Mayo Clinical Trials Newsletter AMayo Alliance for Clinical Trials Publication

Transcription

1 2005 Volume 3, No. 1 Mayo Clinical Trials Newsletter AMayo Alliance for Clinical Trials Publication Mayo ACT Welcomes New Medical Director: Russell Wiesner, MD Table of Contents Understanding the Crisis in Human Subjects Research Meeting Principal Investigator Obligations: FDA Form 1572 Review and Self- Study: Federal Policy for the Protection of Human Subjects Education Modules Mayo Clinical Trial Services mcts@mayo.edu Russell H. Wiesner, MD Medical Director of Mayo ACT Russell Wiesner, MD, joined the Mayo Clinical Trial Services (MCTS) team effective February 1, 2005, as Medical Director for Mayo Alliance for Clinical Trials (Mayo ACT). Dr Wiesner is Professor of Medicine in the Mayo Liver Transplantation Center and has been providing consultative services for Mayo ACT for the past 2 years. Enthusiasm, knowledge, and experience in clinical research are just a few of the assets that Dr Wiesner brings to Mayo ACT. He has high expectations for the organization. Our long-term goals are to develop into a worldleading academic research organization by developing and disseminating knowledge to improve the care of patients through innovative clinical research, says Dr Wiesner. Dr Wiesner s research interests include liver allocation and applying evidence-based research to improve liver allocation in the United States, as well as immunosuppressive therapy and its relationship to the recurrence of hepatitis C. He also has ongoing interest in cytomegalovirus infection and outcomes of liver transplantation. He has lectured extensively and has published numerous original articles in peer-reviewed journals such as the New England Journal of Medicine, Hepatology, Transplantation, American Journal of Transplantation, and Liver Transplantation. He served as editor of the journal Liver Transplantation and associate editor of American Journal of Transplantation and World Journal of Gastroenterology. Dr Wiesner also serves as the principal investigator for the National Institutes of Health Liver Transplantation Database. Dr Wiesner has been president of the International Liver Transplant Society and has served on the Executive Councils of both the International Liver Transplant Society and the American Society of Transplantation. He has served on numerous committees for the American Association for the Study of Liver Disease, American Society of Transplantation, and the International Liver Transplant Society. Presently he is on the Liver and Intestinal Committee for the United Network of Organ Sharing (UNOS) and chairs the Liver Disease Severity Committee, which has been involved in developing the Mayo End-Stage Liver Disease model for organ allocation. He also recently completed his tenure as president of the UNOS Board of Directors. Dr Wiesner received his medical degree from the Medical College of Wisconsin in Milwaukee in He completed his residency in Internal Medicine and fellowship in Gastroenterology and Hepatology at Mayo Clinic in Rochester, Minnesota, and joined the staff at Mayo Clinic in the Department of Gastroenterology and Hepatology in He helped initiate the Mayo Clinic Liver Transplant Program in 1985 and served as Medical Director of Liver Transplantation from 1986 through Welcome, Dr Wiesner!

2 Understanding the Crisis in Human Subjects Research by Jeremy Sugarman, MD, MPH, MA (Harvey M. Meyerhoff Professor of Bioethics and Medicine, Phoebe R. Berman Bioethics Institute and Department of Medicine, Johns Hopkins University, Baltimore, Maryland). Presented at the Fifth Annual Current Issues in Clinical Research Conference titled Improving Clinical Research: Local Practice and National Issues held at the Mayo Civic Center in Rochester, Minnesota, August 26-27, Deaths of research subjects and federal closures of research programs at several highly respected academic institutions signal a crisis in research with human subjects. The public may now lack trust in the research system, which is represented in a Time magazine cover that declared, How Medical Testing Has Turned Millions of Us into Human Guinea Pigs. Donna Shalala, former US Secretary of the Department of Health and Human Services, said in the New England Journal of Medicine in 2000, The medical and research communities, including institutional review boards (IRBs), agree with the Department of Health and Human Services that this appalling state of affairs is unacceptable. We cannot tolerate or excuse inadequacies in our system of protection for human research subjects. Early Protections Before the current elaborate system was in place for protecting the rights, interests, and welfare of research subjects, investigators typically didn t ask human subjects to participate in experiments that were risky investigators would take the risk themselves. For example, the scientist who first showed that it was possible to place a catheter in the human heart waited until everyone was away from the laboratory at night, inserted a catheter into his own arm, and then climbed two flights of stairs to take a radiograph of it. Up until the middle of the last century, it wasn t the norm for physicians to seek formal permission from patients for most clinical practice. Physicians made decisions in the context of research just like they made other decisions for patients. More than 4000 radiation experiments were funded by the US government during the Cold War, and most of them were done with the subjects consent. Surprisingly, there was only one case in which actual harm was able to be documented, because scientists paid exquisite attention to minimizing risk. However, participants were wronged in a moral sense, because things were done to them without their permission. The Nuremberg Code was written in 1949 as a result of human experiments conducted by the Nazis. Briefly, the code includes the following requirements: Voluntary consent Anticipation of scientific benefits Benefits outweigh risks Experimentation on animals before humans Avoidance of suffering No intentional death or disability Protection from harm Subject s freedom to stop at any time Qualified investigators Investigators obligation to stop if harm occurs Other formal codes of outlining ethical research followed, such as the Declaration of Helsinki. Despite these codes, a series of scandals were revealed. Henry Beecher published an article in the New England Journal of Medicine in 1966 that chronicled 22 studies that had been published that he believed were unethical. The types of studies Beecher thought were unethical included hepatitis studies on retarded institutionalized children, and studies in which live cancer cells were injected into patients without their permission. Beecher s expose and the revelation of the United States Public Health Services Study of Untreated Syphillis in the Negro Male, which is sometimes termed the Tuskegee Syphilis Study that involved poor African American men, shed light on the inadequacy of investigators and sponsors to protect the rights and interests of human research subjects. Three Pillars of Protection Our current system of research is based on three pillars of protection: Investigators and sponsors IRBs Informed consent Investigators and sponsors have a fiduciary responsibility to protect participants; to provide credible results with good scientific design; to ensure responsible conduct of research without cheating, lying, or stealing; and to maintain comprehensive documentation. IRBs provide prospective review to be sure that subject selection is fair and that risks are 2 Mayo Clinical Trials Newsletter

3 minimized and benefits maximized. In addition, IRBs provide continuing review to learn from experience and data and ensure that studies are safe and will not unduly harm subjects. Informed consent has to be based on the subject s adequate decision-making capacity and ability to make a voluntary choice once given sufficient and understandable information about the research. A Matter of Trust Many people have participated in research because they have had trust. In in-depth interviews, research participants talked about trusting in their doctors not to steer them wrong if they re involved in research. Participants also trust in the institutions they rely on for their health care and in the research enterprise as a whole. Our goal in the context of research and those charged with its oversight is to make sure that the system is trustworthy through good clinical practice, IRB review, informed consent, and disclosures of conflict of interest. Without a trustworthy system if the key to participation is trust the ability to do important research will be compromised. The Duke Experience: But for the Grace of God In May 1999, the Office of Protection of Research Risks (OPRR; now changed to OHRP: Office of Human Research Protection) suspended all research activity at Duke University Medical Center for four days after Duke took inadequate corrective actions in response to warning letters. This action meant stopping all research activities not just enrolling subjects, not just the administration of study drugs but all research activities, including analyzing and reporting on data. The suspension scared people at the highest echelons of university administrations The question, Could this happen here? Has to be on their minds, stated Robert Levine in the Chronicle of Higher Education on May 28, Many leaders of academic institutions and IRB administrators seemed to realize, But for the grace of God, it could have been us. information technology system, re-reviewed all of their protocols, formed five IRBs, and established ongoing communication and reporting with the regulatory authorities. Restoring Trust Institutions must create an ethics infrastructure and deal with their institutional culture. As Gary Ellis, the former head of OPRR noted, the leaders of research institutions set the tone for ethical conduct of research in their institutions. Education is also crucial. Investigators don t learn how to be a clinical researcher in medical school. Many of the investigators who went through the educational program at Duke said they never knew the history of the development of the current approach to oversight but with that background, the rules now made sense. Once they knew the rationale for the regulations, they found that it was easier to follow them. The reason Duke was closed was not simply that they had deficiencies in their research program, but that they responded to the OPRR with arrogance. Had they responded with the necessary humility that s required for the kind of work we do, they may not have been closed. Clinical research is about human capital it is about people s lives. Ultimately, if we practice medicine and we want to be able to do that with safe and effective drugs, biologics, and devices, we need clinical research. We ve got to respect the people that we enroll in human research, and we can t be arrogant. A Harris interactive poll was conducted in February 2002 asking more than 2000 adults their feelings about clinical research. The results (see box on page 4) suggest that there is much work to be done to restore trust. As Gary Ellis stated in Nature (May 20, 1999): The difficult work now begins building a broad and deep programme of protecting human subjects is going to take some time. After going through a difficult process Duke developed an action plan that reflected the desire to become leaders in the ethics of clinical research and research oversight. Duke created a mandatory, meaningful, educational program before educational programs were required. They also brought in consultants, increased resources for the IRB and staff, developed a better continued on page Mayo Clinical Trials Newsletter 3

4 Results of 2002 Harris Interactive Poll (2,031 adults polled) How confident are you that patients in clinical trails: Get very good medical care? 32% very confident Are treated as patients, not as guinea pigs? 24% very confident Are told honestly and clearly of the risks of participating? 25% very confident Are not recruited just so that the doctors and hospitals involved can make more money? 20% very confident As stated earlier, to restore trust in the clinical research system, it is necessary to be alert to the changing landscape and create an ethics infrastructure and institutional culture. Components of an ethics infrastructure include the following: Adequate resources Recognition of IRB members Education Analysis of the current system Supportive institutional culture People engaged in clinical research and its oversight are uniquely positioned to develop mechanisms to ensure the protection of human subjects. Creating an infrastructure for doing so is an urgent task that has pragmatic, legal, and ethical implications. Researchers conducting clinical trials need humility and should continually remind themselves that research deals with human lives. Meeting Principal Investigator Obligations: FDA Form 1572 The responsibility for protecting the rights, safety, and welfare of subjects in a clinical trial as well as ensuring all legal, medical, and ethical aspects of the trial rests solely with the investigator. The Investigator must be a qualified practitioner (eg, MD, DDS, PharmD, etc) with prescriptive authority who is qualified to conduct the study. In addition, the Investigator is responsible for any individuals assisting in the conduct of the trial. In the United States, the responsibilities of investigators are determined by a combination of Food and Drug Administration (FDA) regulations (for the Investigator), good clinical practice (GCP), and sound management principles. The Investigator must fulfill certain responsibilities by law. In order to participate in clinical trials, Investigators are required to complete numerous forms/records. One of the commonly used forms is the FDA Form FDA Form 1572 Before a sponsor is permitted to allow an Investigator to participate in an FDA-regulated study, the Investigator must submit a signed and dated FDA Form 1572 (Statement of Investigator) to the sponsor. This two-page document requests information specific to the investigative site and requires documentation of the qualifications of the Investigator. In signing the 1572, the Investigator agrees to ensure that an investigation is conducted according to the signed Investigator statement, the investigational plan, and applicable regulations (Title 21, Code of Federal Regulations [CFR] ). After the Investigator has signed the 1572, the sponsor will forward it to FDA. The 1572 states the Investigator s commitments and is considered a contract between FDA and the Investigator. NOTE: Only studies conducted under an Investigational New Drug Application (IND) require that a 1572 be signed. Investigational Device Regulations Regulations differ somewhat for device studies. For example, an Investigator may be asked to complete an Investigator Agreement rather than an FDA Form Regulations found in 21 CFR Parts 50, 54, and 56 still apply, but in addition, 21 CFR 803, 812, and 814 govern investigational device studies. Specific Investigator obligations can be found in 21 CFR Mayo Clinical Trials Newsletter

5 FDA Form 1572 Investigator Commitments Iagree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects. I agree to personally conduct or supervise the described investigation(s). I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met. I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR Part I have read and understand the information in the Investigator s brochure, including the potential risks and side effects of the drug. I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments. I agree to maintain adequate and accurate records in accordance with 21 CFR Part and to make those records available for inspection in accordance with 21 CFR Part I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects. I agree to comply with all other requirements regarding the obligations of clinical Investigators and all other pertinent requirements in 21 CFR Part 312. Investigator Regulations Below are the Investigator regulations that are expected by the FDA. We have addressed each of them to help you interpret them. Study Conduct The Investigator will personally conduct or supervise the investigations. [21 CFR (c)(l)(i)(c)] Note: This responsibility may NOT be delegated. Human Subject Protection The Investigator is responsible for protecting the rights, safety, and welfare of subjects under the Investigator s care. [21 CFR ] Investigator s Brochure The Investigator will read the Investigator s Brochure and understand the potential risks and side effects of the drug. [21 CFR (c)(l)(vi)(f); ICH 4.1.2] Investigational Drug Administer the drug only to subjects under the Investigator s personal supervision or under the supervision of a subinvestigator responsible to the Investigator. Give investigational drug only to those authorized to receive it. Maintain adequate records of the disposition of the investigational drug, including dates, quantity, and use by subjects. Return unused supplies of the drug to the sponsor, or otherwise provide for their disposition under [21 CFR , 21 CFR , 21 CFR (a); ICH 4.6 (Investigational Products)] Note: The Investigator must ensure the person dispensing or administering the drug has been properly trained to do so and is in compliance with any local or state laws (eg, an RN must have a physician s order to dispense or administer drugs). Controlled Substances The investigative drug must be stored in a securely locked, substantially constructed enclosure. The continued on page 6 Mayo Clinical Trials Newsletter 5

6 Investigator must take adequate precautions to prevent theft or diversion into illegal channels of distribution. [21 CFR ]. Subject Medical Records and Other Source Documents Study personnel must prepare and maintain adequate and accurate case histories that record all observations and other pertinent data required by the sponsor. They must also make the records available for inspection to any properly authorized officer of FDA. [21 CFR (b), 21 CFR ] Note: FDA prefers to see the original source of documentation (ie, where pen was first put to paper). Note: Financial Disclosure documents are required of the Investigator and all those listed on the Adverse Experiences The investigator must report AEs to the sponsor. [21 CFR (b); ICH 4.11] Note: Although the regulation is directed at AEs it is important to follow the sponsor s requirements for expedited reporting of SAEs. Typically, the sponsor will define SAE criteria and time frames for reporting in the protocol. Record Retention It is necessary to maintain records (all study-related documentation) collected for the study for 2 years after study discontinuation, drug approval, or drug disapproval. [21 CFR (c)] Note: Two years after study discontinuation does not mean when the study closed at your site. This means 2 years after the sponsor determines to file an application to market, determines not to file an application to market, or decides to abandon the research completely and notifies you of these actions. Some studies conducted under International Conference on Harmonization (ICH) Guidelines may require storage as long as 15 years. (ICH ) Canada requires all documentation to be retained for 25 years. Investigator Reports The Investigator must submit reports to the sponsor at the times required by regulations and the sponsor: Progress reports Safety reports; adverse events (AE) and serious adverse events (SAE) Final Report at study end Financial Disclosure [21 CFR , 21 CFR 54; ICH 4.10, 4.11, 4.13] Institutional Review Board (IRB) The Investigator is responsible for assuring that the IRB is in compliance with 21 CFR 56. Obtain the IRB s initial and continuing review and approval of the study. Promptly report all changes in the research activity and unexpected risks to subjects or others to the IRB. Do not make any changes in the research without IRB approval, except when necessary to eliminate an immediate hazard to a subject. (21 CFR 56, 21 CFR ; ICH 4.4) Note: Follow IRB requirements for reporting. Protocol Compliance Changes to the protocol are to be made only after receiving sponsor and IRB approval except to eliminate immediate hazards to human subjects. (21 CFR ICH 4.5) Note: If departure from the protocol occurs, the nature of the departure and actions taken to prevent reoccurrence must be documented in the study files. Informed Consent and IRB Requirements Obtain informed consent in compliance with 21 CFR 50 and 56. Obtain IRB approval of the informed consent document or form prior to implementing the consent process with any subject. 6 Mayo Clinical Trials Newsletter 7

7 Obtain informed consent before enrolling subjects in the study. Provide each subject with sufficient time to make his decision about participating in the study. Ensure the consent document contains all the required elements and that the subject understands the language in the consent form. The consent may not contain any language that is exculpatory or waives or appears to waive any of the subject s rights. (21 CFR 50 and 56; ICH 4.8) Investigative Staff The Investigator is responsible for ensuring that staff is qualified, capable, and trained to perform their studyrelated responsibilities. In addition, personnel must be kept informed of study-related information and changes. (21 CFR (c)(l)(vi)(g); ICH 4.1.5) Investigator Disqualification An Investigator may be disqualified to participate in clinical trials for repeated or deliberate failure to comply with regulations or submitting false information to the sponsor. (21 CFR ) In this fast-paced and ever-changing research environment it is important that Investigators and study staff recognize and follow regulations, which include those agreed to when signing an FDA Form Caring for a patient is different than caring for a research subject. It is important to note that an Investigator may not make a decision for care that is not allowed by the protocol without first discussing with the sponsor and documenting the deviation from the protocol. Review and Self-Study: Federal Policy for the Protection of Human Subjects After reviewing these regulations, complete the Self-Study Test on page Applicability. a. The regulations in this subpart are applicable to all biomedical and behavioral research conducted or supported by the Department of Health and Human Services involving prisoners as subjects. b. Nothing in this subpart shall be construed as indicating that compliance with the procedures set forth herein will authorize research involving prisoners as subjects, to the extent, such research is limited or barred by applicable State or local law. c. The requirements of this subpart are in addition to those imposed under the other subparts of this part Purpose. Inasmuch as prisoners may be under constraints because of their incarceration, which could affect their ability to make a truly voluntary and uncoerced decision whether or not to participate as subjects in research, it is the purpose of this subpart to provide additional safeguards for the protection of prisoners involved in activities to which this subpart is applicable Definitions. As used in this subpart: a. Secretary means the Secretary of Health and Human Services, and any other officer or employee of the Department of Health and Human Services, to whom authority has been delegated. b. DHHS means the Department of Health and Human Services. c. Prisoner means any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures, which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing. d. Minimal risk is the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine continued on page Mayo Clinical Trials Newsletter 7

8 medical, dental, or psychological examination of healthy persons Composition of Institutional Review Boards where prisoners are involved. In addition to satisfying the requirements in of this part, an Institutional Review Board, carrying out responsibilities under this part with respect to research covered by this subpart, shall also meet the following specific requirements: a. A majority of the Board (exclusive of prisoner members) shall have no association with the prison(s) involved, apart from their membership on the Board. b. At least one member of the Board shall be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity, except that, where a particular research project is reviewed by more than one Board, only one Board need satisfy this requirement. [43 FR 53655, November 16, 1978, as amended at 46 FR 8386, January 26, 1981] Additional duties of the Institutional Review Boards where prisoners are involved. a. In addition to all other responsibilities prescribed for Institutional Review Boards under this part, the Board shall review research covered by this subpart and approve such research only if it finds that: 1. The research under review represents one of the categories of research permissible under (a)(2); 2. Any possible advantages accruing to the prisoner through his or her participation in the research, when compared to the general living conditions, medical care, quality of food, amenities and opportunity for earnings in the prison, are not of such a magnitude that his or her ability to weigh the risks of the research against the value of such advantages in the limited choice environment of the prison is impaired; 3. The risks involved in the research are commensurate with risks that would be accepted by nonprisoner volunteers; 4. Procedures for the selection of subjects within the prison are fair to all prisoners, and immune from arbitrary intervention by prison authorities or prisoners. Unless the principal investigator provides to the Board justification in writing for following some other procedures, control subjects must be selected randomly from the group of available prisoners, who meet the characteristics needed for that particular research project; 5. The information is presented in language which is understandable to the subject population; 6. Adequate assurance exists that parole boards will not take into account a prisoner s participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on his or her parole; and 7. Where the Board finds there may be a need for follow-up examination or care of participants after the end of their participation, adequate provision has been made for such examination or care, taking into account the varying lengths of individual prisoner s sentences, and for informing participants of this fact. b. The Board shall carry out such other duties as may be assigned by the Secretary. c. The institution shall certify to the Secretary, in such form and manner as the Secretary may require, that the duties of the Board under this section have been fulfilled Permitted research involving prisoners. a. Biomedical or behavioral research conducted or supported by DHHS may involve prisoners as subjects, only if: 1. The institution responsible for the conduct of the research has certified to the Secretary that the Institutional Review Board has approved the research under of this subpart; and 2. In the judgment of the Secretary the proposed research involves solely the following: (i) Study of the possible causes, effects, and processes of incarceration and of criminal behavior, provided that the study presents no more than minimal risk, and no more than inconvenience to the subjects; (ii) Study of prisons as institutional structures, or of prisoners as incarcerated persons, provided that the study presents no more 8 Mayo Clinical Trials Newsletter 9

9 than minimal risk, and no more than inconvenience to the subjects; (iii) Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis, which is much more prevalent in prisons than elsewhere; and research on social and psychological problems, such as alcoholism, drug addiction and sexual assaults), provided that the study may proceed only after the Secretary has consulted with appropriate experts, including experts in penology medicine and ethics, and published notice, in the FEDERAL REGISTER, of his intent to approve such research; or (iv) Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject. In cases, in which those studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups which may not benefit from the research, the study may proceed only after the Secretary has consulted with appropriate experts, including experts in penology medicine and ethics, and published notice, in the FEDERAL REGISTER, of his intent to approve such research. b. Except as provided in paragraph (a) of this section, biomedical or behavioral research conducted or supported by DHHS shall not involve prisoners as subjects. Subpart D Additional Protections for Children involved as Subjects in Research [SOURCE: 48 FR 9818, March 8, 1983, unless otherwise noted.] To what do these regulations apply? a. This subpart applies to all research involving children as subjects, conducted or supported by the Department of Health and Human Services. 1. This includes research conducted by Department employees, except that each head of an Operating Division of the Department may adopt such nonsubstantive, procedural modifications as may be appropriate from an administrative standpoint. 2. It also includes research conducted or supported by the Department of Health and Human Services outside the United States, but in appropriate circumstances, the Secretary may, under paragraph (e) of of Subpart A, waive the applicability of some or all of the requirements of these regulations for research of this type. b. Exemptions at (b)(1) and (b)(3) through (b)(6) are applicable to this subpart. The exemption at (b)(2) regarding educational tests is also applicable to this subpart. However, the exemption at (b)(2) for research involving survey or interview procedures or observations of public behavior does not apply to research covered by this subpart, except for research involving observation of public behavior, when the investigator(s) do not participate in the activities being observed. c. The exceptions, additions, and provisions for waiver, as they appear in paragraphs (c) through (i) of of Subpart A, are applicable to this subpart. [48 FR 9818, March 8, 1983; 56 FR 28032, June 18, 1991; 56 FR 29757, June 28, 1991] Definitions. The definitions in of Subpart A shall be applicable to this subpart as well. In addition, as used in this subpart: a. Children are persons, who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. b. Assent means a child s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent. c. Permission means the agreement of parent(s) or guardian to the participation of their child or ward in research. d. Parent means a child s biological or adoptive parent. e. Guardian means an individual, who is authorized under applicable State or local law, to consent on behalf of a child to general medical care. continued on page Mayo Clinical Trials Newsletter 9

10 IRB duties. In addition to other responsibilities assigned to IRBs under this part, each IRB shall review research covered by this subpart, and approve only research which satisfies the conditions of all applicable sections of this subpart Research not involving greater than minimal risk. HHS will conduct or fund research, in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in Research involving greater than minimal risk, but presenting the prospect of direct benefit to the individual subjects. HHS will conduct or fund research, in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject s well-being, only if the IRB finds that: a. The risk is justified by the anticipated benefit to the subjects; b. The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and c. Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject s disorder or condition. HHS will conduct or fund research, in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject, only if the IRB finds that: a. The risk represents a minor increase over minimal risk; b. The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social or educational situations; c. The intervention or procedure is likely to yield generalizable knowledge about the subjects disorder or condition, which is of vital importance for the understanding or amelioration of the subjects disorder or condition; and d. Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in Research not otherwise approvable, which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. HHS will conduct or fund research that the IRB does not believe meets the requirements of , , or , only if: a. The IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, and b. The Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law), and following opportunity for public review and comment, has determined either: 1. That the research in fact satisfies the conditions of , , or , as applicable, or 2. The following: (i) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (ii) the research will be conducted in accordance with sound ethical principles; (iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in Mayo Clinical Trials Newsletter 11

11 Requirements for permission by parents or guardians and for assent by children. a. In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine that adequate provisions are made for soliciting the assent of the children, when in the judgment of the IRB the children are capable of providing assent. In determining whether children are capable of assenting, the IRB shall take into account the ages, maturity, and psychological state of the children involved. This judgment may be made for all children to be involved in research under a particular protocol, or for each child, as the IRB deems appropriate. If the IRB determines that the capability of some or all of the children is so limited that they cannot reasonably be consulted, or that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children, and is available only in the context of the research, the assent of the children is not a necessary condition for proceeding with the research. Even where the IRB determines that the subjects are capable of assenting, the IRB may still waive the assent requirement under circumstances, in which consent may be waived in accord with of Subpart A. b. In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine, in accordance with and to the extent that consent is required by of Subpart A, that adequate provisions are made for soliciting the permission of each child s parents or guardian. Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for research to be conducted under or Where research is covered by and , and permission is to be obtained from parents, both parents must give their permission, unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child. c. In addition to the provisions for waiver contained in of Subpart A, if the IRB determines that a research protocol is designed for conditions or for a subject population, for which parental or guardian permission is not a reasonable requirement to protect the subjects (for example, neglected or abused children), it may waive the consent requirements in Subpart A of this part and paragraph (b) of this section, provided an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and provided further that the waiver is not inconsistent with Federal, state or local law. The choice of an appropriate mechanism would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity, status, and condition. d. Permission by parents or guardians shall be documented in accordance with and to the extent required by of Subpart A. e. When the IRB determines that assent is required, it shall also determine whether and how assent must be documented Wards a. Children, who are wards of the state or any other agency, institution, or entity can be included in research approved under or , only if such research is: 1. Related to their status as wards; or 2. Conducted in schools, camps, hospitals, institutions, or similar settings, in which the majority of children involved as subjects are not wards. b. If the research is approved under paragraph (a) of this section, the IRB shall require appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis. One individual may serve as advocate for more than one child. The advocate shall be an individual, who has the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child s participation in the research, and who is not associated in any way (except in the role as advocate or member of the IRB) with the research, the investigator(s), or the guardian organization. continued on page Mayo Clinical Trials Newsletter 11

12 Addendum: 46 FR 8392 Research Activities Which May Be Reviewed Through Expedited Review Procedures Research activities involving no more than minimal risk, and in which the only involvement of human subjects will be in one or more of the following categories (carried out through standard methods) may be reviewed by the Institutional Review Board through the expedited review procedure, authorized in of 45 CFR Part Collection of: hair and nail clippings, in a nondisfiguring manner; deciduous teeth, and permanent teeth if patient care indicates a need for extraction. 2. Collection of excreta and external secretions, including sweat, uncannulated saliva, placenta removed at delivery, and amniotic fluid at the time of rupture of the membrane prior to or during labor. 3. Recording of data from subjects 18 years of age or older, using noninvasive procedures routinely employed in clinical practice. This includes the use of physical sensors that are applied either to the surface of the body or at a distance, and do not involve input of matter or significant amounts of energy into the subject, or an invasion of the subject s privacy. It also includes such procedures as weighing, testing sensory acuity electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, diagnostic echography, and electroretinography. It does not include exposure to electromagnetic radiation outside the visible range (for example, x-rays, microwaves). 4. Collection of blood samples by venipuncture, in amounts not exceeding 450 milliliters in an eight-week period, and no more often than two times per week, from subjects 18 years of age or older, and who are in good health and not pregnant. 5. Collection of both supra- and sub-gingival dental plaque and calculus, provided the procedure is not more invasive than routine prophylactic sealing of the teeth, and the process is accomplished in accordance with accepted prophylactic techniques. 6. Voice recordings made for research purposes, such as investigations of speech defects. 7. Moderate exercise by healthy volunteers. 8. The study of existing data, documents, records, pathological specimens, or diagnostic specimens. 9. Research on individual or group behavior or characteristics of individuals, such as studies of perception, cognition, game theory, or test development, where the investigator does not manipulate subjects behavior, and the research will not involve stress to subjects. 10. Research on drugs or devices, for which an investigational new drug exemption or an investigational device exemption is not required. [SOURCE: 46 FR 8392; January 26, 1981.] 12 Mayo Clinical Trials Newsletter

13 Self-Study Test Title 45 Code of Federal Regulations (CFR) Part 46 Protection of Human Subjects (Sections ) Linda S. Knowlton, CCRP Protocol Coordinator for Cancer Center Statistics The self-study sections are reprinted from SoCRA Source, a publication of the Society of Clinical Research Associates (SoCRA). If you have already completed these sections in SoCRA Source, you cannot use them again towards recertification. The answer key is on page The regulations in Subpart C are applicable to the biomedical and behavioral research conducted by the Department of Health and Human Services involving as subjects. a. fetuses b. pregnant women c. prisoners d. all of the above 2. Any individual involuntarily confined or detained in a penal institution is known as prisoner. a. true b. false 3. The probability and magnitude of physical or psychological harm that is normally encountered in daily lives of healthy persons is known as. a. minimal risk b. risk c. high risk d. all of the above 4. The composition of the board where prisoners are involved shall meet the following requirements: a. at least one board member must be a prisoner b. a majority of the board shall have no association with the prison involved c. a and b d. none of the above 6. The term parent can refer to an adoptive parent. a. true b. false 7. An individual may not serve as an advocate for more than one child. a. true b. false 8. An individual who is authorized under state or local law to consent on behalf of a child for general medical care is known as a. a. guardian b. parent c. a and b d. all of the above 9. Which of the following is not an additional duty of the IRB where prisoners are involved: a. the risks are not commensurate to those of non-prisoner volunteers b. selection procedures are fair to all prisoners c. decisions regarding parole are not based on study participation d. the information is presented in a language which is understandable to the subject population 5. means a child s affirmative agreement to participate in research. a. Permission b. Assent c. Participation d. None of the above 10. are persons who have not attained the legal age for consent to treatments or procedures involved in the research. a. Parents b. Guardians c. Children d. Wards Mayo Clinical Trials Newsletter 13

14

15 Announcing Two New Web-Based Education Modules Mayo Clinical Trial Services has released two new modules in the first quarter of They are Investigational New Drug (IND) Applications and Patient Privacy and Confidentiality. On April 14, 2003, the Privacy Rule of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) went into effect, creating new national regulations for the protection of privacy and confidentiality for patients and research subjects. The module on Patient Privacy and Confidentiality for subjects in clinical research will assist research personnel in identifying the rights the HIPAA Privacy Rule assures for individuals Protected Health Information and recognizing the responsibilities of researchers in regard to individual subject s health information. The second module focuses on INDs and will assist research personnel in understanding what an IND application is, how an IND application is used, and where to get information about IND applications. It provides an overview of the purpose, requirements, and procedures for completing an IND application. Mayo Clinical Trials Newsletter The Mayo Clinical Trials Newsletter is published by Mayo Clinical Trials Services to update investigator sites about current issues related to conducting multicenter clinical trials in our continuing effort to bring quality and scientific excellence to clinical trials. A complimentary subscription of the Mayo Clinical Trials Newsletter is provided to Mayo Alliance for Clinical Trials investigators and coordinators. Please send address changes to mcts@mayo.edu or Mayo Clinical Trials Newsletter, 3050 Superior Drive NW, Rochester, MN, The Mayo Clinical Trails Newsletter can also be accessed online at: Contributors: Anne Holland, RN, CCRP Terry Jopke Linda Knowlton, CCRP Nancy Stanley Editorial Board: Anne Holland, RN, CCRP Terry Jopke Mary Laven Denise Masoner Russell Wiesner, MD Anita Workman Thomas Zimmerman ACCME physician and nonphysician credit or a certificate of completion is available for individuals who successfully complete the quiz associated with each module by achieving a score of 80% or greater. Please call the MCTS Education Office at for additional details. Self-Study Test Answers: 1. c. prisoners (Section a) 2. a. true (Section c) 3. a. minimal risk (Section d) 4. c. a and b (Section a and b) 5. b. assent (Section b) 6. a. true (Section d) 7. b. false (Section b) 8. a. guardian (Section e) 9. a. the risks are not commensurate to those of nonprisoner volunteers (Section [3]) 10. c. children (Section a) Mayo Clinical Trials Newsletter 15

16 Mayo Clinical Trials Newsletter 2005 Table of Contents Mayo ACT Welcomes New Medical Director: Russell Wiesner, MD Understanding the Crisis in Human Subjects Research Meeting Principal Investigator Obligations: FDA Form 1572 Review and Self-Study: Federal Policy for the Protection of Human Subjects Announcing Two New Webbased Education Modules MC Superior Drive NW Rochester, MN Non-Profit Organization U.S. POSTAGE PAID Rochester, MN Permit 146