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  1. Investigator Responsibilities for Research Jan Zolkower, MSHL, CIP, CCRP January 13, 2012

  2. Agenda • Review Investigator Responsibilities • Discuss recent FDA Warning letters and OHRP Determination letters • Review of Advanced Notice of Proposed Rulemaking (ANPRM) • Q & A

  3. PI Responsibilities • In a nutshell, the PI is responsible for: • Human Subject Protection • Training • Conflict of Interest • IRB Approval • IND/IDE • Study Conduct • Informed Consent • Amendments • Continuing Review • Data Safety Monitoring • Adverse Events • Complaints • Record Retention In other words…EVERYTHING!

  4. FDA Warning Letter L. Diaz, MD, Infectious Disease Associates of the Palm Beaches – November 4, 2011 1) Failure to conduct or adequately supervise the clinical investigations 2) Failure to ensure that the investigation was conducted according to the investigational plan 3) Failure to return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug

  5. FDA Warning Letter - continued The PI’s written affidavit stated: • Admission that he had a lack of involvement and oversight in the conduct of the two clinical trials being cited • He found letters from monitors, sponsors, and IRB’s that he had never opened and/or had never seen before (letters that noted the study had been suspended/terminated for failure to submit the continue review reports) • Adverse events were not evaluated/graded per protocol • Admission that he had ignored the clinical trials • Study documentation ended after his SC left in 2007 • He had no knowledge of how the studies were monitored

  6. FDA Warning Letter - continued The warning letter notes: • It was the PI’s responsibility to ensure the studies were conducted properly and in compliance with FDA regulation in order to protect the rights, safety, and welfare of human subjects • The PI’s statements indicate systemic failure in the conduct of investigational research and there are significant concerns about the safety of the subjects enrolled in the study and the integrity of the data from the site • Despite the PI’s statement he will not conduct FDA-related clinical trials in the future he is still required to submit in writing the actions he has taken to prevent similar violations in the future (required in 15 working days)

  7. FDA Warning Letter - continued The FDA letter included the following statement: “Failure to adequately and promptly explain the violations noted above may result in regulatory action without further notice."

  8. General Responsibilities of Investigators (VI.B.1) • Subject: Procedure for General Responsibilities of InvestigatorsProcedure:This procedure outlines the general responsibilities of Investigators conducting research involving humans. I. Investigator Responsibilities. • A. The Investigator will obtain knowledge regarding federal, state, and local laws and regulations, institutional policies, IRB policies and procedures, the ethical principles of The Belmont Report, and Good Clinical Practice (GCP) Guidelines, if applicable, prior to conducting research involving humans. • B. The Investigator will assure protection of the participant’s rights and safety by adequate design and conduct of research, as well as oversight of all research processes and procedures and other research personnel involved in research activities. • C. The Investigator will apply for IRB review and approval according to IRB policies and procedures prior to conducting human subjects research.

  9. General Responsibilities of Investigators • D. The Investigator will complete the required IRB training through the University of Miami Collaborative IRB Training Initiative (CITI). Instructions and access to training is available on the IRB Website at in the left column under “Education and Training” and “VU Human Subjects Training Program.” The Investigator will assure that all key study personnel (KSP) have completed the required IRB training prior to IRB submission of research applications. In addition, the Investigator will participate and assure that all KSP participate in continuing education at least annually as required by IRB policy. • E. The Investigator will respond to all IRB requests for additional information in regards to verifying knowledge, training, and resources adequate to perform research involving human participants.

  10. General Responsibilities of Investigators • F. The Investigator will assure that required approvals from other university committees or institutions are granted prior to beginning research activities. • G. The Investigator will assure the proper handling, storage, and dispensing of all investigational agents and when not using the services of the Investigational Drug Service (See IRB Procedure XI.B.1 for proper procedure). • H. The Investigator will disseminate new information regarding the use of FDA agents in research to participants as he/she becomes aware.

  11. Training • PI must complete initial and annual VU IRB human research protections training. • It is also the responsibility of the PI to assure that other Investigators and key study personnel who are responsible for the design and conduct of the research are adequately trained in human research protections and completion of continuing education requirements.

  12. Training • The PI is also responsible for ensuring that all individuals conducting the research are adequately qualified and licensed to perform the research related procedures. • In 2008, the VU IRB sent a letter to Investigators after OHRP sent a determination letter to an IRB and PI citing them for “failing to meet 45 CFR 46.111(a)(1),” which states that risks to subjects are minimized.

  13. FDA Warning Letter M. Thurmond-Anderle, MD – February 25, 2011 Failed to conduct the studies or ensure they were conducted according to the investigational plan, and to protect the rights, safety, and welfare of subjects. The protocol required a pharmacist or appropriately qualified person prepare and provide the infusion bags containing the study medication or placebo. Our investigation revealed that your office manager, who is not a pharmacist and does not appear to be appropriately qualified to prepare infusion bags, inaccurately prepared the study drug or placebo for infusion at approximately one-tenth of the protocol-specified dose.

  14. Conflict of Interest • All conflicts of interest (PI and KSP) must be disclosed to the IRB and the Medical Center Conflict of Interest Committee (MCCOIC). • Disclosures must be provided with the initial IRB application, at each continuing review and within 10 days of becoming aware of any previously undisclosed financial interest (via a Request for Amendment).

  15. Conflict of Interest • New NIH COI reporting requirements become effective on September 26, 2011; however, the compliance date for institutions applying for or receiving PHS funding from a grant, cooperative agreement, or contract must be in full compliance no later than August 24, 2012. • Changes include: • Reducing the minimum payment researchers will be required to report (from $10,000 to $5,000). • Each Investigator must complete financial conflict of interest training prior to engaging in research related to any PHS-funded grant or contract and at least every four years.

  16. Types of IRB Determinations • Non-Research • Research = systematic investigation designed to develop or contribute to generalizable knowledge. • Case studies • Quality assurance projects • Non-Human Subjects • Human subject = a living individual about whom an Investigator obtains data either through intervention or interaction with the individual or identifiable private information. • De-identified specimens from a repository • BioVU

  17. Types of IRB Determinations • Exempt – 6 categories • Educational tests, surveys, interviews, observations of public behavior • Collection or study of existing data • Expedited – 9 categories; minimal risk • Research on individual or group characteristics • Collection of data from voice, video, or image recordings • Blood draws – 550ml/8wks; < 2 draws/wk or 50cc (3cc/kg) • Standard – greater than minimal risk • Pharmaceutical/drug studies • Device studies • Intervention studies

  18. Investigational Drugs • When the PI holds the IND for the investigational agent, a copy of the FDA acknowledgement letter is required as part of the IRB submission. • The PI will complete the Form 1572 (Investigator Statement, which assures the PI will comply with FDA regulations related to the conduct of an investigation using an investigational drug or biologic) and submit it to the FDA or Sponsor and provide a copy to the IRB.

  19. Form #1135 • The PI must also submit IRB Form #1135, Supplemental Form for Investigator Held IND(s) to the IRB with their submission. • Notes the Sponsor-Investigator is responsible for implementing and maintaining quality assurance and quality control systems with written SOP’s. • States criteria PI will use to select qualified investigators. • Asks who will be the qualified medical personnel who will be available to advise on trial-related medical questions or problems.

  20. Investigational Devices • When an IDE is required, the Investigator will complete the FDA’s Investigator’s Agreement form for submission to the FDA. A copy of this form must be submitted with the initial IRB application. • The initial IRB submission should also include all correspondence from the sponsor and/or FDA in regards to the determination of the device as being a non-significant (NSR) or a significant risk device (SR).

  21. Form #1134 • The IRB is required to document the basis for risk determination based on the proposed use of a device in the research by considering the nature of the harm that may result from the use of the device. • Form #1134 requests information about the device, if it meets any of the exemption categories, if another IRB has made a determination about the device, as well as if any special training is needed to use the device and accountability information.

  22. Study Conduct • Investigators responsibilities during the conduct of an approved research study include: • Obtaining and documenting informed consent of subjects or subjects’ legally authorized representative PRIOR TO the subjects’ participation in the research unless the IRB has approved a waiver of consent.

  23. Study Conduct • Obtaining prior approval from the IRB for any modifications of the previously approved research, except those necessary to eliminate apparent immediate hazards to the subject(s). • Ensuring progress reports and request for continuing review and approval are submitted to the IRB in accordance with IRB P&P’s, and the institution’s Federal Wide Assurance.

  24. Study Conduct • Providing to the IRB prompt reports of any unanticipated problems involving risks to subjects or others. • Providing to the IRB prompt reports of serious or continuing noncompliance with the regulations or the requirements or determinations of the IRB.

  25. FDA Warning Letter September 29, 2010 L. Snow, MD • 1. Failure to conduct the investigation according to the signed investigator statement – failed to personally conduct or supervise the clinical investigation. “We note that your failure to adequately supervise this study led to the significant problems identified below with the conduct of the study.” • 2. Failure to maintain adequate accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation – FDA investigators were unable to determine the total morphine dose administered to subjects due to the discrepancies and inaccuracies in the hospital records and case report forms. • 3. Failure to ensure that the investigation was conducted according to the investigational plan – AE’s not reported, blinding not maintained, and study required procedures were not completed.

  26. FDA Warning Letter August 12, 2011 Yale Cohen, MD • 1. Failed to ensure the investigation was conducted according to the investigational plan – several instances in which AEs and/or SAEs identified in either clinic visits or hospital records were not documented in case report forms. • 2. Failed to prepare and maintain adequate and accurate case histories on each individual administered the investigational drug or employed as a control in the investigation – no documentation the PI ordered the study drug dose to be maintained, withheld or adjusted, or that the PI confirmed the dosing decisions recorded by the study coordinator were in line with his orders. FDA states, “As a clinical investigator, you are responsible for properly documenting the dosing and administration of drugs dispensed during the course of this clinical trial…” • 3. Failed to obtain IRB approval before making changes in the research – did not receive IRB approval to use the mail and telephone for the re-consenting process of those actively participating in the clinical trial. The PI was previously cited for items 1 and 2 in 2008/2009.

  27. Informed Consent Process • Continuous process • The Investigator assures the informed consent process in research is an ongoing exchange of information between the research team and the study participants throughout the course of a research study. Informed consent is a continuous process of communication and acknowledgement over time, not just a signed document. • Free from coercion and undue influence • An Investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. • Documentation • Provide document for review • Questions • Verbalizes Understanding

  28. Elements of Informed Consent Required • Research (Purpose/Duration/Procedures) • Risks/discomforts • Benefits • Alternatives • Confidentiality • Whom to contact • Compensation/ treatment for research related injury • Right to refuse or withdraw • New required element for FDA – Additional • Unforeseen risks to subject (fetus) • Anticipated reasons for termination from the study by PI • Costs • Consequences of withdrawal by participant • New findings • Number of subjects

  29. Documentation: • Should be legible, factual and thorough. • Should include items such as when the person: was initially provided information about the study; was given a copy of the consent form; was contacted to determine interest; and signed the document. • Include details of special situations.

  30. Persons Who Cannot Read/Write • The informed consent dialogue is extremely important when the investigator is obtaining informed consent from a research subject who cannot read. • An impartial witness must be present during the initial informed consent conversation. • If the research subject wishes to enroll in the study the subject may consent orally and if able, may sign and date the consent form. • After the subject has consented the witness signs and dates the consent form to attest that: • The subject received the information, the risks/benefits/alternatives were discussed and informed consent was freely given.

  31. Who is an Impartial Witness? Someone who: • Does not have a financial, personal, academic or professional stake in the study. • Understands the language of the informed consent dialogue. • Is willing to observe the consent process and if necessary, ask questions of the research subject to gauge her/his understanding.

  32. Amendments • Any changes to the IRB approved research must be submitted, reviewed, and approved by the IRB PRIOR to implementation. • The only time the investigator may make a modification to research activities without prior IRB approval is to avoid an immediate hazard to the participant. The PI must report the event to the IRB within 10 working days. • The Request for Amendment form is no longer listed as a form on the IRB website. To create an amendment, log into DISCOVR-E and click the “Create Submission” button located on the upper right corner.

  33. Continuing Review • Continuing Reviews must occur at a frequency no less than 12 months but may be required more often. • Periodic review of research activity is necessary to determine: • If changes in risk/benefit have occurred; • If there are any unanticipated findings involving risks to subjects; and • If there is any new information regarding the risks and benefits that should be provided to participants.

  34. Continuing Review • There is no grace period extending the conduct of research beyond the expiration date of IRB approval. • Screening and enrollment of new subjects can not occur after the expiration of IRB approval. • If a study expires, the Investigator will cease all research activities as instructed in the expiration notice. The Investigator will immediately submit continuing review requirements or notify the IRB of study closure.

  35. FDA Warning Letter October 10, 2010 H. Lippton, MD • 1. Failure to assure that an IRB that complies with the requirements set forth in Part 56 was responsible for the initial review and approval of the protocol – IRB’s need to review accurate information. The PI stated since the last submission no KSP had been convicted or charged with a crime when in fact the PI entered a plea of “guilty,” was convicted of health care fraud, was sentenced to be imprisoned for 18 months and had his license to practice medicine in the state of Louisiana suspended for a period of two years. PI blamed study coordinator for inaccurate response. • 2. Failed to protect the rights, safety and welfare of the subjects under your care - failure to provide accurate information to the IRB so that it can fulfill its responsibilities with respect to protecting the rights, safety, and welfare of human subjects.

  36. FDA Warning Letter - Continued • The Research Site Submission Form that you signed and certified as accurate on April 2, 2009, provided false information to the (redacted) IRB about your 2002 conviction and medical license suspension. By failing to ensure that the Research Site Submission Form provided accurate information to the (redacted) IRB, you failed to protect the rights, safety, and welfare of the human subjects under your care, as required by 21CFR312.60.

  37. Data Safety Monitoring • The Investigator will provide a detailed description of the data safety monitoring plan (DSMP) in the initial application as well as the study protocol. This is required even in the absence of a DSM or DSMB. • All DSM or DSMB reports are to be submitted to the IRB within 10 days of receipt by the Investigator when the report identifies a new risk or a change in the risk-potential benefit profile. A “Request for Amendment” will accompany the reports along with the amended documents (e.g., consent document, IRB application).

  38. Adverse Events - OHRP • Unanticipated problems include any incident, experience, or outcome that meets all of the following criteria: • 1) unexpected (in terms of nature, severity, or frequency); • 2) related or possibly related to participation in the research; and • 3) suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized.

  39. Adverse Events - FDA • Unexpected Adverse Event • FDA defines this as any event where: • 1) the specificity or severity of which is not consistent with the current Investigator Brochure (IB); or • 2) if an IB is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application.

  40. Adverse Events - FDA • Serious Adverse Event • FDA defines a serious adverse event as an event that results in any of the following outcomes: • death; • a life-threatening adverse event; • inpatient hospitalization or prolongation of existing hospitalization; • a persistent or significant disability/incapacity; • a congenital anomaly/birth defect; or • requires intervention to prevent permanent impairment or damage.

  41. IRB Definition (Policy III.L) • Unanticipated Problems Involving Risk to Participants or Others • Any event that was: • 1) unanticipated; • 2) related; and • 3) places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized.

  42. OHRP Reporting • Example of Adverse Event FAL Language • The Committee has accepted the reported Adverse Event and determined that no changes to the protocol or consent form(s) are needed at this time. However, please note that this event requires reporting to the Office for Human Research Protections (OHRP) due to its categorization as a serious adverse event (SAE) per IRB Policy III.L. Reporting of Adverse Events, Serious Adverse Events and Unanticipated Problems Involving Risk to Participants or Others. This report is initiated by the Institutional Review Board (IRB) and, thus, requires no further action on your part at this time. You will receive a copy of this report for your records when it has been finalized.

  43. OHRP Reporting • The IRB letter will outline: • the nature of the event; • the findings of the organization and IRB; • actions taken by the organization or IRB; • reasons for the organization’s or IRB’s actions; and • plans for continued investigation or action.

  44. Non-Compliance • Non-Compliance with the Protocol • An incident involving non-adherence to the protocol, but • One that typically does not have a significant effect on the subjects’ rights, safety or welfare and/or on the integrity of the resultant data. • Non-compliance with the Protocol may result from the actions of the participant, investigator, or study personnel.

  45. Complaints • It is the responsibility of the Investigator to notify the HRPP of any participant or other individual’s complaints regarding the research. The complaint may be reported at continuing review if it involves no risk to the participants or others or does not change the risk/benefit ratio (e.g., a participant complains that he/she does not like the Investigator’s clinic hours and subsequently withdraws from the research).

  46. Complaints • Examples of complaints: • Have not received compensation • Have been billed for a research procedure • Upset with some aspect of the study • Wants results when the ICD stated they would not be shared • Information regarding study participation has not been sent as promised • Parking

  47. Record Retention • Retention of records as required by HHS regulations for at least three years after the completion of the study. • Retention of records as required by FDA when the study was conducted under an IND is a minimum of two years after the marketing application is approved for the drug for the indication for which it was being investigated. • All Health Insurance Portability and Accountability Act (HIPAA) related documentation must be maintained for at least six (6) years from the date of the last use or disclosure of the Protected Health Information (PHI).

  48. Advance Notice of Proposed Rulemaking (ANPRM)

  49. 2011 OHRP – Proposed Changes to the Common Rule • Advanced Notice of Proposed Rule Making (ANPRM) was published in the Federal Register on July 26, 2011. • Initial comment period was to close on September 26, 2011, but was extended to October 26, 2011. • Public comments will be used to develop revisions to the Common Rule.

  50. 2011 OHRP – Proposed Changes to the Common Rule • In brief, what aspects of the Common Rule is the government reexamining?The government has two overarching goals with respect to the revisions it is considering to  the Common Rule:  (1) to enhance the protection of research subjects and (2) to improve the efficiency of the review process.