely?  Have all persons assisting with the trial been adequately trained about the protocol? Their related duties and functions?

9. 4.3 Medical Care of Trial Subjects  Is there a qualified physician (PI or Co-PI) responsible for all trial related medical decisions?  During or following participation in a trial, the PI must ensure that adequate medical care is provided for any adverse event. The Investigator should inform a subject when medical care is needed for a concurrent illness.  GCP recommends that a PI inform the subjects primary physician about participating in the trial if the subject has no objections!  Does the PI make a reasonable effort to ascertain the reasons why a subject withdraws from the study?

10. 4.4 Communication with the IRB  Before starting any trial, does the PI have written approval from the IRB for the study? (Including written IC, recruitment procedures including advertisements and any other written materials to be given to the subjects)  Are all IB’s sent to the IRB whenever they are updated?  During the study trial, have all new documents been sent to the IRB for review?

11. 4.5 Compliance with the Protocol  Is the PI conducting the study according to the protocol that has been approved by the IRB?  If there is a deviation from the protocol, the sponsor and the IRB needs to be informed.  However, the PI may implement a deviation or change to eliminate an immediate hazard to the subject without prior approval, but ASAP must notify and submit all necessary forms to the IRB, sponsor and /or the regulatory authorities.  Has the PI or designee documented and explained any/all deviations from the protocol?

12. 4.6 Investigational Product  Is there an accountability receiving/dispensing log for all drugs or devices?  Is the Pharmacy performing this functions and maintaining the records?  If not, does the PI have the appropriate records that document delivery, inventory, who received each device/drug, return of the product and it’s disposal. Are the dates, quantities, batch/serial numbers, expiration dates of all doses recorded? How is it stored?  Do you have documentation that the correct use has been explained to each subject? Is there any documentation that you have checked at intervals to see if they are following the correct instructions?

13. 4.7 Randomization Procedures and Unblinding  Has the PI followed the trial’s randomization procedures outlined in the protocol?  If the code is broken (unblinded), did the PI promptly document and explain to the sponsor the circumstances surrounding the incident? (such as accidental, or due to a serious adverse event)

14. 4.8 Informed consent of trial subjects  Before beginning a trial, the PI needs an IRB approval of the Informed Consent to be used.  The regulations stipulate what needs to be in the informed consents.  Obtaining Informed Consent is a process not just the signing of the document and occurs throughout the subject’s participation in a trial.

15. 4.9 Records and Reports  Can the PI ensure the accuracy, completeness, legibility and timeliness of the data reported to the sponsor?  Can the data reported on CRF’s be verified by the source documents? Any discrepancies need to explained by a note to file.  CRF’s should be dated and signed by the person completing the forms and any changes or corrections need to be done correctly. A line through the entry and a date and initial next to the correction. The original entry can never be obliterated (i.e. no white out/crossing out completely)  Essential documents need to be retained until at least 2 years after the last approval of a marketing application and/or the discontinuance of clinical development. RI State Law requires 5 years!

16. So what are some of the other PI requirements? What is the HIPAA Authorizations for Research?  When the research involves the use or disclosure of PHI, unless otherwise noted, you are responsible for obtaining an authorization from prospective subjects.  Only copies of the signed, IRB approved research authorization, may be utilized during the period of time your research has IRB approval to enroll subjects.  All subjects must be given signed copies of the authorization.  Keep the originals in your secured research files and,  When appropriate, you should place copy of the authorization in the subject’s medical record.

17. What about required trainings?  Human Subject Protection (HSP) Training is required of investigator’s and the research personnel participating in the research study before an approval letter is granted. This includes all persons listed on the “abstract” as “key personnel”. Re-certification is required every 3 years.  Each PI must also sign a HIPAA Security Certificate annually.  HIPAA for Research is an annual requirement. Each department in Lifespan must provide this training to their employees.  The research department has provided a HIPAA module along with the HSP and GCP modules on the CITI training site which can be reached by logging onto the site at http://www.citiprogram.orghttp://www.citiprogram.org

18. What is the role of the Investigator’s staff in Human Subject Research? Any individuals working on a Human Subject Research Project falls under the supervision and direction of a PI and may be involved in some or all of the following:  Do you oversee the planning, scheduling, and implementation of day-to-day clinical activities and procedures?

19. Are you responsible for:  Planning or the carrying out the programs for:  Recruitment,  Screening and Enrollment  Do you instruct subjects on treatment methods and the protocol?

20. Or you might be involved with  Setting up and maintaining the data collection  Ensures that all clinical activities are carried out according to the protocol  Do you monitor and record patient response to treatment, and communicate the study data and results to investigators?

21. Are you the person who  Develops and/or coordinates the maintenance of records on medication dispensation and inventory usage during the course of the study  Administers prescribed study medications, performs phlebotomy, monitors vital signs, and/or performs other specialized nursing procedures, as appropriate to the specific needs of the study and individual subjects.  Ensures the confidentiality of subject records?

22. Thoughts for successful clinical trials  The safety and well-being of your study subjects always comes first.  The need to establish a good, collegial working relationship with your investigator, IRB, sponsor, monitors and the rest of the research community.  To know your protocols and CRF’s thoroughly.  Keep organized.  Read the Federal, State and Institutional regulations/policies.  Keep handy a copy of the GCP guidelines.  Don’t be afraid to admit you don’t know something…find out.  Contact me @ 444-5843 or email dtemple@lifespan.orgdtemple@lifespan.org