Investigator Responsibilities for Research

Investigator Responsibilities for Research Shannon Simmons, BA, CIP March 14, 2014 Process Improvement Team Vanderbilt Human Research Protections Program

Agenda • Review Investigator Responsibilities • Discuss FDA Warning letters • Q & A

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!

FDA Warning Letter L. Diaz, MD– November 4, 2011 • Failure to conduct or adequately supervise the clinical investigations • Delegated responsibilities, but lacked oversight of the study activities • Failure to ensure that the investigation was conducted according to the investigational plan • Included individuals in the study that should have been excluded; not following procedures for classifying AE’s and reporting SAE’s, etc • Failure to return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug. Response from Investigator regarding concerns: • 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

FDA Warning Letter L. Diaz, MD– November 4, 2011(cont).. FDA response to investigator: • It is 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 the PI is still required to submit in writing the actions that has taken to prevent similar violations in the future (required in 15 working days) 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."

FDA Warning Letter A. Ubani, MD,– November 21, 2013 • Failed to ensure that the investigation was conducted according to the investigational plan. • Protocol requires that subjects are excluded that have a history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last five years. • Two subjects enrolled with history of cancer within the five year exclusion criteria • Protocol requires all subjects that are enrolled to have “high cardiovascular risk” as defined by the inclusion criteria. • Subjects were enrolled who did not fit the definition of being at “high cardiovascular risk” as defined by the inclusion criteria in the study protocol. Response from Investigator regarding concerns: • subjects will be screened only after all medical records have been received and reviewed against protocol inclusion and exclusion criteria. FDA response to investigator: • This response is inadequate because there are no details regarding how the corrective actions will be implemented. • There are no details regarding how it will be ensured that medical records are received prior to randomization, and how the PI and the staff will review those records against protocol inclusion and exclusion criteria. • Without these details, it cannot be determined whether the corrective actions appear sufficient to prevent similar violations from occurring in the future.

FDA Warning Letter - continued A. Ubani, MD,– November 21, 2013 • Failed to maintain adequate and 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 • required to prepare and maintain adequate and 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. • Inconsistencies in regards to when lab results were received for visits versus when signature was given by the PI. Date signed off on the lab results were before the date stated that the lab reports were actually received. Response from Investigator regarding concerns: • Laboratory reports will be promptly revised and documented in a timely manner FDA response to investigator: • This response is inadequate response is inadequate because it is unclear what you intend to do with respect to revising laboratory reports. • Failure to maintain adequate and accurate case histories with respect to signature dates raises concerns about the validity and integrity of data captured at your site.

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 approvalaccording to IRB policies and procedures prior to conducting human subjects research.

General Responsibilities of Investigators • D. The Investigator will complete the required IRB training through the University of Miami Collaborative IRB Training Initiative (CITI). Access to training is available on the VHRPP Website at http://www. vanderbilt.edu/irb/ on the right hand side of the webpage under “Links” • E. The Investigator will assure that all key study personnel (KSP) have completed the required Human Subjects trainingprior 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 the VHRPP policy. • Key study personnel is anyone who will have a significant involvement in the planning, conducting, and analysis of any activity that will involve human research participants • F. 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.

General Responsibilities of Investigators • G. The Investigator will assure that required approvals from other university committees or institutions are grantedprior to beginning research activities. • H. 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 VHRPP Procedure XI.B.1 for proper procedure). • I. The Investigator will disseminate new information regarding the use of FDA agents in research to participants as he/she becomes aware.

Training • Investigator Responsibility- To complete initial and annual VU IRB human research protections training. • Initial training involves the completion of one of two “Basic” courses in CITI: “Group 1: Biomedical Research Investigators and Key Study Personnel” Or “Group 2: Social Behavioral Research Investigators and Key Study Personnel” • Annual Renewal of IRB Education/Training requires documentation of the completion of at least one of the following: • Completion of a CITI Course • Attendance of at least one IRB educational course(e.g., IRB Essentials, IRB News you Can Use, and/or Research Matters); or • Completion of the OHRP “Investigator 101” training module; or • Attendance of a local, regional, and national conference regarding human research protections

Training • Investigator’s Responsibility- To provide training regarding the study (i.e. site initiation visit) and the training for the responsibilities that are delegated. • Investigator’s Responsibility- To assure that other Investigators and KSP are adequately trained in human research protections and have met continuing education requirements as well as specific study training.

Training • The Investigator is also responsible for ensuring that all individuals conducting the research are adequately qualified and licensed to perform the research related procedures.

FDA Warning Letter B. Doft, M.D., –June 12, 2013 (Second Time around) Failure to ensure that the investigation was conducted according to the investigational plan. • Required the subject to have a Best Corrected Visual Acuity (BCVA), using Early Treatment Diabetic Retinopathy Study (EDTRS) charts, of 20/40−20/320. Two subjects who did not meet this inclusion criterion were included in the study. • Protocol stated that the "Best corrected visual acuity (BCVA) will be measured by trained and certified personnel at the study sites". BCVA was measured by uncertified personnel in 5 subjects in 14 instances. • VA examiner will be masked to the patients' study eye and will conduct refraction, VA assessments, and low luminance testing . . . No other direct patient care tasks can be performed by the VA examiner". The VA examiners measured the intraocular pressure (IOP), without being masked to the study eye, in nine subjects Response from FDA: • Enrollment of subjects who do not meet eligibility criteria and failure to ensure that certified and properly masked evaluators measured VA raise concern about the validity and integrity of the data collected at the site.

FDA Warning Letter B. Doft, M.D- Cont (Second Time Around) Failure to obtain informed consent • Two subjects underwent study procedures (i.e., BCVA, IOP, ocular imaging, fluorescein angiograms, optical coherence tomography, eye dilation, or the collection of laboratory examples) prior to signing the informed consent form. • A subject underwent screening procedures prior to signing the consent form on the same day. Additionally, the same subject could not read the informed consent form, because the form was provided after the subject’s eyes were dilated. Response from FDA: • Failure to obtain informed consent in accordance with 21 CFR Part 50 prior to involving subjects in research raises concerns about the protection of study subjects enrolled at the site.

FDA Warning Letter H. Frazer, Pharm D, Clinical Investigator– June 5, 2013 Failed to prepare and maintain adequate and 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 • Study protocol required that patient enter pain assessments into the LogPad, however, five pain assessments were entered by the study coordinator and reflect the study coordinator’s or nursing staff’s assessments, rather than the subject’s assessments. Response from Investigator regarding concerns: • Subject was put on a “vent” (ventilator), was sedated, and was unable to participate in the evaluation of pain, via the LogPad or otherwise • Indicated that the study coordinator entered data directly into the LogPads, based on information received either from the nursing staff or from study subjects. Indicated that the study coordinator entered pain scores “based on the staff nurses educated guess as to the pain level when the patient was obviously in pain as evidence of the patient’s tossing and painful expressions on the patient’s face. • Stated that “at times when the patient was either unwilling to complete the pain score or too disoriented to write into the diary or use the LogPad, [the study coordinator] asked the patient what her pain score was and entered that value onto the diary and added the patient’s initials. • Indicated that once made aware of this practice, the site had already enrolled 8 subjects into the study, and all of them had completed the trial. The monitors also challenged the validity of the pain data. FDA response to Investigator: • This response was inadequate it did not provide information that would mitigate the violation’s significant impact on data integrity, reliability, and validity • Failed to provide a corrective action plan.

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) or University Conflicts Committee (UCC). • 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). • Investigators must comply with all recommendations of the MCCOIC and/or the UCC to minimize the conflict.

Conflict of Interest • New NIH COI reporting requirements compliance date for institutions became effective by 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.

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

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

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. If the Sponsor holds the IND the IRB will accept the IND number pre-printed in the Sponsor’s protocol as verification that the Sponsor has completed filing with the FDA. • When an IND is required 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.

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). • The research will not start until the IDE letter from the FDA has been submitted to the IRB.

Supplemental Form for Devices • 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. • The 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.

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.

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 VHRPP P&P’s, and the institution’s Federal Wide Assurance.

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. • This requires monitoring and/or internal auditing of your studies.

FDA Warning Letter February14, 2012 J. Louis G., M.D • Failure to conduct the investigation according to the signed agreement, the investigational plan, applicable FDA regulations, and any conditions of approval imposed by an Institutional Review Board (IRB) or FDA • Implanted with the control article on the incorrect cervical spine level then performed a second surgery to remove and then reinsert on the correct disc level without that procedure being authorized in the protocol. FDA Response to Investigator: • Major safety concern because it placed additional risks of serious harm due to the need for a second surgery only four days after the first. These risks include infection, bleeding, risks associated with anesthesia, and neurological damage including paralysis and death. • The subject was placed at increased risk of developing long-term complications such as worsening pain and disability as a result of the critical error made.

FDA Warning Letter February14, 2012 J. Louis G., M.D-cont • Failure to maintain accurate, complete, and current records of each subject’s case history • Failure to report adverse events that were a direct result of the implanted device. • Note to file states pain in cervical area-event not recorded in Case report Form • Note to file pain in shoulder-event not documented in Case report Form • Physician note signed by investigator and the subject’s medical monitor report of persistent hand and forearm numbness noted to be related to device-no documentation to show this event was noted as a SAE in the Case Report Form FDA response to Investigator: • Inconsistency and inaccurate records of AEs and SAEs are major subject safety and data quality concerns. • Discrepancies in reporting AEs may call into question the integrity and reliability of the data obtained during the course of the study and increase the risk of harm to the participating subjects.

FDA Warning Letter February14, 2012 J. Louis G., M.D-cont • Failure to ensure that an investigation is conducted in accordance with the signed agreement, investigational plan, applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA and failure to submit progress reports on the investigation to the sponsor and reviewing IRB at regular intervals • Continual submission of IRB continuing reviews and progress reports late. FDA response to Investigator: • Failure to adhere to these requirements may increase the risk of harm to the participating subjects.

Adherence to the Protocol • If you agreed to participate in conducting the study you agree to follow the protocol completely. • Sites may have different standards of practice however if you agree to participate in the study you MUST follow the protocol. • 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.

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 • Appropriate for vulnerable population circumstances • Answer questions • Verbalizes Understanding

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 • http://www.ClinicalTrials.gov (FDA regulated studies) 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

Informed Consent • FDA Regulated Studies: • For all research involving test articles regulated by the U.S. Food and Drug Administration (FDA), informed consent documents should include a statement that a purpose of the study includes an evaluation of the safety of the test article. • Statements that test articles are safe or statements that the safety has been established in other studies are not appropriate when the purpose of the study includes determination of safety. • In studies that also evaluate the effectiveness of the test article, informed consent documents should include that purpose, but should not contain claims of effectiveness.

Documentation of Consent: • 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.

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.

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.

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.

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 cannot occurafter the expiration of IRB approval. • If a study expires, the Investigator will cease all research activities as instructed in the expiration notice.

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).

IRB Definition (Policy III.L) • Unanticipated Problems Involving Risk to Participants or Others Any serious adverse event that in the Investigator’s opinion: • Was unanticipated (not foreseeable at the time of the occurrence) or unexpected (not previously seen), AND • Involved risk to participants or others AND AND/OR • Any noncompliance with the IRB approved protocol that increased the risk or affected the patients rights, safety or welfare. Should be reported to the IRB

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.

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. • The IRB should to be notified of any noncompliance with the study protocol that results in an increase in risk or a decrease in potential benefit to participants within 10 business days of the Investigator being notified of the deviation.

Clinical investigators are in charge and held accountable • Penalties for significant noncompliance • Warning Letters (posted on FDA website) • Disqualifications/Restrictions/Debarments in conduction FDA regulated research (posted on FDA website) • Criminal prosecutions/prison/fines

Complaints • It is the responsibility of the Investigator to notify the IRB 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.

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

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).

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Conclusion Being the PI of a research study is a huge undertaking that requires attention to detail and a tremendous amount of communication and documentation involving the study team, participants, the IRB, as well as other departments and agencies. Thank you for everything you do to ensure the rights, welfare and safety of the research participants we serve are protected.

Questions

Questions? Comments? Concerns? • For future questions you may contact Shannon Simmons 875-4628 shannon.d.simmons@vanderbilt.edu

Investigator Responsibilities for Research