General Principles for Meeting Regulatory Responsibilities

General Principles for Meeting Regulatory Responsibilities
Terry VandenBosch, RN, PhD, CIP, CCRP Senior Research Compliance Associate Office of Human Research Compliance Review University of Michigan June 1, 2010

Today’s Discussion Describe Best Research Practices (BRP) and Good Clinical Practices (GCP) Compare GCP requirements for FDA regulated studies and regulatory requirements for non-FDA regulated studies Identify common sense principles for implementing best practices and GCP in clinical studies Primarily biomedical and health trials, however, some examples of behavioral or social science research to illustrate points

What is “Best Practice”
Experience-based Evidence-based? Effective and efficient practices to meet 1) ethical principles 2) federal regulations & guidance 4) state laws & practice acts 5) university policies and procedures 6) any applicable study SOPs Best Practices = Responsible Research Practices

Ultimate Goal: Responsible Research Practices
“The University of Michigan is committed to the highest standards of ethical behavior by faculty, staff, and students engaged in the conduct and administration of research and other scholarly activity.” UM Provost Policy Statement on Academic and Research Integrity

Ethical Principles & Best Practices
Ethical principles inform decision-making and basis for federal regulations and guidance Past abuses stimulate use of Best Practices Nuremburg Tuskegee syphilis study Willowbrook retarded children hepatitis study Are these ethical lapses and abuses all in the past? Nicole Wan (healthy volunteer- died), 1996 Jesse Gelsinger (ineligible-died), 1999 Ellen Roche (healthy volunteer-died), 2001 Inadequate monitoring with overdose of pediatric subjects-Pfizer FDA warning letter, April 9, 2010 1996 Nicole Wan (healthy volunteer, died) University cost: multi-million dollar lawsuit; Loss of funding Jessie Gelsinger (ineligible, died) When Jesse Gelsinger signed the informed consent form for the study, no one told him that four previous volunteers had experienced toxic side effects from the modified virus. in an animal tests of safety, two of the monkeys who were infected had died. The dose of virus he was getting was larger than that of any of the previous patients. This problem was confounded by this particular patient. Jesse Gelsinger had a far more extensive liver deficiency than any of the previously tested patients and was ineligible for participation in the study. Although Jesse Gelsinger had signed a sheet of paper, he had not given informed consent. He did not know about the risks identified in previous animal research. He did not know about risks identified in previous human volunteers. He did not know that his liver deficiency was worse than any of the previous seventeen research subjects. He did not know that dose that he was receiving was larger than that given to any previous subject. All federal funding cut off to entire University for several weeks; Restricted involvement of investigator in clinical research for more than 5 yrs 2001 Ellen Roche (healthy volunteer, died) All federal funding cut off to entire University for period of time Pfizer failed to properly monitor an investigational new drug trial — a repeat violation — which led to widespread overdosing of pediatric subjects, the FDA says. April 9, 2010 FDA Warning Letter

Ethical Principles-Belmont
Belmont Report – 1979 Summarized ethical principals identified by National Commission for the Protection of Human Subjects Prompted by the Tuskegee Syphilis Experiment and the Willowbrook hepatitis study 3 basic ethical principles: (1) Respect for persons (2) Beneficence (3) Justice For forty years between 1932 and 1972, the U.S. Public Health Service (PHS) conducted an experiment on 399 black men in the late stages of syphilis. These men, for the most part illiterate sharecroppers from one of the poorest counties in Alabama, were never told what disease they were suffering from or of its seriousness. Informed that they were being treated for “bad blood,” their doctors had no intention of curing them of syphilis at all. The data for the experiment was to be collected from autopsies of the men, and they were thus deliberately left to degenerate under the ravages of tertiary syphilis—which can include tumors, heart disease, paralysis, blindness, insanity, and death. “As I see it,” one of the doctors involved explained, “we have no further interest in these patients until they die.” Even when penicillin was discovered in the 1940s—the first real cure for syphilis—the Tuskegee men were deliberately denied the medication. From 1963 to 1966, the Willowbrook Study involved a group of children diagnosed with mental retardation, who lived at the Willowbrook State Hospital in Staten Island, New York. These innocent children were deliberately infected with the hepatitis virus; early subjects were fed extracts of stools from infected individuals and later subjects received injections of more purified virus preparations. Investigators defended the injections by pointing out that the vast majority of them acquired the infection anyway while at Willowbrook, and it would be better for them to be infected under carefully controlled research conditions. The study's purpose was to study the history of the disease when left untreated and later to assess the effects of gamma globulin as a therapeutic intervention. Gamma Globulin is proteins in human blood plasma, which include most antibodies. The antibody substances are produced as a protective reaction of the body's immune system to the invasion of disease producing organisms. When a patient is injected, it creates a rapid but temporary immunity in patients who have been exposed to disease. This study generated a variety of concerns, such as the deliberate infection of the children and the attempts to convince the* parents to enroll them in the study in exchange for admission to the hospital (which was deliberately short of space). The Tuskegee Study Group were invited to receive "special treatment", which was actually a diagnostic lumbar puncture Peter Buxtun, PHS venereal disease investigator, the Tuskegee “whistle-blower”

Respect for Persons Ethical convictions Applying the principle
Acknowledge autonomy of the individual Protect those with diminished autonomy Applying the principle Informed consent The elements of informed consent Information, comprehension, voluntary Vulnerable populations Informed consent investigator plans the process and IRB approves or does not approve IRB needs enough information to approve the process (not just the written document) Information “…the extent and nature of information provided should be such that a reasonable person has enough information to decide whether or not to participate in the research” pg. 33 Dunn & Chadwick Comprehension “The manner and context in which information is conveyed are as important as the information itself” Dunn & Chadwick, pg. 34 Too fast to understand, language or maturity barriers, context of situation (just be cardiac cath example), Assent for children, the decisionally impaired? Voluntariness No undue influence or coercion Coercion-Threat of harm if don’t become part of the research (You might lose certain if you don’t participate-don’t discuss the alternatives) Undue influence Circumstances (context) free from undue influence Large payments (in poorer neighborhoods) Subject misunderstanding the “therapeutic misconception” in the care giving relationship Adapted from Dunn & Chadwick, 2004

Beneficence Ethical convictions Applying the principle Do no harm
Maximize possible benefits Minimize possible harms Applying the principle Investigator & IRB Minimize risks Weigh risks and benefits When appropriate, a plan to monitor and ensure safety How can we really do no harm when the investigator is the one proposing the study that has risk? Unrealistic expectation that a study won’t have risks. An assumption such as that would shut down the research enterprise. Be realistic, and, Maximize possible benefits and minimize possible harms (data safety and management plan) Investigator follows the protocol (what if an investigator let a subject into the study that didn’t meet inclusion & exclusion criteria and the person had a serious illness episode? Use asthma example. IRB required by regulation to assess risks and benefits and the balance of benefits should outweigh the risks. How will the risks be presented to the subject? “The underlying problem is how to resolve the tension between individual interests and scientific progress, where the latter is justified in terms of benefits to future individuals”, pg. 16 Moreno article in Vol. 1, Poynter ctr volumes Difficult task!!!! “Beneficence …requires that we protect against risk of harm to subjects and also that we be concerned about the loss of the substantial benefits that might be gained from research”. Risks reasonable in relation to potential benefits

Justice Ethical Convictions Applying the principle
Fairness in distribution of burdens and benefits of research participation Applying the principle Investigator-subject selection IRB asks “Is the selection of subjects equitable?” Ed Goldman presentation, January, 1998 Some balancing acts: Can we balance basic principles? Which principles take precendence when principles conflict? If pure utilitarian theory is used, then beneficence is the most important of the three principles and should win. All three principles can be balanced against each specific protocol. A protocol with a high degree of benefit could then outweigh respect for person or distributive justice. Each protocol could be required to fulfill all three of the princip0les. This may rule out too many protocols. Respect for person and distributive justice could be taken together and if they outweigh beneficence, then the IRB could refuse to approve the protocol. In other words, all other things being equal, then a judgment could be based on beneficence…. Mid 1990’s NIH guidance on inclusion of women. For example, the notion of taking one “baby” dosage aspirin per day developed through research on men. In fact, men subjects in most risky research. Did men shoulder the burdens for others in our society? What was learned about syphilis for the Tuskegee experiments was valuable information and there were many publications. Did others shoulder a burden so that we might have the advantages of the applications of advances in science? What is studies about different types of care for asthma are more attractive to people with low incomes and without health care? Don’t select subjects just for convenience. See additional info in Dunn and Chadwick, pg. 36

Regulations Regulations developed in response to egregious, harmful research conduct Developed on ethical principles Congressional legislation signed into law by President Laws interpreted in CFR (Code of Federal Regulations) by responsible federal agency CFR regulations detail how law is implemented Noncompliance with CFR may result in criminal prosecution, fines, sanctions or debarment from research

Regulations (cont’d) Regulations are not specific
Regulations don’t address everything that is important in the protection of human subjects No regulations address decision-making capacity of possible subjects Regulations MUST be met Example FDA 21 CFR 50.20 …no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. …[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.]… The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. ..[No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.] FDA Information Sheet Guidances-A guide to Informed consent “The IRB should ensure that technical and scientific terms are adequately explained or that common terms are substituted. The IRB should ensure that the informed consent document properly translates complex scientific concepts into simple consepts that the typical subject can read and comprehend. Although not prohibited by the FDA regulations, use of the working, “I understand…” in informed consent documents may be inappropriate as many prospective subjects will not “understand” the scientific and medical significance of the all the statements. Consent documents are more understandable if they are written just as the clinical investigator would give an oral explanation to the subject…” Example OHRP 45 CFR (b)-Children’s Assent “Assent means a child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent. (45 CFR (b)). “ OHRP FAQ children’s guidance This means the child must actively show his or her willingness to participate in the research, rather than just complying with directions to participate and not resisting in any way. When judging whether children are capable of assent, the Institutional Review Board (IRB) is charged with taking into account the ages, maturity, and psychological state of the children involved. The IRB has the discretion to judge children’s capacity to assent for all of the children to be involved in a proposed research activity, or on an individual basis. The IRB should take into account the nature of the proposed research activity and the ages, maturity, and psychological state of the children involved when reviewing the proposed assent procedure and the form and content of the information conveyed to the prospective subjects. For research activities involving adolescents whose capacity to understand resembles that of adults, the assent procedure should likewise include information similar to what would be provided for informed consent by adults or for parental permission. For children whose age and maturity level limits their ability to fully comprehend the nature of the research activity but who are still capable of being consulted about participation in research, it may be appropriate to focus on conveying an accurate picture of what the actual experience of participation in research is likely to be (for example, what the experience will be, how long it will take, whether it might involve any pain or discomfort). The assent procedure should reflect a reasonable effort to enable the child to understand, to the degree they are capable, what their participation in research would involve..”

Federal Guidance and Information Sheets
Published by federal agencies to provide more information or to recommend best practices Interprets application of regulations Current thinking NOT legally binding FDA “… An alternative approach may be used if such approach satisfies the requirements of the applicable statue, regulations, or both…” Guidance “should” be met Example FDA 21 CFR 50.20 …no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. …[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.]… The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. ..[No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.] FDA Information Sheet Guidances-A guide to Informed consent “The IRB should ensure that technical and scientific terms are adequately explained or that common terms are substituted. The IRB should ensure that the informed consent document properly translates complex scientific concepts into simple consepts that the typical subject can read and comprehend. Although not prohibited by the FDA regulations, use of the working, “I understand…” in informed consent documents may be inappropriate as many prospective subjects will not “understand” the scientific and medical significance of the all the statements. Consent documents are more understandable if they are written just as the clinical investigator would give an oral explanation to the subject…” Example OHRP 45 CFR (b)-Children’s Assent “Assent means a child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent. (45 CFR (b)). “ OHRP FAQ children’s guidance This means the child must actively show his or her willingness to participate in the research, rather than just complying with directions to participate and not resisting in any way. When judging whether children are capable of assent, the Institutional Review Board (IRB) is charged with taking into account the ages, maturity, and psychological state of the children involved. The IRB has the discretion to judge children’s capacity to assent for all of the children to be involved in a proposed research activity, or on an individual basis. The IRB should take into account the nature of the proposed research activity and the ages, maturity, and psychological state of the children involved when reviewing the proposed assent procedure and the form and content of the information conveyed to the prospective subjects. For research activities involving adolescents whose capacity to understand resembles that of adults, the assent procedure should likewise include information similar to what would be provided for informed consent by adults or for parental permission. For children whose age and maturity level limits their ability to fully comprehend the nature of the research activity but who are still capable of being consulted about participation in research, it may be appropriate to focus on conveying an accurate picture of what the actual experience of participation in research is likely to be (for example, what the experience will be, how long it will take, whether it might involve any pain or discomfort). The assent procedure should reflect a reasonable effort to enable the child to understand, to the degree they are capable, what their participation in research would involve..”

University of Michigan Policies and Procedures
Standard Practice Guide Approved by Regents Section 303, Human Research Protection Program (HRPP) Operations Manual IRB Guidance & SOPs See IRB websites 303 - Research Policy for Research with Human Subjects - 115 Kb University of Michigan Technology Transfer Policy - 81 Kb Research - 87 Kb Indirect Costs - 19 Kb Policy for Research with Human Participants - 47 Kb Operations Manual (Link to Full Version) Office of the Vice President for Research Human Research Protection Program (HRPP) The HRPP Operations Manual (OM) is designed to illuminate the system and its overarching governing rules and to serve as a reference for investigators, IRBs, administrators, and others. Scope of Human Research at the University Mission Statement and Organizational Summary Part 1: Introduction, Purpose and Ethical Principles - describes the mission of the University of Michigan, the purpose of the University's Human Research Protection Program (HRPP) and authority under which it operates, and the scope of research conducted at the University. (PDF version) Categories of Participants Types of Human Research Conducted Protection from Undue Influence Limitation on Institutional Authority Institutional Authority Ethical Principles Organizational Entities that Support the HRPP Key Organizational Representatives Part 2: Organization of the HRPP - describes the organization of the University of Michigan's Human Research Protection Program (HRPP) and the roles and responsibilities of the various units that guide and support the program. (PDF version) Policy Implementation, Communication and Education Organization Monitoring and Oversight Recordkeeping and Reporting HRPP Committees and Working Groups OHRCR DRDA The IRBs The Academic Units SOPs, Procedures and Guidance Primary Responsibility to Human Subjects Authority of the UM IRBs Other Research Reporting Units Cancer Center Biomedical Engineering Protocol Review Committee Clinical Trials Office IDS IBC MICHR RSS Independence of Research Review Units to Undue Influence Roles and Responsibilities of Other Units Supporting the HRPP Research Centers Introduction Part 3: HRPP Policy - describes the process by which HRPP policies are developed, approved and implemented, and articulates minimum requirements for IRB standard operating policies and procedures. (PDF version) IRB Standard Operating Policies and Procedures The Operations Manual IRB Functions and Operations Organization and Personnel General Review and Approval Procedures Application Submissions Determining whether and under what authority the research is regulated Initial and continuing review and review of other applications Reporting changes in research Monitoring and verification Frequency of review Criteria for IRB Approval Criteria for Expedited Review Lapses in approval Risk-benefit analysis Minimizing risk Equitable subject selection Informed consent Vulnerable subjects Privacy and confidentiality protection Data monitoring Institutional approval Notification of Decisions IRB Meetings Test article accountability procedures Response to Complaints and Allegations of Noncompliance and Related Reporting Requirements Records and Reports IRB Member and Consultant Conflicts of Interest IRBs Reviewing and Monitoring FDA-Regulated Research Educational Activities Part 4: Activities Subject to the HRPP - explains when a researcher becomes engaged in human research and describes the University's policy on exempt research. (PDF version) Other Review Units Quality Assurance and Quality Improvement Determining Whether Research Involves Human Subjects Determining What is Research and What is Not Authority to Make Human Research/Not Human Research Determinations and Notification of Decisions Determining When Research Begins and Ends Determining Whether the University is Engaged in Human Research Authority to Make Human Research/Not Human Research Determinations Quality Improvement Activities vs. Human Research Student Practicum and Internships Illustrations Public Health Not Human Research Policy on Exempt Research Notification and Documentation of Exempt Status Authority to Grant Exempt Status Categories of Eligibility for Exempt Determination Which UM IRB Part 5: IRB Jurisdiction and Cooperative Research - describes the scope of jurisdiction of the various University IRBs and policies on cooperative research and deferred review. (PDF version) Dearborn Flint Behavioral Sciences Health Sciences Cooperative Research Ensuring Adequate IRB Capacity IRBMed Engagement in Human Research Coordinated or Joint Review Researcher and IRB Responsibilities with Regard to Performance in Which the University is Involved Default Position on Outside Entities Engaged in University Research IRB of Record Procedures for Ceding Authority to Another IRB Procedures for a UM IRB to Become IRB-of-Record for Another Institution Statement of Principles Unaffiliated Investigators Responsibilities of the HRPP and Local IRB in Multi-Site Research Eligibility to Perform Research at the University of Michigan Part 6: Roles and Responsibilities of Investigators and Research Staff - describes the roles and responsibilities of investigators and research staff engaged in University research. (PDF version) Roles and Responsibilities of Investigators and Research Staff Other Key Personnel Who May Apply to Serve as Principal Investigator on IRB Applications Generally Minimizing risks to subjects and protecting subject rights and welfare Compliance with IRB and other review unit requirements Accountability and additional administrative requirements Conflict of interest disclosures Obtaining and documenting informed consent Studies Regulated by the FDA Investigator responsibilities Education Manufacturers Sponsor-investigator Part 7: Participant Protection - describes some of the ways research participants are protected under the HRPP. (PDF version) Payment to Research Subjects Data and Safety Monitoring Plans HRPP Protection Extends to All Subjects Vulnerable Subjects Research Involving Pregnant Women and Fetuses Research involving neonates Research involving pregnant women and fetuses Research involving, after delivery, the placenta, the dead fetus, or fetal material Research Involving Prisoners Research not otherwise approvable IRB composition Who is a Prisoner? Research Involving Children Permitted categories of research Additional conditions on research involving prisoners Research involving no more than minimal risk Research Involving Adults with Cognitive Impairment or Otherwise Impaired Decision-Making Capacity Otherwise unapprovable research Research involving greater than minimal risk with no prospect of direct benefit to individual subjects Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects Compensation for Injuries Determination that an IND or IDE is Required Part 8: Use of Test Articles - describes when or under what circumstances an Investigational New Drug application or Investigational Device Exemption is needed; and describes IRB responsibilities with respect to protocols involving investigational test articles. (PDF version) Investigational Devices Investigational Drugs and Biologics Device studies exempt from IDE requirements Significant risk (SR)/non-significant risk determinations Early and Expanded Access to Test Articles Institutional or Employee Sponsorship of INDs and IDEs Withholding Final Approval Pending Verification of IND or IDE Acquisition Investigational Drugs Treatment INDs Single patient INDs for emergency or compassionate use Open label protocols or open protocol INDs Parallel track studies Treatment use Compassionate use Emergency use Continued Access Charging for Test Articles Additional Exceptions Charging for Investigational Drugs and Biologics Investigational Medical Devices and Radiological Health Products Treatment Protocols and Treatment INDs Clinical Trials Conflict of Interest of Investigators and Research Staff Applicable Policies Part 9: Conflicts of Interest and Commitment (PDF version) Identification of Significant Financial or Outside Management Interests in Human Research That Could Form the Basis of a Conflict of Interest Sponsored projects Human subject protocol application IRB, sponsored project, and technology transfer consultants to Conflict of Interest committees Sponsored project and technology transfer negotiations Disclosures first received by schools and colleges pursuant to DOI/COC policies Conflict of Interest of IRB Members, Consultants and Staff Conflict Review and Management Role of the Division of Research Development Administration Part 10: Sponsored Projects - describes policies and procedures for the administration of sponsored project agreements for human subjects research. (PDF version) Institutional Conflicts of Interest Agreements with Sponsors Communication of Findings that May Affect the Safety of Human Research Participants or Their Willingness to Continue in the Research Study Medical Care for Human Research Participants with A Research-Related Injury Human Research Protection Program Dissemination of Findings From the Research Communication of Findings that May Directly Affect the Medical Care of Research Participants Part 11: Standards, Compliance and Education - describes selected laws and regulations impacting human research conducted at the University of Michigan and the University's implementation and educational activities to promote compliance with these regulations. (PDF version) Governing Laws, Regulations and Other Standards Federal Research Laws and Regulations Department of Health and Human Services National Institutes of Health, Office of Biotechnology Activities Food and Drug Administration Office of Human Research Protections Other Federal Agencies Office of Research Integrity Access to Legal Counsel International Research Other Legal Standards That Impact Human Research Other Related Laws, Regulations, and Standards Informed Consent and Legally Authorized Representatives General Requirements for Informed Consent Who May Give Consent Children as subjects Michigan Law Requiring Special Consent Incompetent and incapacitated people Breast cancer treatment Pregnancy termination HIV/AIDS testing Electroconvulsive therapy Terminal illness Surgery for mental health patients Confidentiality of and Access to Research Records and Other Information Research Involving Use or Disclosure of Patient Health Information Confidentiality of Research Records Generally HIV/AIDS and Other Serious Communicable Diseases Research Involving Student Records Substance abuse treatment Mental health treatment Mandatory Disclosure Requirements Michigan Freedom of Information Act Court orders and subpoenas Standards for reporting abuse, neglect and domestic violence Public health reporting: disease surveillance Protecting Against Disclosure: Certificates of Confidentiality Stem Cell Research Research Involving Pregnant Women, Fetuses and Neonates Research Involving Prisoners and Other Detained Persons Document Control and Record Retention and Destruction Data and Specimen Repositories State Professional Licensing Laws and Institutional Credentialing Policies IRB Responsibilities Investigator and Sponsor-Investigator Responsibilities Registration of Clinical Trials Electronic Records and Electronic Signatures Screening Logs Lotteries Education and Training for the Research Community Research Involving Human Specimens Part 12: Quality Assurance and Research Compliance - describes the University's quality assurance, quality improvement and enforcement activities. (PDF version) Tracking and Communicating New Developments Educational Initiatives for the Research Community Quality Assessment, Improvement, and Assurance Compliance Oversight Quality Improvement Performance Measurement and Quality Assessment Noncompliance Review Procedures Response to Complaints or Allegations of Noncompliance Process Summary Definitions Rights of faculty, staff, or others accused of noncompliance Assurances of appropriate confidentiality Receipt and Initial Handling of Allegations of Noncompliance How Compliance Concerns are Brought Forward Policy against retaliation for reporting Chair and Board Considerations and Determinations Institutional Notification and Reporting Requirements Response to Determinations of Noncompliance Detailed Procedures for Investigating Allegations of Noncompliance Procedures for Review and Reporting of Unanticipated Problems Involving Risks to Subjects or Others, Serious or Continuing Noncompliance, or Suspension or Termination of IRB approval. Roles and Responsibilities Background Researchers All documents published on this website comprising the Operations Manual are in Adobe Acrobat (PDF) format. Free Acrobat Reader software is available on the Adobe website. Office of Human Research Compliance Review March 2008

What is “GCP” A type of “Best Practice” term coined by the International Conference on Harmonization (ICH) and used by FDA Refers to FDA regulations, guidance and notices for Drugs, Devices & Biologics FDA assures …the safety and efficacy of pharmaceuticals, biologics, and medical devices on the market in the U.S.A. What entities covered by FDA GCP? IRB Investigator Research Sponsor NIH- “Scientific and ethical standards of human subject research” Sponsor means a person who takes responsibility for and initiates a clinical investigation. It can be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization.

ICH E6– International Conference on Harmonization
Multi-national body, USA, EU & Japan, est. 1989 Meets periodically to resolve different technical requirements for drug registration Goal: Create guidelines and standards for conducting clinical trials allowing sponsors to generate a single set of data to meet submission requirements of the three regions Originally based on ethical principles from the Declaration of Helsinki-1964 with revisions Adopted as guidance for drugs/biologics by FDA in 1997 Also used by FDA in reference to devices

ICH-E6 “GCP” Definition
A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that: the Data and Reported Results are Credible, and Accurate, and that the Rights, Integrity, and Confidentiality of Trial Subjects are Protected Adopted as guidance by FDA in 1997 = Quality Data = Ethics

FDA Regulations and ICH Guidelines
Companies that wish to have study data accepted by the regulatory agencies in the US, EU, and/or Japan need to follow the ICH guideline. Differences between FDA Regulations and ICH GCP Guidelines: ICH Guideline states general principles is more prescriptive than regulations e.g., 21 CFR 50 requires signature and date of subject while ICH E6 says one should also have the signature of the investigator.

Why GCP? Failures Subject safety
Ethical Atrocities Preventable Research Deaths/Injury Scientific Fraud Subject safety Public trust and support of research mission Assure valid data for evidence-based Health Care Drug development trajectory long, arduous, expensive (GCP assures safety and quality data) Useful products brought to market with known safety profile and effectiveness The better the GCP-the sooner the product is available for patients Advance science and contribute to the public good Society supports the mission of research People volunteer to be subjects

Best Practices, GCP & Types of Studies
Investigator Initiated May or may not be FDA regulated NIH (HHS) supported 45 CFR 46 17 Federal agencies and the “common rule” Part A of 45 CFR 46 e.g., Dept. of Energy, Dept. of Education FDA Regulated 21 CFR 312 Drugs & Biologics 21 CFR 812 Devices 21 CFR 50 Protection of Human Subjects 21 CFR 56 Institutional Review Boards Can GCP which is biomedically and investigational product driven be applied to investigator initiated health related studies with a financial sponsor such as NIH?

Research Clinical Trials “Best Practices” and ICH E6 GCP
Both can be viewed as a series of key activities or “practices” Order of activities may vary and may be simultaneous Multiple parties participate but PI remains accountable Study scientific and ethical quality achieved by defining key study “best practices” and assuring oversight to implement them Referring to ICH E6 GCP which has much more defined conduct of research than regulations Will let audience know when referring to ICH E6 and when to “Best Practices”, again, considering GCP a specialized, and more detailed, subset of Best Practices

“Best Practices” Key Activities
Obtain Informed consent Provide for Subject Safety & Medical Care Follow the IRB approved protocol or submit amendment to IRB Maintain Confidentiality Record keeping-Maintain accurate, current, organized records and submit reports Maintain communication with IRB Provide appropriate oversight of qualified staff FDA-Investigational Product Accountability FDA-Essential Documents Binder Additional areas Conflict of interest Communication with sponsor (FDA) Shipping regulations

“People and Paper” Skills
Negotiation Communication Time management Record keeping Computer Organization Oversight of other research staff Detail-oriented Knowledge of regulations and their application Intimate knowledge of protocol Research conduct requires many skills! Now let’s talk about the role of research coordinator or research manager, or research staff These are critical skill sets in addition to good working knowledge of UMHS systems and Regulations

Obtain Informed Consent

Informed Consent as a Process
Interpersonal communication skills assess subject understanding and motivation to participate Informed consent is freely given and is obtained from each subject prior to study participation The consent discussion is in language understandable to the participant or the representative and is done by a qualified person The consent process provides sufficient opportunity for the participant or the participant’s legally authorized representative to consider whether to participate The consent process minimizes the possibility of coercion or undue influence (Research is not the same as therapeutic txmt) The consent discussion is free of exculpatory language The IRB approved document without any changes and with the elements of informed consent is used Children’s “assent” & “Parental Permission” Blue highlighted not regulatory IRBMED classes Many issues Disability Foreign language Lack of decision-making ability Children Some research may be exempt from the regulations. IRB generally helps people make that decision When does a study start? What are study related activities? a) Basic elements of informed consent. Except as provided in paragraph (c) or (d) of this section, in seeking informed consent the following information shall be provided to each subject: (1) A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental; (2) A description of any reasonably foreseeable risks or discomforts to the subject; (3) A description of any benefits to the subject or to others which may reasonably be expected from the research; (4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject; (5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained; (6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained; (7) An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject; and (8) A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. (b) Additional elements of informed consent. When appropriate, one or more of the following elements of information shall also be provided to each subject: (1) A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable; (2) Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent; (3) Any additional costs to the subject that may result from participation in the research; (4) The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject; (5) A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject; and (6) The approximate number of subjects involved in the study. Element II.3.F. The IRB or EC has and follows written policies and procedures to evaluate the consent process and to require that the Researcher appropriately document the consent process. Adapted from AAHRPP, 2009

Informed Consent Monitoring
Privacy respected Voluntary Conducted as a process by PI Process follows the IRB approved protocol Waiver of consent possible Copy of consent given to subject Consent signed prior to any study procedures Re-consent completed and documented as appropriate 100% of consents used correct IRB approved version and were appropriately signed and dated Provide handout to track informed consent versions Provide handout to audit own informed consent documents Regulation(s): 45 CFR 21 CFR 50.20, 25-27

What does the public think?
The mission of the Center for Information and Study on Clinical Research Participation (CISCRP), a first-of-its-kind non-profit organization founded in 2003, is to: Educate, inform and empower patients, the public, medical and research professionals, the media and policymakers about clinical research participation and what it means to be an active participant in the process Promote greater awareness and understanding of clinical research participation and the role that it plays in public health Facilitate more effective collaboration among all members of the clinical research enterprise Provide resources for the research community to better understand the study volunteer ODC=Opinion Dynamics of Cambridge, a national leader in market research, polling and consulting in healthcare, associations education, energy, etc. CISCRP/ODC Survey, 12/2006

“It is a confusing time to be a subject-or to be thinking about becoming one…”
The media presents stories about the need for more research and research funding alongside reports of serious harms to subjects in research trials” …”If we fail to answer this question adequately, we risk a serious erosion of trust in the research enterprise.”… ”Accountability for balancing protection and access [to trials and to knowledge for society] falls to those at every level in the conduct of research.” Moreno, 2001 Jonathan D. Moreno, Ph.D., is Emily Davie and Joseph S. Kornfeld Professor of Biomedical Ethics and Director of the Center for Biomedical Ethics at the University of Virginia. Moreno, 2001

Provide for Subject Safety and Clinical Care

Adverse Events & Harms Adverse event (AE) defined
. Adverse event (AE) defined Prevent, monitor for, identify, provide immediate care for, track, analyze cause, report to IRB, may submit protocol amendment or changes to consent document & notify Sponsor (FDA) IRBMED Guidance and timetable for reporting AEs at Harms Physical Psychosocial Social Economic Legal Dignitary IRBGMED Glossary Accessed 5/25/10 Adverse Event (AE): Harm, any experience or abnormal finding that has taken place during the course of a research project and was harmful to the subject participating in the research, or increased the risks of harm from the research, or had an unfavorable impact on the risk/benefit ratio. Note that the Food and Drug Administration also includes in its definition abnormal preclinical or laboratory findings which may not yet have resulted in direct harm to subjects (e.g. a bacteria is identified in a culture from the same batch of cells used to produce a vaccine which has been administered, even if no cases of infection have been reported). (See also Serious Adverse Event , Adverse Drug Reaction, and abnormal preclinical finding .) Make a spreadsheet of AEs. eResearch will provide a table of all AEs that have been submitted. The National Bioethics Advisory Commission (2001) described six harms: physical, psychological, social, economic, legal, and dignitary.

What Can Result in Harms?
The protocol/treatment Side effects of drugs/biologics or adverse device effects NOT following the protocol NOT maintaining up-to-date records NOT maintaining communication with investigator and/or study sponsor Prevent harm Qualified person monitors overall study Monitor laboratory results and tests and treat as appropriate May withdraw subject from study Know emergency procedures for breaking a study blind Keep primary care provider in communication as appropriate AEs are graded by Seriousness Relatedness to the study Expected/Unexpected NOT following the protocol Informed consent process Recruitment Eligibility Intervention/Interaction Follow up 45 CFR (b)(4)iii & (5)i (4) Written procedures which the IRB will follow (i) for conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution; (ii) for determining which projects require review more often than annually and which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review; and (iii) for ensuring prompt reporting to the IRB of proposed changes in a research activity, and for ensuring that such changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject. (5) Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB; and (ii) any suspension or termination of IRB approval. Adverse Events (AEs), Other Reportable Information and Occurrences (ORIOs), and Unanticipated Problems Involving Risks to Subjects or Others (UaPs) Investigators and research staff are responsible for reporting information concerning the approved research to the IRB in a timely fashion, understanding and adhering to the reporting guidance provided here and on the detail pages linked below, and not implementing any changes to the research prior to IRB approval of the change via an amendment application ( when changes are necessary to eliminate apparent immediate hazards to the subject, implement the change and report by an ORIO and/or amendment submission within 7 days after the action is taken). This includes all information with the potential to impact the risk or benefit assessments of the research. Failure to follow these requirements may require the institution to take disciplinary actions, restrict research privileges, and report the non-compliance to government agencies and/or study sponsor.

Follow the Protocol or Amend it

The Tension in Research
“The principal duty of a physician is to the well-being of the individual.” “The principal duty of society (social ethics) is to the greatest good for the greatest number of people.” Research is protocol driven Clinicians often want to adapt the protocol for an individual Faith Fitzgerald, 2010, “Ethics in International Research”, SoCRA Source, Issue 63, February 2010, pg , quote on pg 64

Know and Follow the Protocol
Changes to the protocol, “…may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject.” Read it FDA-each person on study team signs it Protocol Readily Available No mix ups-Clearly label current version Follow it Prevent and track any protocol deviations Notes to file-circumstances, CAPA Report to IRB and sponsor as applicable Amend protocol with IRB as needed Follow randomization procedures If applicable, procedures follow data safety and monitoring plan (DSMP) submitted to IRB and funding agencies Appropriate laboratory or tissue collection Follow procedure in protocol Label appropriate Follow shipping guidance in protocol & federal guidance

Maintain Confidentiality

Data Confidentiality & Security: Outcomes
Data maintained according to IRB approved protocol Access to confidential data is restricted Safe & secure storage Don’t share passwords! Mobile device security for researchers at UM Electronic data security Questions to Guide Research Protections at OHRCR website

Implications for Confidentiality
Being notified only, with no re-consent or opt out process, before their information goes to a national database 47% completely unacceptable 20% somewhat unacceptable No notification or re-consent at all, before their information is sent to a national database 54% completely unacceptable 16% somewhat unacceptable How much do current and potential subjects want to be informed, give consent and maintain confidentiality of their data? In The Havasupai Settlement: Implications for HRPPs, IRBs, and Researchers May 20, 2010 2:00 –3:00 PM ET William Freeman, MD, MPH, CIPDirector of tribal community health programs and human protections administrator, Northwest Indian College, and program director of the Northwest Indian College Center for Health Pearl O’Rourke, MDDirector of human research affairs, Partners HealthCare System, Inc and associate professor of pediatrics, Harvard Medical School Potential Implications for Research and HRPPs: Finding out what is wanted In the Havasupai Case, as in much research, researchers did not find out what participants wanted or expected. Little research has examined what participants want in research. The results of one recent study, by EJ Ludman et al, are helpful. Group Health of Puget Sound conducted a large study, that asked 1,340 participantsalreadyenrolled in a genetics study to consent to have DNA and information sent to national database. 88% permitted sending the information. The researchers then interviewed a random sample of 365 from the entire group of 1,340 (both permitters and refusers). (Continued.) Importance of “reconsent” (being asked to permit sending information to a national database) 69% very important 21% somewhat important Requiring participants to contact the researcher themselves, to opt out of sending their information to a national database 27% completely unacceptable 28% somewhat unacceptable Being notified only, with no reconsent or opt out process, before their information goes to a national database 47% completely unacceptable 20% somewhat unacceptable No notification or reconsent at all, before their information is sent to a national database 54% completely unacceptable 16% somewhat unacceptable These results are useful to begin to understand “what potential and current participants want.” We need results

Record Keeping & Reports
Maintain Accurate, Current, Organized Records and Submit Reports

Study Files Organized, accurate, up-to-date
Direct/Indirect subject identifiers Direct-subject identifiers stored with data Indirect-subject identifiers in key & not stored with data Informed consent-stored with files? FDA-Complete, sign and submit FDA Form 1572 Work efficiently Study schema of subject progress for complex procedures Checklist of forms completed Maintain records for: FDA- two years after FDA approves NDA NIH- three years after study terminated HIPAA- six years after study terminated

ALCOA (FDA) FDA Documentation Guidance
A Attributable (who, when) L Legible (readable, pen, no white out, single line) C Contemporaneous (up-to-date) O Original (source document) A Accurate (verifiable with source) PAGE 1 of 10 Subject number at the top of the page for hard copies Example of when gave surveys to statistician and not all came back

Source Data and Documents (FDA)
All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification Source Document Definition Original documents, data, and records, (e.g., ALL study records such as visits, CRF/Data Collection Forms, and, Subjective self-report instruments, hospital, clinical and office charts, laboratory notes, notes to file, subject diaries, checklists, pharmacy dispensing records, recorded data from automated instruments, X-Rays, digital records… Source Data Generate and Keep source documents in original records May be using Electronic Data Capture (EDC) Exercise What is a Source Documents? A source document is any information that is recorded for the first time. (Avoid sticky notes or napkins!) Create a display on Source Data versus Documents (e.g., patient vitals data (e.g., 120/80 versus a page from the patient chart) : Flip Chart/Wall board Source Document (I.e., chart page) 120/80 160 lbs 5’10” ekj Mar 10, 2003 Source Data

Maintain Communication with the IRB

IRB Communications and Submissions
Interact with IRB Ask questions Get to know UM IRB contacts Initial IRB submission and approval Ongoing oversight AEs, protocol deviations, unanticipated problems, DSMC reports or safety officer reports, UM OHRCR report, new information that changes risk/benefit of study participation Continuing review Terminate a study Don’t let it expire!

Study Oversight & Qualifications

Overall PI/Investigator Responsibilities
Ensure a study is conducted according to the protocol or study plan and applicable regulations FDA Form 1572 Protect the rights, safety, and welfare of subjects under the investigator’s care FDA-Control drugs, biological products, and devices under investigation Office for Human Research Protections (OHRP) OHRP Investigator Responsibility Frequently Asked Questions . In FDA’s experience, the following factors may affect the ability of an investigator to provide adequate supervision of the conduct of an ongoing clinical trial at the investigator’s site: Inexperienced study staff Demanding workload for study staff Complex clinical trials (e.g., many observations, large amounts of data collected) Large number of subjects enrolled at a site A subject population that is seriously ill Conducting multiple studies concurrently Conducting a study from a remote (e.g., off-site) location Conducting a study at multiple sites under the oversight of a single investigator, particularly where those sites are not in close proximity FDA Guidance for Industry: Investigator Responsibilities, Oct 2009

Study Oversight by the PI/Investigator
Are individuals who are delegated study tasks qualified to perform them? Have individuals received training to the protocol and to the tasks? Oversight and involvement in ongoing conduct of the study Where reasonably possible, oversight of 3rd parties During inspections of investigation sites, FDA has identified instances in which study tasks have been delegated to individuals lacking appropriate qualifications. Examples of tasks that have been inappropriately delegated include: Screening evaluations, including obtaining medical histories and assessment of inclusion/exclusion criteria Physical examinations Evaluation of adverse events Assessments of primary study endpoints Obtaining informed consent 4 Guidance for industry, E6 Good Clinical Practice: Consolidated Guidance, section 5 Ibid, section 4.1.5 The investigator should maintain a list of the appropriately qualified persons to whom significant trial-related duties have been delegated.5 This list should also describe the delegated tasks, identify the training that individuals have received that qualifies them to perform delegated tasks Contains Nonbinding Recommendations 4 (e.g., can refer to an individual’s CV on file), and identify the dates of involvement in the study. The investigator should have sufficient time to properly conduct and supervise the clinical trial. The level of supervision should be appropriate to the staff, the nature of the trial, and the subject population. In FDA’s experience, the following factors may affect the ability of an investigator to provide adequate supervision of the conduct of an ongoing clinical trial at the investigator’s site: Inexperienced study staff Demanding workload for study staff Complex clinical trials (e.g., many observations, large amounts of data collected) Large number of subjects enrolled at a site A subject population that is seriously ill Conducting multiple studies concurrently Conducting a study from a remote (e.g., off-site) location Conducting a study at multiple sites under the oversight of a single investigator, particularly where those sites are not in close proximity Guidance for Industry: Investigator Responsibilities, Oct. 2009

Adequate Resources Appropriate facilities Appropriate equipment
Correct equipment available Calibrated Preventive maintenance Study staff training Proper laboratory facilities (FDA=CLIA certified) Reference ranges for laboratory tests Details of analytical methods Quality assurance information Laboratories performing testing on human specimens and reporting patient-specific results must be certified under the provisions of CLIA. If researchers wish to provide diagnostic results to subjects or use test results to alter care, they should have laboratory tests performed by a clinical laboratory that has been certified by CLIA. Facilities only collecting or preparing specimens (or both) or only serving as a mailing service and not performing testing are not considered laboratories. Clinical and analytical laboratories may have to follow Good Laboratory Practices (GLP) From Janet Tarolli, 5/26/10 Yes, sponsors ask for documentation of certification for laboratories used in clinical research studies. The University of Michigan Department of Pathology Laboratories is accredited by CLIA and CAP. Often both CLIA (Clinical Laboratory Improvement Amendments) and CAP are requested, but usually one or the other suffices. Most commonly requested is the CLIA, closely followed by the CAP (College of American Pathologists) >From what I can tell from ILAC's web site, ILAC is not itself an accreditor of laboratories, but an international cooperation of accreditation bodies. CAP is lsted on their site as a member. The Clinical Trials Office maintains copies of CLIAs and CAPs in the regulatory binder of all studies, not just sponsored studies: industry-sponsored; investigator-initiated, including consortia; and NCI cooperative groups.

Delegating Tasks The investigator should ensure that any individual to whom a task is delegated is qualified by education, training, and experience (and state licensure where relevant) to perform the delegated task The level of supervision should be appropriate to the staff, the nature of the trial, and the subject population.

Study logs & Oversight Delegation log with study roles, tasks and dates worked on study Signature log with initials log Train to protocol Training log Stay up-to-date on subject and overall study progress Regular staff meetings (FDA-take minutes) The investigator should develop a plan for the supervision and oversight of the clinical trial at the site. Supervision and oversight should be provided even for individuals who are highly qualified Contains Nonbinding Recommendations 5 and experienced. A plan might include the following elements, to the extent they apply to a particular trial: Routine meetings with staff to review trial progress, adverse events, and update staff on any changes to the protocol or other procedures Routine meetings with the sponsor’s monitors A procedure for the timely correction and documentation of problems identified by study personnel, outside monitors or auditors, or other parties involved in the conduct of a study A procedure for documenting or reviewing the performance of delegated tasks in a satisfactory and timely manner (e.g., observation of the performance of selected assessments or independent verification by repeating selected assessments) A procedure for ensuring that the consent process is being conducted in accordance with 21 CFR Part 50 and that study subjects understand the nature of their participation and the risks A procedure for ensuring that source data are accurate, contemporaneous, and original A procedure for ensuring that information in source documents is accurately captured on the case report forms (CRFs) A procedure for dealing with data queries and discrepancies identified by the study monitor Procedures for ensuring study staff comply with the protocol and adverse event assessment and reporting requirements A procedure for addressing medical and ethical issues that arise during the course of the study in a timely manner

Investigational Product (FDA)
Accountability for the Investigational Product

Investigational Product
Process investigational product Receipt (shipping) and Dispensing Labeling Accountability to reconcile records for each tablet, compounded drug Secure storage of device & device return Return/Destroy drug as determined by sponsor Interface with Investigational Drug Services / Biomedical Engineering staff, as needed Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP)

Essential Documents (FDA)
Maintain Study Binder

Binder Index Contents Subject Logs and Lists
Contact Logs and Monitoring Communications: General Protocol and Amendments Case Report Forms Investigator Information IRBMED Documents Laboratory Information

Binder Index (cont’d) Equipment Investigational Product Information
Investigational Product Accountability Records Adverse Events/Effects Investigator Meeting Documents Regulatory Information Study Reports References Contracts and Grants Patient Data

Additional Best Practices
Conflict of Interest Disclosure Applies to all members of the study team Includes spouses and dependents May have a management plan FDA forms for financial disclosure from sponsor Communication with sponsor (FDA) Annual reports to sponsor Maintain ALL sponsor communications Letters, reports, s, phone log, faxes Report AEs and unanticipated problems Report protocol deviations Monitoring log/visits Laboratories performing testing on human specimens and reporting patient-specific results must be certified under the provisions of CLIA. If researchers wish to provide diagnostic results to subjects or use test results to alter care, they should have laboratory tests performed by a clinical laboratory that has been certified by CLIA. Facilities only collecting or preparing specimens (or both) or only serving as a mailing service and not performing testing are not considered laboratories. Clinical and analytical laboratories may have to follow Good Laboratory Practices (GLP)

Shipping Regulations for Biologics
University personnel who ship infectious substances including patient (clinical) specimens, human-derived research materials, infectious micro-organisms, certain genetically- modified organisms, etc. must complete a training program prior to shipping infectious or biological substances. The Department of Occupational Safety and Environmental Health (OSEH) offers the IATA/DOT Shipping Infectious Substances Class on a monthly basis. More information and schedule can be found on the OSEH website Those who complete training receive a training certificate which is valid for two years. Terry, The transportation of biological materials is highly regulated by the U.S. Public Health Service, the Department of Transportation (DOT) and the International Air Transport Association (IATA) – see below for more detailed breakdown. Federal Regulations U.S. Dept. of Transportation (DOT) – 49 CFR Other federal requirements: CDC, OSHA, USDA, Department of Commerce, International Traffic and Arms (ITAR) and Toxic Substance Control Act (TSCA) DOT regulations primarily cover ground transportation. DOT is the organization that has the authority to fine you for violations. Their authority extends well beyond US boundaries. Import permits from the CDC or USDA may be needed if you are importing human etiological organisms or plant or animal pathogens. Department of Commerce licenses may be needed to export organisms, genetic elements, chemicals, technology or other commodities. TSCA Certification may be needed to import or export certain chemicals. International Regulations (Air shipments) International Civil Aviation Organization (ICAO) International Air Transport Association (IATA) Dangerous Goods Regulations (DGR) Internationally, the UN Committee of Experts (CoE) develops recommended procedures for the transport of all types of dangerous good except Radioactive material. The International Civil Aviation Organization (ICAO) uses the UN recommendations as the basis for developing the regulations for the safe transport of dangerous goods by air. IATA is the international trade organization that interprets ICAO regulations and provides the Dangerous Goods Regulations (DGR). The IATA regulations are more stringent than DOT. The training program OSEH provides follows the IATA regulations. IATA regulations are minimal requirements - your carrier can be more stringent. I cannot answer your other questions about the CLIA or ILAC accreditation and whether the sponsors require documentation of the certification. This falls outside the scope of OSEH activities. I have contacted Janet Tarolli, Clinical Research Coordinator-Healthcare, Training & Education Coordinator, Comprehensive Cancer Center, Clinical Trials Office (CTO) to see if she would have this information. I will pass along her response. Janet Follo (at UM)

Overall Legal or regulatory is not always adequate
A personal commitment to integrity needs to be coupled with a firm understanding of “Best Practices” The public support of research rests on its trust of scientists, scholars and the institutions Individual actions can bolster trust and confidence or, unfortunately, undermine it as well Through research projects funded by NIAID over the years I've worked on studies in various countries in Africa and Southeast Asia. I strongly urge the investigators to get local IRB approval for any research they are doing overseas. The age of consent question pales in comparison to the negative feelings that might be engendered when foreigners zoom in and out collecting data and publishing it without consulting the local constituency. For close to home examples, see yesterday's NY Times front page article on the Havasupai and the University of Arizona. Legal is not always adequate. As for the age question: The local ethics committee can tell you what they accept as legal age to consent in research (the answer is not always clear ). Julia Welch Posted to IRB Forum 4/26/10 May 2010, Journal of Clinical Research Best Practices Vol. 6, No. 5, May 2010 “Can You Handle the Truth?” Subscribe free at © 2010 First Clinical Research and the Author(s) What Am I Missing Here? Thought-Provoking Questions for the Clinical Research Industry By Norman M. Goldfarb 146. Inspections R Us The Heisenberg Uncertainty Principle says it is impossible to know exactly both the position and momentum of an electron. The measurement of one changes the value of the other. A similar principle applies to clinical trials. We cannot know with certainty both a drug's clinical value and the investigators' regulatory compliance. The cost of complete knowledge of the investigator's regulatory compliance increases the cost of clinical studies to the point that they become impractical. Obviously, there is a balance. However, the lowest-cost approach to ethical study conduct is to work with competent investigators who conduct ethical clinical studies without constant surveillance. In other words, investigator selection, training, motivation and judicious inspection are a better use of resources than oppressive paperwork and monitoring. Competent, motivated and self-governing investigators are the way to go. The tighter you squeeze the Jell-O, the less you have in the end. What am I missing here? Do you know a better way? Is something getting under your skin? Please send your ideas for future columns to Author Norman M. Goldfarb is Managing Director of First Clinical Research LLC, a provider of clinical research best practices information, consulting and training services. Contact him at or

FDA GCP BIMO Program Clinical Investigator Inspection
Sponsor/Monitor/CRO Inspection Inspection programs allow the agency to determine: Adherence to applicable regulations Validity of studies in support of pending marketing applications Whether the rights and safety of subjects have been protected Bioresearch Monitoring FDA’s bioresearch monitoring (BIMO) program conducts on-site inspections of both clinical and nonclinical studies performed to support research and marketing applications/submissions to the agency. Links to the compliance programs for each inspection type and contact information for each Center’s BIMO program are also accessible from this site. Office of Good Clinical Practice See the Office of Good Clinical Practice’s (OGCP’s) mission statement1 on the OGCP's Web page. NOTE: Clinical investigator inspection-NOT single study inspection. Performance of this investigator whose agreements are with the study sponsor and the FDA

FDA Common Investigator “Deficiencies”
Failure to follow the investigational plan & Protocol deviations (38%) Inadequate recordkeeping, source documentation, case hx, record retention (27%) Inadequate accountability for investigational product, shipping, handling, storage, labeling (10%) Inadequate subject protection-including informed consent (11%) and adverse event (8%) issues BIMO Program Comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA-regulated research. NAI-No action indicated VAI-voluntary action indicated (usually a 483 issued) OAI-Official action indicated-a 483 has been issued, will go to central FDA office for resolution Toth-Allen, J. APEC GCP Inspection Workshop, 2008

Most Common FDA Sponsor “Deficiencies”
Inadequate monitoring Failure to bring investigators into compliance Inadequate accountability for the investigational product

Selected Recent OHRP Noncompliance Determinations
Informed Consent Failure to obtain the legally effective informed consent of subjects or of the IRB to appropriately waive the requirements to obtain informed consent Failure to document informed consent or of the IRB to appropriately waive the requirements to document informed consent Failure to provide a copy of the informed consent document (ICD) to the subject or the subject's legally authorized representative Inadequate ICD for specific research/lack of basic elements Inadequate ICD for specific research/lack of additional elements ICD language too complex Exculpatory language in ICDs Enrollment procedures did not minimize possibility of coercion or undue influence

Selected Recent OHRP Noncompliance Determinations
Initial and continuing review Research conducted without IRB review and/or approval IRB lacks sufficient information to make determinations required for approval of research Inadequate IRB review at convened meetings IRB review of protocol changes Changes to research initiated without IRB review and approval Inadequate IRB review and/or approval of protocol changes IRB membership, expertise, staff support and workload IRB documentation, findings and procedures OHRP,

Questions?

Resources UM IRBMED & HBHS Workshops
Join MICHR research coordinator network Clinical Trials Network (Duke U) Forms, education, etc. at FDA Device Advice & training Virtual Regulatory Binder NIH-Office of Human Subject Research OHRP Guidance documents ICH E6

ICH E6 Principles Clinical Trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with applicable regulatory requirements. Foreseeable risks should be weighed against anticipated benefits for the individual and for society as a whole; a trial should only be initiated if anticipated benefits justify the risks. The rights, safety and well being of the trial subjects are the most important considerations and should prevail over interests of science and society. The non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. Clinical Trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with applicable regulatory requirements. Foreseeable risks should be weighed against anticipated benefits for the individual and for society as a whole; a trial should only be initiated if anticipated benefits justify the risks. The rights, safety, and well being of the trial subjects are the most important considerations and should prevail over interests of science and society. The available non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. Clinical trials should be scientifically sound, and described in a clear, detailed protocol. A trial should be conducted in compliance with the protocol and amendments that have received prior IRB approval.

ICH E6 Principles Clinical trials should be scientifically sound, and described in a clear, detailed protocol. A trial should be conducted in compliance with the protocol and amendments that have received prior IRB approval. The medical care given to, and medical decisions made for subjects should always be the responsibility of a qualified physician. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). Freely given informed consent should be obtained from every subject prior to clinical trial participation. Clinical trials should be scientifically sound, and described in a clear, detailed protocol. A trial should be conducted in compliance with the protocol and amendments that have received prior IRB approval. The medical care given to, and medical decisions made for subjects should always be the responsibility of a qualified physician. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). Freely given informed consent should be obtained from every subject prior to clinical trial participation

ICH E6 Principles All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol Systems with procedures that assure the quality of every aspect of the trial should be implemented.

General Principles for Meeting Regulatory Responsibilities

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