IRB and Human Subjects

Is an IRB Required Institutional Review Board (IRB): a committee created under federal regulations to conduct a review of and monitor research involving human subjects. In accordance with the Common Rule and FDA regulations, the IRB recommends protocol approval, requires modification to secure approval, or disapproves research. The IRB also is authorized to suspend or terminate research for continued non-compliance with the Common Rule and FDA regulations, or its own findings, determinations, and initial and continuing review procedures:

Independent Verification that Project is Not Human Subject Research: all planned projects involving interaction (direct or indirect) with humans or the use of human specimens or data should be reviewed by Office for Human Research Studies’ (OHRS) for a determination that the activity does not constitute research involving human subjects. OHRS will issue a determination notification to the investigator.

Types of Human Subject Research. The following examples illustrate common types of human subject research conducted under the auspices of the Dana-Farber/Harvard Cancer Center (DF/HCC). These are examples only and are not exhaustive of all human subject research
Biomedical Research. Biomedical research involves research (i) to increase scientific understanding about normal or abnormal physiology, disease states, or development; and (ii) to evaluate the safety, effectiveness, or usefulness of a medical product, procedure, or intervention. Vaccine trials, medical device research, and cancer research are all types of biomedical research.

Clinical Research. Clinical research involves the evaluation of biomedical or behavioral interventions related to disease processes or normal physiological functioning. Clinical research often, but not always, includes drugs, devices, or biological products regulated by the Food & Drug Administration (FDA). The term “clinical trials” implies treatment protocols meant for direct application to a subject population.

Phase I. These trials represent the first or early use of the drug in humans. The major objective of a Phase I trial is to determine the maximum tolerated dose (MTD) of the trial agent given in the schedule for humans while identifying the dose-limiting toxicity (DLT). The Phase I design may also be used to evaluate new schedules or combinations of established drugs and/or radiation.
Phase II. Phase II trials are conducted after the MTD has been determined by the Phase I trial. The major objective is to determine the efficacy of an agent for a given disease or group of diseases. Typically, all subjects receive the same dose of drug (e.g., the MTD defined by the Phase I trial) or undergo the same intervention. A number of Phase II trials are often done utilizing different dosing schedules of the same agent. Alternatively, randomized Phase II studies may compare different dosing schedules or regimens to try to determine which is most promising for further evaluation. The most promising regimen, if shown to be sufficiently active, is then used in the subsequent Phase III trial. Phase II trials also collect additional information relating to toxicity.
Phase III. The major objective of Phase III trials is to compare the efficacy of at least two treatments. This is typically the current standard therapy versus one or more experimental treatment groups. Typically, the primary purpose of a Phase III study is to attempt to determine whether a treatment approach provides a survival advantage as compared with the other(s). Alternatively, if they produce equivalent survival, one might be preferred because it is associated with less toxicity.
Phase IV. Called “post-market approval trials,” these trials take place after a new agent has been approved for use and marketing by the FDA. Phase IV trials are designed to further evaluate the long-term safety and effectiveness of a treatment. These trials are less common than Phase I, Phase II, and Phase III trials and sometimes are required by the FDA.

Multi-Modality Trials. Combination trials are done when two or more modes of therapy, such as surgery, chemotherapy, and immunotherapy, are used in combination in an attempt to evaluate potential benefits of combined modality treatment of disease:

Pilot Studies. Pilot studies involving human subjects are considered human subject research and require IRB review.
Social and Behavioral Research. The goal of social and behavioral research is similar to that of biomedical research—to establish a body of knowledge and to evaluate interventions—but the content and procedures often differ. Social and behavioral research involving human subjects focuses on individual and group behavior, mental processes, or social constructs and usually generates data by means of surveys, interviews, observations, studies of existing records, and experimental designs involving exposure to some type of stimulus or environmental intervention.
Epidemiology Research. Epidemiology research targets specific health outcomes, interventions, or disease states and attempts to reach conclusions about cost-effectiveness, efficacy, interventions, or delivery of services to affected populations. Some epidemiology research is conducted through surveillance, monitoring, and reporting programs—such as those employed by the Centers for Disease Control and Prevention (CDC)—whereas other epidemiology research may employ retrospective review of medical, public health, and/or other records. Because epidemiology research often involves aggregate examination of data, it may not always be necessary to obtain individually identifiable information. When this is the case, the research may quality for exemption or expedited review. In all cases, the IRB, not the individual investigator, will determine when IRB review of the activity is required.
Repository Research, Tissue Banking, and Databases. Research utilizing stored data or materials (cells, tissues, fluids, and body parts) from individually identifiable living persons qualifies as human subject research and requires IRB review. When data or materials are stored in a bank or repository for use in future research, the IRB must review a protocol detailing the repository’s policies and procedures for obtaining, storing, and sharing its resources, for verifying informed consent provisions, and for protecting subjects’ privacy and maintaining the confidentiality of data. The IRB may then determine the parameters under which the repository may share its data or materials with, or without, IRB review of individual research protocols.
Human Genetic Research. Genetic studies include but are not limited to: (a) pedigree studies (to discover the pattern of inheritance of a disease and to catalogue the range of symptoms involved); (b) positional cloning studies (to localize and identify specific genes); (c) DNA diagnostic studies (to develop techniques for determining the presence of specific DNA mutations); (d) longitudinal studies to associate genetic conditions with health, health care, or social outcomes, and (e) gene frequency studies. Unlike the risks presented by many biomedical research protocols considered by IRBs, the primary risks involved in the first three types of genetic research are risks of social and psychological harm, rather than risks of physical injury. Genetic studies that generate information about subjects’ personal health risks can provoke anxiety and confusion, damage familial relationships, and compromise the subjects’ insurability and employment opportunities. For many genetic research protocols, these psychosocial risks can be significant enough to warrant careful IRB review and discussion. Genetic studies limited to the collection of family history information and blood drawing are not automatically “minimal risk” studies. A breach of confidentiality, among other risks, is a major concern in determining if minimal risk is involved.

Quality Assurance Activities vs. Human Subject Research. Quality assurance activities attempt to measure the effectiveness of programs or services. Quality assurance activities constitute human subject research, and require IRB review, when they are designed or intended, at least in part, to develop or contribute to generalizable knowledge. On the other hand, quality assurance activities that are designed solely for internal program evaluation purposes, with no external application or generalization, usually do not constitute human subject research, and usually do not require IRB review. For example, suppose a medical department at the Dana-Farber Cancer Institute (DFCI) conducts a review of patient records and then contacts patients to identify cases where recommended follow-up did not occur. If the sole intent is to improve the rate of follow-up within DFCI, then the activity is not human subject research and does not require IRB review.

However, if the intent of the activity, at least in part, includes extending the findings to patients at facilities outside of the DFCI, or disseminating the findings in such a way that applicability outside the DFCI is stated or implied, then the activity does constitute human subject research, and does require IRB review.

In cases where the intent of the activity changes after it has begun (e.g., findings from an activity intended solely for internal Institutional purposes lead to a desire to generalize and disseminate the results for application outside DFCI), the activity becomes research at the moment the intent to generalize the findings is formed, and the IRB should be contacted immediately. In such cases, the IRB will determine the conditions under which the investigator may pursue the relevant research objectives.

Where any disagreement arises about whether a quality assurance activity constitutes human subject research, the DFCI IRB, not the individual investigator, will determine when IRB review of such activities is required.

Research Activities vs. Innovative Treatments in Medical Practice. In the course of medical practice, sound clinical judgment sometimes leads physicians to employ “innovative” treatments where more common treatments appear to be ineffective or otherwise unsuitable in addressing a patient’s individual needs. Such innovative treatments employed on an occasional basis and solely for clinical purposes do not normally constitute human subject research and do not normally require IRB review.

However, the use of innovative treatments as part of a systematic investigation designed, at least in part, to develop or contribute to generalizable knowledge does constitute human subject research and does require prospective IRB review.

Research Activities vs. Medical Case Reports. Generally speaking, a case report is not considered research because it is not usually “a systematic investigation designed to develop or contribute to generalizable knowledge;” therefore, it does not come under the jurisdiction of the IRB.

There does not appear to be a limit on the number of cases from one’s own patients that form a case report and if exceeded, moves the situation into the category of retrospective chart review and then requires IRB approval. Usually, a non-research case report summarizes one case (or occasionally two, or at most three, cases) to emphasize a discrete instance of disease.

However, it is the nature of the report, not the absolute number of cases, which determines whether or not the activity involves human subject research. A non-research case report may not involve a systematic investigation characterized as developing or contributing to generalizable knowledge. A non-research case report is limited to an account of an observation or a description of a disease process that has little scientific merit and is not subject to scientific analysis. It is not presented as a systematic investigation designed to contribute to generalizable knowledge. A non-research case report should be presented in such a way that it is readily distinguishable from a research report, which usually contains data with statistical analysis, or at least a systematic qualitative analysis, that substantiates the science and the conclusion and thus constitutes a contribution to generalizable knowledge.

Research Activities vs. Commercial Services. DF/HCC facilities and laboratories may occasionally provide tests or other services to non-DF/HCC researchers solely on a non-research basis.

Provision of such services solely on a non-research or commercial basis does not constitute human subject research at DF/HCC and does not require review by the DFCI IRB, provided that all of the following conditions are met:

The research is not otherwise conducted at this Institution;
The research does not otherwise involve employees or agents of this Institution (e.g., as co-investigators, in planning or analysis, or receiving publication credit);
The commercial services are genuinely non-collaborative, meriting neither professional recognition nor publication privileges; and
The commercial services adhere to commonly recognized professional standards for maintaining privacy and confidentiality.

However, if DF/HCC personnel are involved in any way that is more than merely providing a commercial service as described above, then prospective review and approval of the DFCI IRB is required.

–Policies & Procedures for the Protection of Human Subjects in Research