According to the Belmont Report, respect for persons usually demands that subjects…
enter into research voluntarily & with adequate information
According to the Belmont Report, the moral requirement that there be fair outcomes in the selection of research subjects, expresses the principle of:
Justice
A poorly designed protocol is considered unethical because…
research subjects may be put at risk or inconvenienced for insufficient reason
When should an IRB suspend or terminate approval of research?
When it is not being conducted in accordance with the IRB’s requirements
A quorum for a convened IRB meeting requires the presence of…
a nonscientific member
What is required in research involving no more than minimal risk with children?
Adequate provisions are made for assent of the child and permission of parent or guardian
Federal regulations require each IRB to have written procedures for…
initial & continuing review of research and for reporting its findings and actions to the investigator and the institution
What are the 3 ethical principles discussed in the Belmont Report?
Respect for Persons, Justice, & Beneficence
An example of how the Principle of Beneficence can be applied to a study employing human subjects?
Determining that the study has a maximization of benefits & a minimization of risks.
The researcher’s failure to protect research subjects from deductive disclosure is the primary ethical violation of which study?
Harvard “Tastes, Ties, and Time (T3)” study (2006-2009)”
What is an example of how the principle of beneficence is applied to a study involving human subjects?
Ensuring that risks are reasonable in relationship to anticipated benefits
Humphreys collecting data for the Tearoom Trade study under the pretense that he was a lookout is an example of a violation of the principle of:
Respect for Persons
Which study is linked most directly to the establishment of the National Research Act in 1974 and ultimately to the Belmont Report and Federal regulations for human subject protection?
“The Public Health Service Tuskegee Study of Untreated Syphilis in the Negro Male”
The Belmont Principle of beneficence requires that…
potential benefits justify the risks of harm
A subject in a clinical research trial experiences a serious, unanticipated adverse drug experience. How should the investigator proceed, with respect to the IRB, after the discovery of the adverse event occurrence?
Report the adverse drug experience in a timely manner, in keeping with the IRB’s policies and procedures, using the forms or the mechanism provided by the IRB.
How long is an investigator required to keep consent documents, IRB correspondence, and research records?
For a minimum of three years after completion of the study
According to federal regulations, when can the IRB use expedited review on a new, proposed study?
The study involves no more than minimal risk and meets one of the allowable categories of expedited review specified in federal regulations
Amendments involving changes to IRB approved protocols do NOT need prior IRB approval if:
The changes must be immediately implemented for the health and well-being of the subject.
A therapist at a free university clinic treats elementary school children with behavior problems who are referred by a social service agency. She is also a doctoral candidate who proposes using data she has and will collect about the children for a case-based research project. Which of the following statements about parental permission is correct?
The parents of the children might feel pressure to give permission to the therapist to use their children’s data so that she will continue to provide services to their children.
A general requirement for informed consent is that no informed consent may include any exculpatory language. Exculpatory language is that which waives or appears to waive any of the subject’s legal rights or releases or appears to release those conducting the research from liability for negligence. Which of the following statements in a consent form is an example of exculpatory language?
“Taking part in the research is voluntary, but we choose you as a participant, you waive the right to legal redress for any research-related injuries”
A criterion for waiving informed consent is that, when appropriate, subjects are provided additional pertinent information after the study. In which of the following studies would it NOT be appropriate to provide subjects with information about missing elements of consent:
A study in which subjects were assigned to study activities based on an undesirable or unflattering physical characteristic as assessed by members of the research team.
A waiver of the requirement for documentation of informed consent may be granted when:
The only record linking the subject and the research is the consent document and the principal risk is a breach of confidentiality.
As part of the consent process, the federal regulations require researchers to:
Provide potential subjects with information at the appropriate reading comprehension level.
Data are made anonymous by…
Destroying all identifiers connected to the data.
A researcher leaves a research file in her car while she attends a concert and her car is stolen. The file contains charts of aggregated numerical data from a research study with human subjects, but no other documents. The consent form said that no identifying information would be retained, and the researcher adhered to that component. Which of the following statements best characterizes what occurred?
There was neither a violation of privacy nor a breach of confidentiality.
Which of the following constitutes both a breach of confidentiality (the research data have been disclosed, counter to the agreement between researcher and subjects) and a violation of subjects’ privacy (the right of the individuals to be protected against intrusion into their personal lives or affairs)?
A faculty member makes identifiable data about sexual behavior available to graduate students, although the subjects were assured that the data would be de-identified.
The Right of Subject Privacy
The right of the individuals to be protected against intrusion into their personal lives or affairs
The Right of Subject Confidentiality
Refers to a condition in which the researcher knows the identity of a research subject, but takes steps to protect that identity from being discovered by others.
In a longitudinal study that will follow children from kindergarten through high school and will collect information about illegal activities, which of the following confidentiality procedures would protect against compelled disclosure of individually identifiable information?
Securing a Certificate of Confidentiality
When a focus group deals with a potentially sensitive topic, which of the following statements about providing confidentiality to focus group participants is correct?
Confidentiality is not guaranteed: The researcher cannot control what participants repeat about others outside the group.
longitudinal study
a study that observes the same participants on many occasions over a long period of time
Example of Economic Vulnerability
A subject participates in a drug study because treatment is available at no or reduced cost, and he could not otherwise afford it.
Which is an example of a situation where deferential vulnerability might be a factor?
A physician recruiting his patients
Deferential Vulnerability
This includes individuals who informally subordinate to an authority figure. For example, abuse victims, doctor/patient relationships, and/or husband/wife relationships are all situations where one party may feel obligated to follow the advice of another.
Which is true of inducements in research?
Inducements constitute an “undue influence” if they alter a potential subject’s decision-making processes, such that they do not appropriately weigh the risk-benefit relationship of the research.
Example of Medical Vulnerability
Subjects with a serious illness may be at risk for exploitation since they may be desperate for a possible cure.
The most important ethical concerns related to conflicts of interest in research are:
Ensuring the objectivity of research and the protection of human subjects
Current NIH rules require investigators to disclose details regarding financial conflicts of interest to:
Designated institutional officials
The 1998 FDA regulations for requiring disclosure of significant financial interest reflect which threshold:
Any equity interest in a publicly held company that exceeds $50,000
A financial conflict of interest could involve
Receiving stock in a company funding your research.
Conflict of Interest
A situation in which financial or other personal considerations have the potential to compromise or bias professional judgment and objectivity is an example of:
Identify the following groups that are protected in the federal regulations (45 CFR 46), specifically in Subparts B, C and D with additional protections:
Subpart B: Pregnant women, human fetuses and neonates;
Subpart C: Prisoners; and
Subpart D: Children
Minimal Risk
The probability of harm or discomfort…not greater…than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations.
The Belmont Principles
Respect for persons, beneficence, and justice
IRB
An administrative body composed of scientists and nonscientists established to protect the rights and welfare of human research subjects recruited to participate in research activities conducted under the auspices of the institution with which it is affiliated.
Institutional Official (IO)
The person who signs the OHRP Federalwide Assurance and has the legal authority to act and speak for the institution, and should be somone who can ensure that the institution will effectively fulfill its research oversight function.
OHRP
Charged with monitoring and promoting compliance with DHHS regulations that relate to the ethical standards of human-subject resarch. They have the final word on when an institution is not complying with DHHS regulations and what the institution must do to correct the problem.
Minutes
45 CFR 46.115 (2) Require sufficiently detailed documentation to include attendance at the meeting; actions taken by the IRB; the vote on these actions, including the number of members voting for, against, or abstaining; the basis for requiring changes in or disapproving research; and a written summary of the discussion of controverted issues and their resolution.
Research Audit Program
Proactive, non-punitive, and focused on educating investigators about their ethical and regulatory responsibilities in the conduct of research.
IRB Director/Administrator
Primary person responsible for managing the IRB office and many of the administrative aspects of IRB meetings.
IRB Membership
Must consist of at least five members and include at least one scientist, one nonscientist and one person not affiliated with the institution.
IRB Membership Roster
Refers to the number of voting member positions on the IRB.
Alternate Member
When there is more than one member for an IRB roster position.
IRB Subcommittee
Committee consisting of one or more experienced reviewers organized for the purpose of managining a specific task or making a specific type of decision.
Social Harm
Decreases in quality of life that result from information being created or used in a way that is damaging to the individual in question– A result of the creation or transfer of information in a way that may negatively affect the research subject.
Expedited Review
A type of review that can be conducted by the Chair, designated IRB members, or a subcommittee of the IRB.
Research
45 CFR 46.102(d) A systematic investigation including development, testing, and evaluation, designed to develop or contribute to generalizable knowledge.
Human Subject
45 CFR 46.102(f)(1), (2) A living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual OR (2) identifiable private information.
Emergency Use
A treating physician’s request to use an investigational drug/device in a single patient during an immediately life-threatening situation in which no standard acceptable treatment is available and there is insufficient time to convene a quorum for full board IRB approval.
Risk
Probability and magnitude of the potential harm(s) or discomfort(s) anticipated by participating in the research.
Privacy
Can be defined in terms of having control over the extent, timing, and circumstances of sharing one’s self (physically, behaviorally, or intellectually) with others. Individuals’ right to have control over access to themselves and their information.
Confidentiality
Treatment of information that an individual has disclosed in a relationship of trust and with the expectation that it will not be divulged to others in ways that are inconsistent with the understanding of the original disclosure without permission. How information that is obtained from individuals is protected
Criteria for waiver or alteration of consent
45 CFR 46.116(d) An IRB may approve a waiver or alteration of consent requirements if:
*the research involves no more than minimal risk;
*the waiver or alteration will not adversely affect the rights and welfare of the subjects;
*the research could not practicably be carried out without the waiver or alteration; and
*whenever appropriate, the subjects will be provided with additional pertinent information after participation.
Informed Consent
45 CFR 46.116(a),(b); 46.117 Process to obtain informed permission from potential subjects before they participate in research, and an ongoing opportunity to retain subjects in trials whenever new information is available. Must be sought under circumstances that minimize the possibility of coercion or undue influence, and must include the 8 basic information elements described in the regulations. Information must be presented in a language understandable to the subject or LAR. The consent process must be documented with a written form approved by the IRB and signed by the subject/LAR.
Recruitment
The first step in the consent process. How potential subjects are identified and invited to participate in research.
DSMB
A committee that is established specifically to monitor data throughout the life of a study to determine whether it is appropriate, from both scientific and ethical standpoints, to continue the study as planned.
Stopping Rules
General term for specific and predetermined parameters that guide the data monitoring process.
Exculpatory Language
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.
Respect for Persons
Principle underlying the doctrine of informed consent. Requires recognition of the individual as an autonomous agent and protection of the individual with diminished autonomy. Requires that researchers carry out the process of informed consent and protect subject privacy.
Beneficence
The doing of good, obligates the researcher to secure the individual’s well-being by maximizing benefits and minimizing harms to the individual research subject. Requires that the researcher perform a risk/benefit analysis. Requires that competent investigators design ethical research, protect human subjects from risk, and make continuing assessments of the risk/benefit ratio.
Factors that may determine when a DSMB is necessary
A large study population, multiple study sites, highly toxic therapies or dangerous procedures, high expected rates of morbidity or mortality in the study population, high chance of early termination.
Reasons a DSMB may stop a study
efficacy, futility, or safety
Serious or Continuing Non-compliance
A problem that indicates noncompliance that is serious or continuing, OHRP will be notified within 48 hours, regardless of the funding source. If applicable the FDA will be notified.
Renewal Interval
No more than 365 days and is determined by the risk to subjects.
Main Goals of HIPAA
To make health insurance portable and increase accountability in Medicare billing.
Protected Health Information (PHI)
Individually identifiable health information held by a covered entity.
Authorization
Written permission from an individual allowing a CE to use or disclose specified PHI for a particular purpose.
Designated Record Set
The part of medical records that must be disclosed to the individual–research information that is specifically for research is not typically part of this.
Data Use Agreement
An agreement in which the data recipient promises not to attempt to re-identify or contact the individuals.
Limited Data Set (LDS)
Allows more identifiers than a de-identified data set–in particular allows all dates and ZIP codes , but street addresses are not allowed–this set is still considered PHI and is subject to the minimum necessary requirements of the Privacy Rule.
Business Associate Contracts (BACs)
For activities related to treatment, payment, or operations–the only research activities for which this might be pertinent are obtaining authorizations and creating a limited or de-identified data set.
Federalwide Assurance (FWA)
A type of contract established by OHRP that specifies when and how an institution will comply with DHHS research regulations. Written documentation of an institution’s commitment to comply with federal regulations governing human subjects research–covers all federally supported or conducted research involving human subjects.
Human Protections Administrator
An employee or agent of the FWA institution who exercises day-to-day operational responsibility for the institution’s program for protecting human subjects. AKA IRB Administrator/Director.
International Conference on Harmonization (ICH)
Designed to streamline the process for developing and marketing new drugs internationally, composed of representatives from the pharmaceutical industry and the regulatory bodies of the US, Japan, and the EU, and has established several international standards of good clinical practice (GCP) for the development of pharmaceutical products.
Differences Between ICH guidelines and US Regulations
Definition of vulnerable subject, Confidentiality of Medical Records, Signature by Person Conducting the Consent Discussion, Subject Receipt of a Signed and Dated Copy of the Consent Form, Assent for Children and Mentally Incapacitated Adults, Impartial Witness for Illiterate Subjects, and Prior Approval for Minor Amendments
Off-label Use
A treating physician administers a drug for an indication other than the approved ones.
Form 483 “Statement of Findings”
Essentially a blank page that the deficiencies found during an FDA audit are written on.
Establishment Inspection Report (EIR)
A report which contains positive and negative observations from the FDA’s audit of an IRB.
Voluntary Action Indicated (VAI) Letter
Letters that simply ask for a correction of minor deficiencies found during an FDA audit.
Official Action Indicated (OAI) Letter
Letter that demands correction for what the FDA believes to be serious deficiencies and/or violations of the regulations–these are called warning letters and often carry some type of sanction for the instituion and its investigators.
Study-oriented Inspections
Inspections that are done at study sites that have participated in pivotal clinical trials (trials that the FDA uses to approve drugs and devices for marketing).
Investigator-oriented Inspections
Inspections that are usually the result of one or more reports of questionable behavior or of questions that have been raised.
The 3 Statutory Responsibilities of OHRP
Administration of assurances, education, and compliance oversight.
Five Basic Categories of Harm as noted in The Belmont Report
social harm, economic harm, legal harm, psychological harm, and physical harm
Vulnerable Persons
Persons who are relatively (or absolutely) incapable of protecting their own interest.
Peer contagion
May be caused by grouping high-risk adolescents for behavioral interventions in which negative behaviors are enforced. This is of particular risk in school-based research.
Activities with schoolchildren that DO NOT qualify for exemption under Subpart D
- Research involving surveys
- Research involving interviews
- Observation of public behavior when the researcher participates in the activities being observed
Fetus
The product of conception from the time of implantation until delivery.
Pregnancy
Encompassing the period of time from confirmation of implantation until expulsion or extraction of the fetus.
Viable
Able to survive if given the benefit of available medical therapy to the point of independently maintaining heartbeat and respiration.
Non-Viable
A fetus that has not attained a gestational age of 20 weeks and does not exceed 400 grams in weight.
Human Pluripotent Stem Cells (hPSCs)
Cells that are self-replicating, are derived from human embryos or fetal tissue and are known to develop into cells and tissues of the three primary germ layers. Research on such cells may be conducted only if the cells were derived from human embryos that were created for the purposes of fertility treatment and were in excess of the clinical need of the individuals seeking such treatment.
Research equipoise
The state in which genuine uncertainty exists regarding which intervention—experimental or control—is better. Neither the experimental or control intervention is preferred.
Risk/Benefit Analysis
Potential risks of study participation must be weighed against potential benefits. Compensation must never be considered as a potential benefit.
Parent
A child’s biological or adoptive parent.
Guardian
An individual who is authorized under applicable state or local law to consent on behalf of a child to general medical care.
Assent
A child’s affirmative agreement to participate in research. The regulations do not indicate an age at which this ought to be possible.
Prisoner
Any individual involuntarily confined or detained in a penal institution, including situations where a human subject becomes one after the research has commenced.
Minimal Risk as Defined in Subpart C
The probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons. In non-prisoner research, IRBs consider a wide range of risks, representing the possibility of physical, psychological, social, economic, or legal harms. In Subpart C, however, only physical or psychological harm is mentioned.
Component Analysis
An ethical analysis of risks and benefits built on the recognition that clinical research often contains a mixture of therapeutic and non-therapeutic procedures and that separate moral standards are required for each.
Treatment IND
Investigational drugs are allowed to be used for treatment of a single patient while Phase II/III studies are still underway only when the manufacturer agrees to provide the drug and the FDA issues this patient-specific IND.
Emergency Use IND
A special category of drugs for studies invoking the special waiver of consent for treatment studies in an emergency setting. A set of rules under which therapeutic trials in an emergency setting can be done. These rules provide for a community consultation in lieu of individualized consent and restrict the research to a very serious condition under circumstances that preclude getting surrogate consent in a timely manner.
Anonymous Samples
Samples collected without direct identifiers and involve the lowest level of risk.
Anonymized Samples
Samples that were originally collected with direct identifiers and from which the identifiers have been irretrievably stripped from the sample and replaced with a random code.
Identified Samples
Samples in which the identity of the donors can be readily ascertained.
Coded or Linked Samples
Samples where the direct identifier is replaced with a code and a key to the code exists. These samples are the most used in research.
Placebo
Any medical treatment that is inactive for the condition being evaluated other than the effect which may result from a person’s thinking that he or she may be receiving an active treatment.
Historical Control Group
A control group that is chosen from studies that were completed in the past.
Noninferiority Trial
A trial that uses active treatment control where the goal is to show that the study drug is not less effective than the control by more than a defined amount.
Intrapatient Dose Escalation
A dosing scheme that allows patients to be given successively higher doses of an experimental drug if the initial dose administered proves to be well tolerated but unable to achieve the efficacy target.
Benefit
The positive value or advantage of being part of the research study.
Nuremberg Code
Ten points (not law) determined to be essential for conducting research with humans. Summarized, they include:
*Informed consent
*Research should be based on prior animal work
*Risks should be justified by anticipated benefits
*Only qualified scientists may conduct research
*Physical/mental suffering must be avoided
*Research in which death or disabling injury is expected should not be conducted
Declaration of Helsinki
1964 World Medical Association code of research ethics that reinterpreted Nuremberg Code, specifically with regard to clinical trials with therapeutic intent. Subsequently, journal editors required research be conducted in accordance with the declaration.
Beecher Article
1966 Dr. Henry K Beecher (anesthesiologist) wrote an article in NEJM describing 22 studies with controversial ethics that had been conducted by reputable researchers and published in major journals.
Willowbrook Hepatitis Study
1956 Willowbrook – an institution for mentally retarded children – initiated a study to determine the natural history of viral hepatitis, and to test the effectiveness of gamma globulin as an agent for innoculating against hepatitis. Children were deliberately infected with a mild form of hepatitis. Ethical problems: exploitation of vulnerable population, withholding risk information, coercion.
Jewish Chronic Disease Study
1963 liver cancer cells were injected into senile patients without their knowledge as part of a study of immunity to cancer. Researchers believed cells would be rejected, so did not think it was necessary to frighten the patients by telling them. Ethical problems: lack of informed consent, vulnerable population.
San Antonio Contraception Study
1971 Mexican-American women seeking contraceptives from a clinic participated in a study that involved taking oral birth control then crossover to placebo. Subjects were not informed of the crossover. Ten of 76 participants became pregnant. Ethical problems: lack of informed consent, vulnerable population, risks outweighed benefits.
Milgram Study
1963 a series of social psychology experiments conducted by Yale University psychologist Stanley Milgram. They measured the willingness of study participants, men from a diverse range of occupations with varying levels of education, to obey an authority figure who instructed them to perform acts conflicting with their personal conscience (administering electric shocks to a subject who was allied with the research and who pretended to feel pain) ; the experiment found, unexpectedly, that a very high proportion of people were prepared to obey, albeit unwillingly, even if apparently causing serious injury and distress. Ethical problems: deception, unanticipated psychological harms
Public Health System Syphilis Study
1932-1971 PHS study designed to document the natural history of syphilis in African-American men. At the time the study was initiated, there was no known treatment for syphilis. Men were recruited without truly informed consent, and received “treatments” such as spinal taps that had no real curative intent. After penicillin was found to be safe and effective treatment for syphilis in the 1940s, the men in the study were denied antibiotics. The study resulted in 28 deaths, 100 cases of disability and 19 cases of congenital syphilis. Ethical problems: lack of informed consent, deception, withholding information, withholding treatment, putting men and their families at risk, exploitation of a vulnerable population who would not benefit from participation.
The National Commission/The National Research Act
1974 Congress authorized the formation of the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. The Commission was charged with the task of identifying the basic ethical principles that underlie the conduct of human subject research. In 1979, the Commission published the Belmont Report.
Justice
Requires research to treat potential and enrolled subjects fairly. This means selecting subjects equitably and disallows exploiting vulnerable populations.
Jesse Gelsinger
1999 18-year-old Jesse Gelsinger participated in a gene therapy trial to treat his rare metabolic condition, which had previously been controlled with medication and diet. Shortly after treatment on study, Jesse experienced multi-organ failure and subsequently died. Serious concerns were raised afterward about conflict of interest, data safety monitoring and informed consent.
Identifiable Private Information
45 CFR 46.102(f)(2) Information about behavior that occurs in a context in which an individual can reasonable expect that no observation is taking place, and information which as been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (e.g., a medical record).
Exempt Categories
Research that does not require IRB review because involvement of human subjects is limited to six types of activities/settings:
1) Research conducted in established or commonly accepted educational settings, involving normal educational practices;
2) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior;
3) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior if the human subjects are elected or appointed public officials or candidates for public office;
4) Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects;
5) Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine:
(i) Public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs;
6) Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without additives are consumed or (ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.
Local Context
45 CFR 46.107 IRBs must be knowledgeable about the local research context:
*The IRB must be sufficiently qualified through the experience and expertise and diversity of its members, including race, gender, cultural background, and sensitivity to such issues as community attitudes to promote respect for its advice and counsel.
*The IRB must be able to evaluate research in terms of institutional commitments and regulations, applicable law, and standards or professional conduct and practice.
Subpart D – Research Involving Children
Additional protections for research involving children include:
*45 CFR 46.402(d) Children are defined as persons who have not attained legal age for consent in the jurisdiction in which the research will be conducted.
*45 CFR 46.404-408 There are 4 permissable categories of research involving children:
- not >min risk with assent according to age/ability, permission from one parent;
- >min risk but with prospect of direct benefit to participant with assent according to age/ability, permission from one parent;
- >min risk no direct benefit, but likely to yield generalizable knowledge about the subject’s disorder or condition, with assent according to age/ability, and permission from both parents (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); and
- not otherwise approvable but presents an opportunity to understand/ prevent/alleviate a serious problem affecting the health or welfare of children), with assent according to age/ability, and permission from both parents (with the same caveats noted previously). In addition, the DHHS Secretary must consult with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and provide an opportunity for public review and comment, then determine that the research either:
- satisfies the conditions of §46.404, §46.405, or §46.406, as applicable, or
- agree 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; twill be conducted in accordance with sound ethical principles; and adequate provisions are made for soliciting the assent and permission.
*45 CFR 46.409 Children who are wards of the state or any other agency can only be included in research under very limited conditions.
Subpart C – Research Involving Prisoners
Additional protections for research involving prisoners include:
*45 CFR 46.303(c) Prisoner is defined as any individual who is involuntarily confined or detained in a penal institution.
*45 CFR 46.304(b) At least one member of the IRB must be a prisoner or a prisoner representative when reviewing research involving prisoners.
*45 CFR 46.305 IRBs must certify to DHHS that research involving prisoners:
(1) meets one of the categories of research permissible under 46.306;
(2) Any possible advantages accruing to the prisoner through his or her participation in the research are not coercive;
(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;
(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 prisoners’ sentences, and for informing participants of this fact.
*45 CFR 46.306 Biomedical or behavioral research conducted or supported by DHHS may involve prisoners as subjects only if 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 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 and published notice in the Federal Register.
Certificates of Confidentiality (COC)
Public Health Act Section 301(d) Gives the HHS Secretary authority to issue COCs which protect the privacy of subjects in health research projects against compulsory legal process. NIH issues the COCs. Effectiveness is retroactive once granted. Some regulations can supersede COCs (e.g., domestic abuse, child abuse). COCs only afford protections for information that is recorded solely in research records (cannot protect clinical records against forced disclosure).
8 Criteria for IRB Approval
- Minimize risk to subjects
- Assess the risk/benefit ratio (potential benefits must outweight the risks)
- Ensure equitable selection of subjects
- Evaluate the informed consent process
- Review/edit the informed consent documents
- Review privacy and confidentiality provisions
- Data and safety monitoring plan
- Vulnerable populations
Phase 0-4 Drug Trials
*Phase 0: exploratory studies that often use only a few small doses of a new drug in a few patients.
*Phase 1: usually the first studies that involve people. The main reason for doing phase I studies is to find the highest dose of the new treatment that can be given safely without serious side effects.
*Phase 2: Testing for efficacy in a small population of patients with disease, usually at the MTD found to be safe in Phase I. Some phase II studies randomly assign participants to different treatment groups (much like what’s done in phase III trials), but generally there is no placebo/sham arm. These groups may get different doses or get the treatment in different ways to see which provides the best balance of safety and effectiveness.
*Phase 3: compare the safety and effectiveness of the new treatment against the current standard treatment in a large group of subjects at multiple sites. Randomized, double-blind studies are the gold standard; placebo arms are common.
*Phase 4: Long term study of drugs that have already been approved by the FDA, to look at safety over time, or to study other aspects of treatment such as quality of life or cost effectiveness. Usually involves thousands of subjects.
510(k) Device
A medical device that is considered substantially equivalent to a device that was/is legally marketed (a predicate device). FDA is given 90 days notice when such a device is planned to be marketed.
Investigational Device Exemption (IDE)
Exemptions from certain regulations found in the Medical Device Amendments that allow shipment of unapproved devices for use in clinical investigations.
Significant/Non-Significant Risk Devices
Significant 21 CFR 812.3(m): An investigational medical device that presents a potential for serious risk to the health, safety or welfare of the subject, and is:
*intended for use as an implant; or
*used to support or sustain life; or
*used to diagnose, cure, mitigate or treat disease.
Non-Significant: An investigational medical device that does not meet the definition of an SR.
The IRB must review a
sponsor’s SR or NSR determination for every investigational medical device study reviewed and
modify the determination if the IRB disagrees with the sponsor. If FDA has already made the
SR or NSR determination for the study, the agency’s determination is final.
Sponsors of studies using NSR devices must still adhere to abbreviated IDE requirements at 21 CFR 812.2(b).
Premarket Approval
Process of scientific and regulatory review by the FDA to ensure the safety and effectiveness of Class III devices before they become FDA approved.
Device Classifications
Class I Devices
Considered to be at the lowest level of risk of all medical devices and are therefore required to comply with the lowest level of regulatory control. Examples of Class I devices include: elastic bandages, dental floss and enemas.
Class II Devices
Simple devices, though they are considered to be at slightly higher risk than Class I devices and therefore require more stringent regulatory controls to provide assurance of their effectiveness and safety. Examples of Class II devices include: condoms, pregnancy testing kits and powered wheelchairs.
Class III Devices
Class III devices are generally considered to be the most complex devices. They are also considered to be at the highest risk and therefore require more stringent regulatory controls to provide assurance of their effectiveness and safety. Examples of Class III devices include: implantable pacemakers and breast implants.
Deception in SBER
Deception or incomplete disclosure is permitted only when the researcher documents that an alteration of the usual informed consent requirements is justified under the criteria presented in the federal regulations at 45 CFR 46.116(d). Specifically, the IRB must review and document:
- There is some scientific value and validity to the use of deception;
- The relative efficacy of alternative procedures was considered in relation to the proposed use of deception;
- The deception does not extend to influence potential subjects’ willingness to participate;
- The possibility of experimentally induced harm, and whether there are sufficient procedures in place to remove or mitigate such harm through debriefing after study participation; and
- The potential of deception to facilitate unwanted and inappropriate invasions of privacy.
Engaged in Research
Once an activity is determined to involve non-exempt human subjects research, each institution involved in some aspect of the research must determine their “engagement” in that research in order to know if certain regulatory requirements apply to that activity.
In general, an institution is considered engaged in a particular non-exempt human subjects research project when its employees or agents for the purposes of the research project obtain: (1) data about the subjects of the research through intervention or interaction with them; (2) identifiable private information about the subjects of the research; or (3) the informed consent of human subjects for the research.
Institutions that are engaged in non-exempt human subjects research are required by 45 CFR part 46 to:
*hold or obtain an applicable OHRP-approved FWA [45 CFR 46.103(a)]; and
*certify to the HHS agency conducting or supporting the research that the research has been reviewed and approved by an IRB designated in the FWA, and will be subject to continuing review by an IRB [45 CFR 46.103(b)].
Expedited Review Categories
Research activities that present no more than minimal risk to human subjects, and involve only procedures listed in one or more of the following categories, may be reviewed by the IRB through the expedited review procedure authorized by 45 CFR 46.110 and 21 CFR 56.110:
- Clinical studies of drugs and medical devices only when condition (a) or (b) is met:
(a) Research on drugs for which an investigational new drug application (21 CFR Part 312) is not required.
(b) Research on medical devices for which (i) an investigational device exemption application (21 CFR Part 812) is not required; or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling. - Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows:
(a) from healthy, nonpregnant adults who weigh at least 110 pounds (amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more frequently than 2 times per week); or
(b) from other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected (amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week). - Prospective collection of biological specimens for research purposes by noninvasive means.
- Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing.
- Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for nonresearch purposes (such as medical treatment or diagnosis).
- Collection of data from voice, video, digital, or image recordings made for research purposes.
- Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies.
- Continuing review of research previously approved by the convened IRB, as follows:
(a) where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; or
(b) where no subjects have been enrolled and no additional risks have been identified; or
(c) where the remaining research activities are limited to data analysis. - Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories 2-8 do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified.
Humanitarian Device Exemption (HDE)
A marketing application for an HUD (Section 520(m) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)). An HDE is exempt from the effectiveness requirements of Sections 514 and 515 of the FD&C Act and is subject to certain profit and use restrictions.
Humanitarian Use Device (HUD)
A medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in not more than 8,000 individuals in the United States per year (Section 3052 of the 21st Century Cures Act (Pub. L. No. 114-255).
Unanticipated Problem Involving Risks to Subjects or Others (UPIRSO)
OHRP/FDA considers unanticipated problems to include any incident, experience, or outcome that meets all of the following criteria:
- unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
- related or possibly related to participation in the research (meaning there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
- suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
All UPIRSOs should be reported to appropriate institutional officials (as required by an institution’s written reporting procedures) and to OHRP/FDA within one month of the IRB’s receipt of the report of the problem from the investigator.
Size & Composition of IRB
45 CFR 46.107(a) Each IRB shall have at least 5 members.
45 CFR 46.107(c) Each IRB shall include at least one member whose primary concerns are in scientific areas and at least one member whose primary concerns are in nonscientific areas.
45 CFR 46.107(d) Each IRB shall include at least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution.
Quorum
The minimum number (e.g., more than half) of voting members on a given IRB who are required to be present for the discussion and vote on a study.
45 CFR 46.108(b) IRBs must review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are in nonscientific areas. In order for the research to be approved, it shall receive the approval of a majority of those members present at the meeting.
IRB Lines of Authority
There are no federal regulations about lines of authority; however the following are best practice for maintaining the IRB’s autonomy and credibility/ authority:
*IO is a high-ranking administrative officer who is authorized to act on behalf of the institution and assume overall responsibility for compliance with federal regulations. Should not be the same person who directs grants and sponsored research because of conflict of interest.
*IRB Chair acts on behalf of the IRB, should report to the IO.
*Chief IRB Administrator directs the IRB support office or HRPP, should report to IO.
*IRB Chair and IRB Administrator work together but do not report to each other.
*IRB Staff usually report to IRB Administrator.
IRB Staff Responsibilities
*Screening protocols before IRB review
*Agenda preparation
*Meeting logistics
*Taking minutes
*Drafting correspondence
*Triage of amendments/ modifications
*Database and information management
*Triage of adverse events/safety reports
*Responding to subject concerns
*Triage of protocol violations
*Writing/revising policies & procedures
*Education & training
Subpart B – Research Involving Pregnant Women and/or Human Fetuses
45 CFR 46.204 Pregnant women or fetuses may be involved in research if all of the following conditions are met:
(a) preclinical studies, including studies on pregnant animals, and clinical studies, including studies on nonpregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses;
(b) The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means;
(c) Any risk is the least possible for achieving the objectives of the research;
(d) the pregnant woman’s consent is obtained in accord with the informed consent provisions of subpart A;
(e) If the research holds out the prospect of direct benefit solely to the fetus then the consent of the pregnant woman and the father is obtained in accord with the informed consent provisions of subpart A;
(f) Each individual providing consent under paragraph (d) or (e) of this section is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate;
(g) For children as defined in §46.402(a) who are pregnant, assent and permission are obtained in accord with the provisions of subpart D of this part;
(h) No inducements, monetary or otherwise, will be offered to terminate a pregnancy;
(i) Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy; and
(j) Individuals engaged in the research will have no part in determining the viability of a neonate.
Subpart B – Research Involving Neonates
45 CFR 46. 205 Neonates of uncertain viability and nonviable neonates may be involved in research if all of the following conditions are met:
(1) preclinical and clinical studies have been conducted and provide data for assessing potential risks to neonates.
(2) Each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the neonate.
(3) Individuals engaged in the research will have no part in determining the viability of a neonate.
(4) (b) Neonates of uncertain viability. Until it has been ascertained whether or not a neonate is viable, a neonate may not be involved in research covered by this subpart unless the following additional conditions have been met:
*The IRB determines that:
(i) The research holds out the prospect of enhancing the probability of survival of the neonate to the point of viability, and any risk is the least possible for achieving that objective, or
(ii) The purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the research; and
*The legally effective informed consent of either parent of the neonate or, if neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent’s legally authorized representative is obtained , except that the consent of the father or his legally authorized representative need not be obtained if the pregnancy resulted from rape or incest.
(4) (c) Nonviable neonates. After delivery nonviable neonate may not be involved in research covered by this subpart unless all of the following additional conditions are met:
(1) Vital functions of the neonate will not be artificially maintained;
(2) The research will not terminate the heartbeat or respiration of the neonate;
(3) There will be no added risk to the neonate resulting from the research;
(4) The purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means; and
(5) The legally effective informed consent of both parents of the neonate is obtained (the waiver and alteration provisions of §46.116(c) and (d) do not apply). However, if either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, the informed consent of one parent of a nonviable neonate will suffice. The consent of a legally authorized representative of either or both of the parents of a nonviable neonate will not suffice.
(4) (d) Viable neonates. A neonate, after delivery, that has been determined to be viable may be included in research only to the extent permitted by and in accord with the requirements of subparts A and D.
Waivers of Parental Permission/Child Assent
45 CFR 46.116 This mainly applies to research conducted in public schools. IRBs must find and document that:
- The research involves no more than minimal risk to the subjects.
- The waiver or alteration will not adversely affect the rights and welfare of the subjects.
- The research could not practicably be carried out without the waiver or alteration.
- Whenever appropriate, the subjects will be provided with additional pertinent information after participation.
Passive Consent & Parental Notification
Used in school-based research. Involves notifying parents that research will take place and giving them an opportunity to state they do not want their child to participate. Not equivalent to informed consent. May only be used in school-based research if the IRB has waived the requirement for parental permission.
Educational Harm
The harm caused by diverting instructional time to research activities. It is the school, not the researcher, that decides when it is appropriate to use class time for research. However, researchers should build in transitional activities to assist student subjects in returning to classwork after research participation. One strategy is to close potentially unsettling research activities with a positive activity.
The Family Educational Rights and Privacy Act (FERPA)
Describes the process researchers must use to access students’ educational records. Requires schools to have written permission from a parent or a student who is 18 or older before releasing any identifiable information from a student’s record. Schools may disclose without consent “directory” information such as student’s name, address, telephone number, date/place of birth, honors/awards, and dates of attendance.
The Protection of Pupil Rights Amendment (PPRA)
Amended by the “No Child Left Behind Act” of 2001, gives parents some level of control over the content of third-party survey research and any instructional materials developed by researchers. Identifies 8 sensitive topics and includes 2 provisions for parental review and approval of surveys that include any of these 8 topics:
- Political affiliations or beliefs of the student/parents
- Mental and psychological problems of the student/family
- Sex behavior/attitudes
- Illegal, antisocial, self-incriminating or demeaning behavior
- Critical appraisals of other individuals with whom respondents have close family relationships
- Legally recognized privileged or analogous relationships, such as those of lawyers, physicians, ministers
- Religious practices, affiliations, or beliefs of the student/parents
- Income (other than that required by law to determine eligibility for participation in a program or for receiving financial assistance under such program)
Research Conducted at Private Schools
FERPA and PPRA apply only if a school receives federal funding. If research is conducted under an applicable program of the US Dept of Education, then the regulations apply.
Veterans Health Administration (VHA) Handbook
Outlines the procedures for implementing 38 CFR 16, which is the VA’s correlate to the Common Rule for the protection of human subjects. It applies to all research involving human subjects that is conducted by VA personnel on official VA time or in VA facilities, regardless of the funding source.
Specifics of VA research include:
- All VA facilities involved in human subjects research must hold an FWA.
- Only the facility director is authorized to serve as the IO.
- PI and subinvestigators must be VA employees paid directly by the VA, appointed to work without compensation, or be assigned to the VA under the terms of an Intergovernmental Personnel Act.
- In addition to IRB review, the VA R&D committee must approve all research (with or without human subjects, and including IRB-exempt research) to be undertaken at the facility or using facility resources or personnel on VA time.
- VA policy prohibits the use of commercial IRBs, and there are specific requirements about how many VA-salaried employees must serve on an IRB that reviews VA research.
- Research involving children or prisoners may not be conducted by VA investigators on official duty or at VA facilities unless a waiver has been granted by the Chief Research & Development Officer.
- VA consent forms must be written on VA Form 10-1086 and approval information must be stamped on every page.
- A witness must sign consent.
- Research-related injuries will be treated by the VA when the research was approved by the VA R&D committee and is conducted under the supervision of one or more VA investigators.
- Non-veterans may only be enrolled in VA-approved research when there are insufficient numbers of veterans to complete the study.
- In general , compensating subjects is prohibited in VA-approved research. There are some exceptions, but must be IRB approved.
- The VA defines LARs beyond what is defined in the Common Rule.
- The ORO advises the VA’s Under Secretary on all matters regarding compliance and assurance for human subjects protections (and animal welfare), research safety, physical security, and research misconduct.
Tearoom Trade Study
1970 The study is an analysis of homosexual acts taking place in public toilets. Humphreys asserted that the men participating in such activity came from diverse social backgrounds, had differing personal motives for seeking homosexual contact in such venues, and variously self-perceived as “straight,” “bisexual,” or “gay.” His study called into question some of the stereotypes associated with the anonymous male-male sexual encounters in public places, demonstrating that many of the participants lived otherwise conventional lives as family men and respected members of their communities, and that their activities posed no danger of harassment to straight males. Because the researcher misrepresented his identity and intent and because the privacy of the subjects was infringed during the study, Tearoom Trade has caused a major debate on privacy for research participants and is now often used as an example of highly controversial social research.
Wichita Jury Study
1953 Researcher’s audio-taped jurors deliberating on cases, without their permission. Public criticism about the basic problem of deceiving people for research purposes in a setting where privacy and confidentiality were critically important. It is not appropriate to compromise the integrity of important social institutions, even if it’s the only way to answer important research questions.
Stanford Prison Experiment/Zimbardo
1971 An attempt to investigate the psychological effects of perceived power, focusing on the struggle between prisoners and Prison officers. It was conducted at Stanford University by a research group led by psychology professor Philip Zimbardo using college students. It was funded by the U.S. Office of Naval Research as an investigation into the causes of difficulties between guards and prisoners in the United States Navy and United States Marine Corps. Guards and prisoners had been chosen randomly from the volunteering college students. Some participants developed their roles as the officers and enforced authoritarian measures and ultimately subjected some prisoners to psychological torture. Many of the prisoners passively accepted psychological abuse and, by the officers’ request, actively harassed other prisoners who tried to stop it. Zimbardo, in his role as the superintendent, allowed abuse to continue. Two of the prisoners left mid-experiment, and the whole exercise was abandoned after six days.
Tudor/Monster Study
1939 A stuttering experiment performed on 22 orphan children in Davenport, Iowa. It was conducted by Wendell Johnson at the University of Iowa. Graduate student Mary Tudor conducted the experiment under Johnson’s supervision. Half of the children received positive speech therapy, praising the fluency of their speech, and the other half, negative speech therapy, belittling the children for speech imperfections. Many of the normal speaking orphan children who received negative therapy in the experiment suffered negative psychological effects and some retained speech problems for the rest of their lives.
Science Club Study
1940s The Fernald School was the site of joint experiments by Harvard University and MIT that exposed young male children to tracer doses of radioactive isotopes. The experiment was conducted in part by a research fellow sponsored by the Quaker Oats Company. MIT Professor of Nutrition Robert S. Harris led the experiment, which studied the absorption of calcium and iron.
The boys were encouraged to join a “Science Club”, which offered larger portions of food, parties, and trips to Boston Red Sox baseball games. The 57 club members ate iron-enriched cereals and calcium-enriched milk for breakfast. In order to track absorption, several radioactive calcium tracers were given orally or intravenously.
Radiation levels in stool and blood samples would serve as dependent variables. In another study, 17 subjects received iron supplement shots containing radioisotopes of iron. Neither the children nor their parents ever gave adequate informed consent for participation in a scientific study.
Stateville Prison Malaria Study
1940s Prisoner-subjects were infected with malaria for the purpose of testing the safety and efficacy of novel anti-malaria drugs. Over time, commentators have shifted from viewing the malaria research at Stateville as a model of ethical clinical research to seeing the experiments as paradigmatic of abusive human experimentation.
The Radioactive Drug Research Committee (RDRC) program
1975 The FDA published a Federal Register notice classifying all radioactive drugs as either new drugs requiring an Investigational New Drug Application (IND) for investigational use (21 CFR 312) or as generally recognized as safe and effective when administered under the conditions specified in the RDRC regulations (21 CFR 361.1). The RDRC program under 21 CFR 361.1 permits basic research using radioactive drugs in humans without an IND when the drug is administered under the following conditions:
- The research is considered basic science research and is done for the purpose of advancing scientific knowledge. Under § 361.1(a), this type of research is:
*intended to obtain basic information regarding the metabolism (including kinetics, distribution, dosimetry, and localization) of a radioactive drug or regarding human physiology, pathophysiology, or biochemistry,
*not intended for immediate therapeutic, diagnostic or similar purposes (e.g. preventive benefit to the study subject from the research), and
not intended to determine the safety and effectiveness of a radioactive drug in humans. - The research study is approved by an FDA-approved RDRC based on the following requirements [§ 361.1(b)(1)(iv)]:
*qualified study investigators
*properly licensed medical facility to possess and handle radioactive materials
*appropriate selection and consent of research subjects
*appropriate quality assurance of radioactive drug administered
*sound research protocol design
*reporting of adverse events by the investigator to the RDRC
*approval by an appropriate Institutional Review Board (IRB) - The pharmacologic dose of the radioactive drug to be administered is known not to cause any clinically detectable pharmacologic effect in humans [§ 361.1(b)(2)].
- The radiation dose to be administered is justified by the quality of the study being undertaken and the importance of the information it seeks to obtain [§ 361.1(b)(1)(iii)] and is within the limits specified in § 361.1(b)(3).