HUMAN SUBJECTS: Questions

Even if you, yourself, are not involved in research with human subjects, it is important that everyone in an academic medical center have an understanding of the basic principles of, and the regulations governing, research with human subjects. Thus, we encourage everyone to become familiar with the federal definition of research with human subjects (available via the second question link below) and understand that any activity that falls within this definition requires PRIOR review and approval by the MUOT IRB.

All MUOT-related research projects involving human subjects or material or information derived from humans (tissue, records, etc.) must be reviewed and approved by the MUOT IRB at least annually, in accordance with the MUOT Human Research Assurance <http://www.meduohio.edu/research/human_assurance/human_assurance.pdf>. Projects not supported by external funding must be reviewed by the same procedures as grant-supported projects. "MUOT-related research" means research carried out on or off campus (including in other states or countries) by MUOT faculty, students, or other employees, as well as all studies using MUOT facilities and/or MUOT patients as subjects. This includes the use of MUOT patient records or surveys of MUOT patients, employees or students. Approval from a "central" or "national" IRB may not replace approval from the MUOT IRB. This requirement may, at times, entail review of projects by two or more IRBs. For example, when an MUOT faculty member is involved in studies involving other institutions which have IRBs as performance sites or sources of data or material.

If any of the activities you contemplate involve interactions or interventions with humans, or the use of data (including medical records) or specimens derived from humans, and you are not absolutely sure that those activities do not represent research, as defined in the federal regulations, you need to read further and/or contact the MUOT IRB office to ascertain whether your activity may be research and thus require PRIOR MUOT IRB review and approval. The person to contact in the MUOT IRB office is Dr. Roland Skeel, IRB Chair. She may be reached via e-mail at <IRB@meduohio.edu >, or via phone at extension 6796. Prior to contacting this office, reading the following material might be very helpful.

IRB APPROVAL OF PROTOCOLS AND PROTOCOL MODIFICATIONS

Research projects involving human subjects may not begin and/or modifications may not be instituted until the Principal Investigator (PI) has received the official IRB approval memo signed by the Chair or his/her designee and, if applicable, the IRB approved consent form, assent form and/or other supporting documents with IRB approval stamp and approval period affixed. IRB approval is granted only via written communication to the PI (i.e. never verbally) and must be signed by the IRB or his/her designee. While discussions between investigators and IRB members and/or IRB staff regarding protocol issues are encouraged, any opinions or guidance provided during these discussions should never be construed as representing IRB approval.

IRB APPROVAL OF RECRUITMENT ADVERTISING

Advertising associated with a research project is governed by the same regulations and institutional policies as the the research protocol, itself. Therefore, advertising may not begin until you have received IRB approval. This approval will include a stamped copy of the actual flyer, e-mail, letter, radio-TV script, etc. To approve audio and audiovisual advertising, the IRB must have a typed copy of the script along with a copy of the actual audiotape or audiovisual tape for the IRB file. Advertising cannot be approved until the IRB application has been reviewed and approved and, in the case of sponsored research, the contract with the sponsor has been executed, since the advertising is dependent upon verbiage in the protocol and/or the contract.

Federal requirements for record retention by investigators vary based on the type of research being conducted and the purpose for which it is being retained. For instance, 21 CFR 312.62 (c) states "An investigator shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified. As of 04/14/2003, 45 CFR 164.528 (Standards for Privacy of Individually Identifiable Health Information - Accounting of Disclosures of Protected Health Information) will require that covered entities maintain a record of disclosures of private health information (PHI) from 04/14/2003 forward, pursuant to 1) a waiver of patient authorization for release of PHI, 2) in the case of disclosures required by law, 3) for public health disclosures and 3) for those disclosures made fraudulently for a period of 6 years from the date of the disclosure. This regulation also requires that a covered entity provide an individual with an accounting of this information if requested (please see the Privacy Rule for specific information about this accounting).

Ohio Statutes require that records related to patients (including clinical research records) be maintained for the current year PLUS a period of 6 years.

Since these regulations are not consistent in the length of time required for retention of research records, the MUOT IRB is requiring that investigators adhere to the strictest of the regulations and maintain these records for a minimum of 6 years, effective immediately. Please revise your policies and procedures for retention of research related records accordingly.

Actually, the federal regulations define RESEARCH and HUMAN SUBJECTS separately. These definitions may be obtained via the following link: <http://www.meduohio.edu/research/query7.html>.

Three basic principles of ethics set forth in The Belmont Report <http://www.fda.gov/oc/ohrt/irbs/belmont.html> are particularly relevant to the protection of human subjects in biomedical and behavioral research:

ALL research involving human subjects in which MUOT employees or students participate, or which involves MUOT facilities, patients, or medical records requires PRIOR review and approval by the MUOT IRB. The following decision/support diagram may assist you in deciding whether or not your activity requires IRB approval: <http://www.meduohio.edu/research/query5.html>. If, after reviewing this decision/support diagram you are not absolutely sure, please contact the MUOT IRB office.

DO I NEED IRB APPROVAL TO USE DATA IN THE MEDICAL RECORDS OF MY OWN PATIENTS FOR RESEARCH PURPOSES?

Although you clearly do not need IRB approval to utilize the data in your patients' medical records for their medical management, you DO need IRB approval to utilize those same data for investigational/research purposes. Furthermore, you may need separate informed consent from these patients to utilize data in their medical records for research purposes. The need for this additional informed consent can be determined only after IRB review.

MY RESEARCH DOES NOT INVOLVE ANY CONTACT WITH HUMAN SUBJECTS, BUT I DO USE MATERIAL DERIVED FROM HUMANS IN MY RESEARCH LABORATORY, DO I NEED MUOT IRB APPROVAL FOR THIS?

The National Cancer Institute has published a booklet that should help you answer this question, but if, after reading it you are not absolutely sure, please contact the MUOT IRB office. The NCI booklet entitled "Research on Human Specimens: Are You Conducting Research Using Human Subjects?" may be obtained via the following link: <http://www?cdp.ims.nci.nih.gov/policy.html>. In addition, MUOT has a policy on the acquisition of fresh human tissue that you should be familiar with. This policy may be obtained via the following link: <http://www.meduohio.edu/research/surg_specimen.pdf>.

WHAT ARE THE RESPONSIBILITIES OF AN INVESTIGATOR INVOLVED IN RESEARCH WITH HUMAN SUBJECTS?

At a minimum, investigators must understand and comply with federal regulations, state and local laws, and MUOT policies governing human subjects research. Lack of understanding of these regulations, laws and policies is not an acceptable reason for noncompliance. Investigator responsibilities are delineated clearly in the Multiple Project Assurance (MPA) that MUOT has filed with DHHS, but they are summarized in an MUOT IRB policy <http://www.meduohio.edu/research/investigator_responsibilities_human_subjects.pdf>. If you are involved in research with human subjects you are required to read the entire Assurance prior to conducting research with human subjects so that you understand your responsibilities and those of this institution. A copy of MUOT's MPA may be obtained via the following link: <http://www.meduohio.edu/research/human_assurance/human_assurance.pdf>.

If you are involved in clinical trials sponsored by pharmaceutical or device companies, you are also subject to FDA regulations governing research to collect data to support the FDA approval of drugs or devices. In this regard, you should be very careful to understand the commitments that you make when signing the FDA form 1572 <http://forms.psc.gov/forms/FDA/fda?1572.pdf>. These commitments are summarized in this document <http://www.mcwirb.org/documents/Module4.pdf>. In addition, ICH Good Clinical Practice regulations <http://www.fda.gov/cder/guidance/959fnl.pdf> also govern investigator actions in clinical trials.

The International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines are, for the most part, similar to FDA Regulations, but the do differ in a number of ways. These differences for Informed Consent and for IRB function are described in the documents accessible via the following links:

HOW MANY PEOPLE MUST SIGN AN INFORMED CONSENT DOCUMENT AND WHO MUST THESE PEOPLE BE?

One notable difference in FDA Regulations and the ICH Guidelines is the ICH requirement (section 4.8.8) that BOTH the study subject (or legally authorized representative) AND the person who conducted the informed consent discussion must sign and date the informed consent document (see below). When the subject is not deciding for himself, or when the consent form must be read to the subject, there must be a witness to the informed consent process and a third signature, that of the witness to the consent process.

4.8.8 "Prior to a subject's participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion."

MUOT's policy, when faced with two sets of regulations governing the same research activity, has always been to adhere to the stricter of the two regulations. That being the case, ALL informed consent documents must be signed and dated in accordance with ICH guidelines. That is, in every case there must be at least TWO dated signatures on every informed consent document, those of the study subject and the individual who conducts the informed consent discussion. In those cases where a subject is not deciding for him or herself, or when the consent document must be read to the subject, there must be a third dated signature on the document, that of a witness to the informed consent

If you currently are using documents that are not set up for these required signatures, please contact Jennifer Wadas in the MUOT IRB office to make arrangements for revision of your form(s).

The IRB Chair can take care of some IRB business between convened meetings of the IRB, but other things MUST be handled by the IRB at CONVENED MEETINGS.

In light of the last item above, it is in the investigator's best interest to submit a well written IRB protocol that has been revised in response to reviews by knowledgeable colleagues, as well as the required Departmental review committee. This should minimize the risk of having a protocol deferred by the IRB until its next monthly meeting.

WHAT IS THE DEFINITION OF "ANONOMYOUS" INFORMATION OR HUMAN BIOLOGICAL MATERIAL? WHAT INDIVIDUAL IDENTIFIERS MUST BE REMOVED TO MAKE INFORMATION OR MATERIAL ANONYMOUS?

The MUOT IRB guidance on individual identifiers that MUST be removed before Information/Records/Samples may deemed to be anonymous have been defined in a document that may be obtained via the following link: <http://www.meduohio.edu/research/individual_identifiers.pdf>. The definition of Individual Identifiers in this MUOT IRB guidance is the same as found in recent HIPAA regulations. Note that for research information/records/samples to be deemed ANONYMOUS there must be NO identifiers that can link the information/records/samples to the subject from whom they were obtained. If your answer to the following question is "YES," you must be recording identifiers: "If I forgot to record a single piece of information regarding a study subject, could I go back to that individual's medical record to correct my omission?"

Many individuals are confused about the use of individual identifiers in research projects, and believe that so long as they do not use identifiers in publications, presentations, etc., that they are not using identifiable information in research. THIS IS NOT TRUE. Any time that an investigator or other personnel working on his/her research project documents/records an identifier at any point during data collection as a part of the research process, this meets the definition of using identifiable information.
In cases where information/records/samples are coded and decoding information required to identify the subject(s) is kept separately (including by another investigator) the information/records/samples may be considered to be CONFIDENTIAL, but they CANNOT be considered ANONYMOUS. In general, projects involving confidential, but not anonymous, information/records/samples are not eligible for waiver of informed consent requirement, even if the risks to subjects are "no more than minimal."

In addition to the requirement that research involving human subjects be reviewed and approved by an IRB PRIOR to initiation of the research, that IRB is also responsible for the Continuing Review of the research. Federal Regulations require that Continuing Review of research must be substantive and meaningful. HHS regulations at 45 CFR 46.111 set forth the criteria that must be satisfied in order for the IRB to approve research. These criteria include, among other things, determinations by the IRB regarding risks, potential benefits, informed consent, and safeguards for human subjects. The IRB must ensure that these criteria are satisfied at the time of both initial and continuing review. OHRP has provided IRBs with Guidance on Continuing Review which must be followed. A copy of this Guidance may be obtained via the following link: <http://ohrp.osophs.dhhs.gov/humansubjects/guidance/contrev2002.htm>. If you wonder why the MUOT IRB asks for so much information on renewal applications, a quick review of the above OHRP Guidance should answer your questions.