Explanation of Federal Regulations for Human Subjects Research, Part 1

Author(s): Elysa Koppelman, Ph.D.

The following is explanation of the federal regulations (45CFR46) concerning research with human subjects. Research with some vulnerable populations, like children and pregnant women, requires additional regulations which are discussed elsewhere.

Understanding and following regulations is important. However, ethical behavior involves more than simple adherence to rules; it requires discretion and judgment. Regulations do not necessarily cover all the choices and they do not give a formula for complete and mature ethical decisions. For example, these regulations tell us that we must get informed consent from potential subjects (or appropriate surrogate). But subtle questions about whether and under what conditions informed consent is actually obtained requires discretion and judgment.

These regulations will be discussed in terms of answering these key questions.

What is Human Subjects Research?, and The IRB review processes: The categories under which protocols are submitted

  1. Protocol for Exemption
  2. Protocol for Expedited Review
  3. Full Protocol for Full Review

What is Human Subjects Research?

All research with human subjects is subject to review by the IRB (Institutional Review Board). Of course, not all activities constitute research with human subjects. Your first step in making sure you are following federal and institutional regulations is to determine whether your proposed activity constitutes research with human subjects.

Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.

Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains data through:

  1. intervention (physical gathering of data or manipulation of environment) or interaction (communication or interpersonal contact) with the individual, or
  2. identifiable private information.
    • Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record).
    • Individually identifiable information is information from which the identity of the subject is or may readily be ascertained by the investigator or associated with the information. Identifiers include patient numbers, social security numbers, and names.

It is important to remember that you may be engaged in human subjects research even if you never come into direct contact with a living human being during the course of your activity. If you are examining medical records, viewing X-Rays of heart patients, or observing the behavior of people as they walk down the street you are engaged in human subjects research. Normally, it is easy to determine whether your activity constitutes human subjects research. When in doubt, contact your IRB.

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The IRB Review Processes

Once you have determined that your activity is research with human subjects, you need to determine what kind of review to which your project is subject.

  1. Protocol for Exemption
  2. Protocol for Expedited Review
  3. Full Protocol for Full Review

Your IRB makes the final determination as to whether your project qualifies for exemption, expedited, or full review. But thinking about these categories ahead of time could help you to design your project in ways that may save you time and energy. Furthermore, many IRB's have different applications for each of these categories, so it helps if you know which category your project is likely to fall under.

Protocol for Exemption

It is the IRB's job to protect the welfare of human subjects. Some research, however, exposes subjects to only minimal risk. Minimal risk, as defined in the federal regulations, means "that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests."

In general, research that (a) exposes subjects to no greater than minimal risk and (b) is designed such that data is recorded in a way that does not identify subjects, either directly or indirectly, qualifies for exemption. You may believe that your protocol qualifies for exemption, but your IRB makes the final determination as to whether your belief is correct. Most IRB's have a special exemption application to fill out and submit. Check with your IRB to determine their process for determining whether your project qualifies for exemption.

The following is a list of categories that fall under the classification of exemption in 45CFR46:

  1. Research conducted in established or commonly accepted educational settings, involving normal education practices, such as:
    1. research on special or regular instructional strategies or
    2. research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.
  2. Research involving the use of educational tests, survey procedures, interview procedures, or observation of public behavior unless:
    1. information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and
    2. any disclosure of the human subjects' responses outside the research can reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation.
  3. Research involving the use of educational tests, survey procedures, interview procedures and observation of public behavior that is not exempt under conditions 2, if:
    1. the human subjects are elected or appointed officials or candidates for public office or
    2. Federal statutes require without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.
  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. (This is often referred to as piggy backing-- a means of using information that is already being obtained for other purposes, like treatment. Notice that doing this means that you are not exposing subjects to any greater risk than they face in their everyday life.)
  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:
    1. public benefit or service programs
    2. procedures for obtaining benefits or services under those programs
    3. possible changes in or alternatives to those programs or procedures
    4. 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, if:
    1. wholesome foods without additives are consumed or
    2. 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 and Safety Inspection Service of the U.S. Department of Agriculture.

Notice that in all of these categories, with the exception of public officials, subjects are exposed to no more than minimal risk and the data is recorded without identifiers or will be kept confidential (by federal law) forever. As you design your research, you may want to keep this in mind. If you can design your research so that you are meeting these requirements without compromising your project, you should do so. Not only will doing so make your life easier, but (as we will see) it is required by the federal regulations.

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Protocol for Expedited Review

Some research protocols will qualify for expedited review; a process which is normally easier and faster for all involved. There are three conditions under which a protocol qualifies for expedited review:

  1. Minor changes in previously approved research during the period (of one year or less) for which approval is authorized.

    When the IRB approves a protocol, it approves a particular protocol for a certain period of time. If, during the approval time, you need to make changes to your protocol, you must report those changes to the IRB before you institute them. (The only exception here are emergency changes made because of unforeseen harm to subjects.) The IRB will then determine whether your changes require a new full review or an expedited review. If the changes are minor, the IRB may approve your submission for an expedited review.

  2. Continuing review of research previously approved by the convened IRB:
    1. where the research is permanently closed to the enrollment of new subjects, all subjects have completed all research-related interventions, and the research remains active only for long-term follow-up of subjects; or
    2. where no subjects have been enrolled and no additional risks have been identified; or
    3. where the remaining research activities are limited to data analysis; or
    4. Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where the above conditions 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.

    When the IRB approves a protocol, it approves a particular protocol for a certain period of time (not more than one year). When your approval time is up, the IRB will send you a letter stating that it is time to apply for continuing review. The IRB must review your protocol again. If your continuing review falls under these conditions, it may qualify for expedited review.

  3. 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 also qualify for expedited review.

    The activities listed below should not be deemed to be of minimal risk simply because they are included on this list. Inclusion on this list merely means that the activity is eligible for review through the expedited review procedure when the specific circumstances of the proposed research involve no more than minimal risk to human subjects.

    • Clinical studies of drugs and medical devices only when condition (a) or (b) is met.
      1. Research on drugs for which an investigational new drug application is not required.
      2. Research on medical devices for which an investigational device exemption application is not required or 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:
      1. from healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more frequently than 2 times per week.
      2. 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. For these subjects, the 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. Examples include: hair and nail clippings in a nondisfiguring manner; deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction; permanent teeth if routine patient care indicates a need for extraction; excreta and external secretions (including sweat); uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gumbase or wax or by applying a dilute citric solution to the tongue; placenta removed at delivery; amniotic fluid obtained at the time of rupture of the membrane prior to or during labor; supra- and subgingival dental plaque and calculus, provided the collection procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques; mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings; sputum collected after saline mist nebulization.
    • 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. Examples include physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subject=s privacy; weighing or testing sensory acuity; magnetic resonance imaging; electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography; moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual.
    • 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.

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Protocol for Full Review

Research with human subjects that does not qualify for exemption or expedited review must be submitted to the IRB for full review. Your next question is how to design your research so that it meets the characteristics for which the IRB is looking. In other words, What must my protocol contain when I submit it to the IRB? In order to get an answer to this question, it is important that you understand the values that underlie the regulations to which your research is subject.

Cite this page: Elysa Koppelman, Ph.D. "Explanation of Federal Regulations for Human Subjects Research, Part 1" Online Ethics Center for Engineering 9/11/2006 2:20:09 PM National Academy of Engineering Accessed: Sunday, September 07, 2008 <www.onlineethics.org/CMS/research/modindex/resethpages/reghum.aspx>


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