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TIP #1: Standard Medical Care vs Research Protocol-Induced Interventions
TIP #2: Sponsor's Obligation to Pay for Treatment of Subject Injury Due to Protocol-Induced Interventions
TIP #3: Readability of IRB Application and Informed Consent Document
TIP #4: Required Elements of Informed Consent
TIP #5: P.I. and Chair Signatures REQUIRED Prior to IRB Review
TIP #1: Standard or Routine Medical Care vs Research Protocol-Induced Interventions
One of the major roles of an IRB is to assess the risks associated with the research projects that it reviews. In doing this, the IRB is required to evaluate those risks associated with interventions that study subjects would not have been exposed to had they not volunteered to participate in the research, so called "Protocol-Induced" risks. When patients also become research subjects, these Protocol-Induced risks generally are superimposed on the risks associated with their disease and the standard/routine therapy thereof.
A significant problem that delays approval of many IRB applications is the lack of clear distinction between those interventions which are a part of standard/routine therapy of a study subject's disease, and Protocol-Induced interventions. Only when Protocol-Induced interventions are distinguished clearly by the applicant can the IRB appropriately judge their risks. In the absence of this clear distinction the IRB is often forced to base its risk assessment on ALL interventions outlined in the application and/or the associated clinical trial protocol provided by the sponsor, rather than just those risks associated with Protocol-Induced interventions. Such a distinction between risks associated with standard/routine therapy and Protocol-Induced interventions is also required by federal regulations in the informed consent document provided to potential study subjects. Section 42.116(a)(1) states that consent document must contain "a statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental."
TIP #2: Sponsor's Obligation to Pay for Treatment of Subject Injury Due to Protocol-Induced Interventions
IRB Application Tip #1 emphasized the need for applicants to distinguish clearly between interventions included in a clinical trial protocol which are considered to be standard or routine therapy and those which are Protocol-Induced. Protocol-Induced interventions are interventions that study subjects would NOT have been exposed to had they not volunteered to participate in the study protocol. To be Protocol-Induced, an intervention itself does not necessarily have to be experimental, it might be a clinically accepted procedure, but in the context of its use in the study protocol, the patient would NOT have been exposed to it were they not a study subject. For example, a second CT scan of the head required by the study protocol, but which would not have been ordered in the routine medical management of a patient's condition, would be a Protocol-Induced intervention.
A clear assessment by the applicant (P.I.) of Protocol-Induced vs standard or routine therapy is essential for the MUOT IRB to accurately determine the RESEARCH RISK involved in the study. Federal regulations provide the following guidance for the IRB: "In the process of determining what constitutes a risk, only those risks that may result from the research, as distinguished from those associated with therapies subjects would undergo even if not participating in research, should be considered." Thus, it is in the applicant's (P.I.'s) best interest to facilitate the IRB's risk assessment by providing clear distinction between research and therapy, i.e., Protocol-Induced interventions vs. interventions associated with standard or routine therapy. Note that it is possible for the risks of the research, i.e., Protocol-Induced interventions, to be minimal, even when the therapeutic procedure(s), i.e., standard or routine therapy present more than minimal risk.
For company sponsored clinical trial protocols in which the MUOT IRB deems the Protocol-Induced interventions to be of greater than minimal risk, using the above criteria, MUOT policy requires that the study sponsor shoulder the full responsibility for subject injury associated with these Protocol-Induced interventions. The same information provided to the IRB distinguishing between Protocol-Induced interventions and standard or routine therapy will also allow the MUOT administrator negotiating the clinical trial agreement with the sponsor to better communicate to the sponsor what MUOT considers to be Protocol-Induced injury. Since all sponsors want to limit their liability in clinical trials, this clearer definition of what MUOT considers to be Protocol-Induced may be the difference between a successful contract negotiation, and MUOT being eliminated as a study site because the sponsor does not want to assume the responsibility for injuries subjects would encounter in the standard or routine therapy portions of the protocol.
For everyone's benefit P.I.s are encouraged to include in their IRB application
(or in clinical trial contract material submitted to RGA, if the contract negotiation
process precedes the IRB process) a list of all study procedures/interventions,
clearly indicating which represent standard or routine therapy vs. Protocol-Induced
interventions. For example, if three arteriograms would be required for routine
therapy, but two more are required by the study protocol, the latter two should
be designated as Protocol-Induced interventions.
TIP #3: Readability of IRB Application and Informed Consent Document
One of the major reasons IRB applications are not approved "as written" is because the IRB application and/or its associated informed consent document is written in language too technical for a layperson to comprehend. Federal regulations require that there be non-scientific members of the IRB who must be able to understand the IRB application, as well as the informed consent document, since they are being asked to approve both. In addition, federal regulations require that:
"An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory 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."
The informed consent document is for study subjects, not for scientific peers. Remember that the average reading level of Americans is at about the 6th to 8th grade level. A University of Michigan web page provides a document entitled "Tips on Preparing Understandable Informed Consent Documents." The University of Michigan also provides a webpage entitled "Simplification Guide to Medical Terms," that may be very helpful. The University of California at Davis also provides a webpage entitled "Glossary of Lay Terms for Use in Preparing Consent Forms…."
Help the IRB and yourself by ensuring that your IRB application and consent documents are written in terms that a layperson can understand, even if it means using more, but less technical, words. Have someone read the material and provide you feedback on how to make it more understandable. Having someone else read the material may also assist in detecting the multitude of careless errors that the IRB finds in may proposals.
TIP #4: Required Elements of Informed Consent
In addition to being written in language understandable to study subjects (See Tip #2), the informed consent document must, at a minimum, contain the 8 required elements of informed consent, plus any of the additional 6 elements of informed consent as necessary for your specific project. Every investigator should be familiar with the federal requirements for informed consent. The PHS Office for Human Research Protection (OHRP) also provides tips on informed consent. IRB applications which have informed consent document(s) that do not meet this requirement cannot be approved until the consent documents are revised appropriately.
There is also MUOT-specific information that must be contained in each informed consent document. For investigators doing studies that involve children, there is MUOT-specific requirements for informed consent documents for investigators doing research with subjects who are children. Parenteral consent is required for research involving research subjects who are children.
If your starting point in constructing an informed consent document is a sponsor's consent form, don't forget that it must be revised to incorporate the required MUOT-specific information to be approvable by the MUOT IRB. Failure to incorporate all of the above required information will result in delayed approval of your IRB application.
TIP #5: P.I. and Chair Signatures REQUIRED Prior to IRB Review
Although P.I. and Chair signatures have always been required on MUOT IRB applications, the IRB office has been flexible with this requirement in the past. Because of recent increased emphasis on documentation from regulators, the IRB can no longer be flexible on this issue. Although IRB applications will be accepted for pre-review with only the P.I.'s signature, when "final" versions of applications are submitted for review, the original and all required copies must contain all required signatures. The original must contain original signatures of the P.I. and his/her chair ("per" or stamped signatures are NOT acceptable), while the copies may contain photocopies of that original signature page.
Page Updated: 6/22/2001
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