Reality vs Urban Myth: The Truth About Regulations HRPP 201 March 2009 Reality vs Urban Myth: The Truth About Regulations Marisue Cody, PhD Deputy Director, PRIDE Reality vs. Urban Myth

Objectives Understand the variety of regulations and other requirements under which the HRPP operates Analyze complex problems when more than one set of requirements apply

Authority & Responsibilities HRPP 201 March 2009 Authority & Responsibilities United States Code (U.S.C.) Code of Federal Regulations (CFR) Directives Handbooks Manuals Memorandums Professional standards Reality vs. Urban Myth

U.S. Codes (law) 5 – Government organization & employees 21 – Food and drugs 38 – Veteran’s benefits 41 – Public contracts 42 – Public health & welfare

Code of Federal Regulations 5 – Administrative personnel 21 – Food & drugs 38 – Pensions, bonuses, & Veterans’ relief 41 – Public contracts & property management 45 – Public welfare 48 – Federal acquisition regulations system

VA Policy & Requirements Brochures - Informational material mass-produced for patients and staff Directives - establish mandatory VHA policies Handbooks - prescribe mandatory VHA procedures and/ or operational requirements Manuals - also prescribe mandatory VHA procedures or operational requirements (older documents not yet replaced by Handbooks) Memorandums - establish mandatory VHA policies which apply within VHA Central Office Information Letters - release nondirective information of one-time interest or short duration; i.e., applications for training opportunities, describing new programs, announcing meetings, reminders etc. Notices - provide significant information of interest VHA-wide Program Guides - contain non-mandatory and non-directive procedures for development of a program VHA Record Control Schedule (RCS 10-1) - provides disposal authorities for VHA general and administrative records and program records.

VA-wide policies Information security Directive 6500 Handbook 6500

VHA Temporary Directives 2008-014 - AUDITING OF VHA HUMAN SUBJECTS RESEARCH TO DETERMINE COMPLIANCE WITH APPLICABLE LAWS, REGULATIONS, AND POLICIES 2007-044 - USE OF A COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 2007-040 - APPOINTMENT OF FACILITY INFORMATION SECURITY OFFICER (ISO) AND PRIVACY OFFICER TO THE INSTITUTIONAL REVIEW BOARD (IRB) OR THE RESEARCH AND DEVELOPMENT (R&D) COMMITTEE

VHA Directives 1058 - RESPONSIBILITIES OF THE OFFICE OF RESEARCH OVERSIGHT 1200 - VETERANS HEALTH ADMINISTRATION RESEARCH AND DEVELOPMENT 1201 - OVERVIEW OF VHA RESEARCH PROGRAMS 1605 - VHA PRIVACY PROGRAM

VHA Handbooks - ORO 1058.03 - ASSURANCE OF PROTECTION FOR HUMAN SUBJECTS IN RESEARCH 1058.04 - DEBARMENTS AND SUSPENSIONS BASED ON RESEARCH IMPROPRIETY IN VA RESEARCH 1058.1 - REPORTING ADVERSE EVENTS IN RESEARCH TO THE OFFICE OF RESEARCH OVERSIGHT 1058.2 - RESEARCH MISCONDUCT

VHA Handbooks - ORD 1200.05 - REQUIREMENTS FOR THE PROTECTION OF HUMAN SUBJECTS IN RESEARCH 1200.06 - CONTROL OF HAZARDOUS AGENTS IN VA RESEARCH LABORATORIES 1200.1 - THE RESEARCH AND DEVELOPMENT (R&D) COMMITTEE HANDBOOK 1200.18 - INTELLECTUAL PROPERTY

VHA Handbooks - Privacy 1605.1 - PRIVACY AND RELEASE OF INFORMATION 1605.2 - MINIMUM NECESSARY STANDARD FOR PROTECTED HEALTH INFORMATION

VHA Handbooks – others…. 1004.1 - VHA INFORMED CONSENT FOR CLINICAL TREATMENTS AND PROCEDURES 1050.1 - VHA NATIONAL PATIENT SAFETY IMPROVEMENT HANDBOOK 1108.04 - INVESTIGATIONAL DRUGS AND SUPPLIES 1907.01 - HEALTH INFORMATION MANAGEMENT AND HEALTH RECORDS

Examples

Conflict of Interest Case An investigator asks you whether he needs to disclose that Lilly has invited him to speak at a seminar they are conducting. The honorarium is under the $10,000 limit. He will be speaking about the outcomes of the clinical trial he has been a lead investigator on. What would you do?

Conflict of Interest 18 USC §11.208 – Bribery, graft, and conflicts of interest 5 CFR §2635 – Standards of ethical conduct for employees of the executive branch 48 CFR §9.500-9.508 – Federal acquisition regulation (institutional COI) Memorandum Sept 23, 2005 – Financial conflicts of interest VHA Handbook 1200.13 – Financial conflicts of interest in research (rescinded). Also mentioned in 1200.05 and 1200.1

HRPP 201 March 2009 Failure to report SAEs A recent OIG report cited a PI and the facility for failure to report SAEs as required by VA policy. The study in question was a longitudinal, observational study of veterans with prostate cancer. There were 105 deaths that were not disclosed AND “it was unlikely that study participation contributed in any way to their deaths.” Why is this a problem? Our review of the records of 105 deceased veterans and the source documents for Protocols A, B, C, and D revealed that the PI for these protocols failed to disclose all adverse events to the IRB. Annual continuing review forms submitted to the IRB require the PI to report the number of deaths occurring from the time of subject enrollment in the study to the time of study closure, whether or not those deaths are related to study interventions. For those studies which involve long-term follow-up, the investigator is required to report any death to the IRB within 60 days of becoming aware that such a death occurred. Our review of the 105 deceased veterans disclosed that 21 of them had no electronic medical record. Of the remaining 84 patients, compensation and pension record interchange (CAPRI) records contained verification of death of 75 patients. Fifteen of these 75 patients had a cause of death documented in the medical record. None of these 15 patient deaths appeared to be related to study interventions. While we do not know the cause of death in the remaining 60 patients, the nature of the study interventions would make it unlikely that study participation contributed in any way to their deaths. Nevertheless, continuing review forms submitted by the PI to the affiliate IRB disclosed 0 deaths in response to the question of how many patients died between the time of enrollment in the study protocol until the time of study disclosure. Despite an April 2006 recommendation by the VA RCO to report these deaths, when we conducted this review in October 2007, none of the 75 verified deaths had been reported. We therefore found that the PI failed to report adverse events as required by VHA policy, and the IRB failed to take action to ensure compliance with this requirement. Reality vs. Urban Myth

Unanticipated Problems and Adverse Events 38 CFR 16.103(b)(5) 21 CFR 56.108(b)(1); 21 CFR 312.32; 21 CFR 812.150(a)(1); 21 CFR 812.3(s) VHA Handbook 1200.05 VHA Handbook 1058.1 VHA Handbook 1050.1 OHRP Guidance on reviewing and reporting unanticipated problems involving risks to subjects or others and adverse events, Jan 15, 2007 Memorandum, Reporting UPRs and AEs to IRBs, Dec 6, 2006

How do you consent a blind person? We have an investigator who wishes to consent a legally blind participant for a study and they did not present this possibility to the IRB when the study was originally approved.  Questions: Can they have a witness to the process (not associated with the study) who also reads the informed consent document orally to the subject before it is presented to them by the investigator? Do they need statements added to the usual statements similar to the following: <Name of witness>, who is not associated with the study, has read the informed consent document to me and was present when <name of investigator> presented the study to me.  (subject would sign) Witness to Informed Consent Process –  I have read the informed consent document to <name of subject> and was present for the oral presentation by the investigator.  If they do this, do they need to have IRB approval for this change in the normal process before consenting the subject?  If so, can it be expedited?

Informed Consent 38 CFR 16.116 & .117; 45 CFR 16.116 & .117; 21 CFR 50.20-27 38 CFR 17.32 VHA Handbook 1200.05 VHA Handbook 1004.1 VHA Handbook 1907.01 VHA Handbook 1605.1 OHRP guidance State laws

Administration of drugs legally marketed by a foreign country A patient suffers from Hansen’s disease (leprosy). He is unable to tolerate any of the U.S. legally marketed drugs for the treatment of his disease because of life-threatening side effects. His disease has progressed to where he is suffering from paralysis of fingers and toes. The patient has been taking a drug marketed in Europe for 13 months which has slowed the progression of his paralysis. The drug is not marketed in the United States. The patient has been admitted to the VAMC with pneumonia. Both he and his wife beg his admitting physician to allow him to continue taking the only drug that has been effective for the treatment of his illness. The drug has been brought to the VAMC by the patient. Question: Can this drug be given to the patient?

Studies involving drugs 21 CFR 11, 50, 54, 56, 312 Good Clinical Practice VHA Handbook 1200.05 VHA Handbook 1108.04

QUESTIONS