By Travis Thomas,2014-06-13 12:24
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Critical Care Research

    and Regulatory Compliance

    CHAPTER 12


    After studying this chapter, you should be able to: ? Discuss the concept of research intent.

    ? I dentify the regulatory authorities who are responsible for research conducted in the United States. ? Describe the responsibilities of the institutional review board (IRB).

    ? List the categories available to the IRB for review of research.

    ? Give examples of the materials the IRB will need to adequately review a research proposal.

    ? Describe the informed consent process.

    ? Discuss how the exception from informed consent (EFIC) impacts emergency and critical care research. CHAPTER OUTLINE

    Learning Objectives

    Case Study: The Pad Trial


    Research Intent

    Ethical Conduct of Research and Research Regulations Irb Responsibilities

    Categories of Review

    Research Exempted from IRB Review

    Expedited Review

    Full Board Review

    What to Submit for Irb Review

    Institution-Specifi c Submission Form

    The Research Protocol

    Informed Consent Document and HIPAA Authorization Supplemental Materials

    Requirements of Irb Approval of Research

    The Informed Consent Process

    The Four Requirements of Informed Consent Special Issues Regarding Informed Consent in Critical Care Research

    Informed Consent for the Use of Biological Samples Summary

    Review Questions



    Additional Reading


    Conducting medical research activities in compliance with Good Clinical Practice guidelines is challenging for experienced investigators and may be overwhelming for the individual making a fi rst attempt to perform a clinical study. Research regulations are extensive and many have resulted in the issuance of guidance documents to facilitate appropriate interpretation and compliance by all members of the research enterprise. The potential for noncompliance with regulations is high, although the actual prevalence is diffi cult to estimate. While not addressing the issue of the extent of regulatory noncompliance, an analysis of warning letters from the Food and Drug Administration (FDA) to investigators 6 and institutional review boards (IRBs) 7 shows that serious violations of the regulations do occur. Investigators have been cited for deviating from the investigational plan, failing to obtain legally effective informed consent, and not reporting adverse events in a timely manner. IRBs have been cited for not having (or not following) adequate written procedures for reviewing research, poor documentation of meeting activities, and inadequate continuing review procedures. [AU3]

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    Research in the critical care setting presents unique circumstances that may further strain the clinical and ethical standards for performing research. Among these are patient populations at high risk for morbidity or mortality, narrow time frames for initiating an intervention to maximize effectiveness, and diffi culties in obtaining informed consent from patients or their surrogates. 8 These issues are infrequently encountered in most other human research situations. Even so, the conduct of critical care research is essential to the development, evaluation, and effective use of new therapeutic approaches in the critically ill patients and should be encouraged. The objectives of this chapter are to provide a general overview of the regulatory requirements of human subjects’ research in the ICU and to assist clinicians in

    writing research protocols that measure up to IRB standards.


    Human research must be conducted in compliance with governmental regulations. Long before the initiation of data collection, or even the writing of the protocol, the question should be asked, “Is this human research?” Many hospital processes and procedures are

    scrutinized for the purposes of quality improvement or resource utilization. They frequently rely on the use of medical records and may collect information prospectively. Yet, these activities are generally not considered research.

    The Code of Federal Regulations defi nes research as “a systematic investigation, including

    research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” 9 There are problems when this defi nition is used by itself to decide if a project

    is a research. A report of a single case could hardly be considered “a systematic investigation.”

    Conversely, a randomized controlled trial would be considered research even if there was no plan to “contribute to general knowledge” by publishing the results. Amdur and Speers provide

    excellent guidance for determining if a project meets the criteria for research. 10 In short, they explain that research is a function of what is being done and what is ultimately motivating the

investigator to conduct the research, what they term research intent. They suggest that


    and IRB members ask the question, “Would the project be conducted as proposed if the

    project investigators knew they would never receive any form of academic recognition for the project, including publication of results in a medical journal or presentation of the project at an academic meeting?” 10 If the answer to this question is no, the proposed activity is research and

    should be submitted for IRB approval. Increasingly, medical journals require evidence of IRB approval as a precondition for publication of research results. Furthermore, there are no regulatory provisions that permit retroactive review and approval of research that has already been conducted. Therefore, having appropriate IRB approval is an important fi rst step in regulatory compliance and facilitates publication of important research results.



    Individuals who participate in human medical research are special; even those who participate in the least invasive, most minimal risk study imaginable. Why? Because each took the time to provide information or engage in a procedure that could lead to better care for The conduct of critical care

    research is essential to the

    development, evaluation, and

    effective use of new therapeutic

    approaches in the critically ill


    IRB approval is an important fi rst

    step in regulatory compliance and

    facilitates publication of important

    research results.


    The Public Access Defi brillation trial prospectively compared the

    effectiveness and safety of cardiopulmonary resuscitation (CPR)

    only to CPR plus the use of an automated external defi brillator

    (AED) in patients experiencing an outpatient cardiac arrest when

    treated by trained community lay volunteers . 1 The primary outcome

    parameter was survival until hospital discharge . The study

    design and regulatory considerations of this trial go well beyond

    what many investigators will need to deal with in their own

    research endeavors. Even so, it can serve as a model for developing

    a study design, 2 , 3 accurately defi ning important study parameters, 4 and developing an approach for conducting exceptions

    from informed consent trials. 5



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    someone they have no knowledge of; often without compensation. As such, human research participants and the information they provide appropriately receive additional protections established in internationally accepted codes for research conduct, laws enacted at the federal and state levels, and regulations promulgated by a variety of governmental agencies. The department of health and human services (DHHS) maintains oversight of human subject research through three separate units. The FDA oversees clinical trials of drugs, devices, vaccines, and other products to be marketed for the diagnosis and treatment of disease. Its authority comes from Title 21 Parts 50 and 56 of the Code of Federal Regulations. The offi ce for human research protections (OHRP) enforces similar regulations from Title 45 Part 46 for research supported by 18 federal agencies (thus being known as the Common Rule). The offi ce for civil rights (OCR) is responsible for enforcing Health Insurance Portability and Accountability Act (HIPAA) regulations. The history of and relationships among these programs are well described in a Library of Congress report. 11


    Once it is decided that the activity being pursued is a research, plans should be made for submitting a proposal to the IRB for review. The primary mission of an IRB is to protect the rights and welfare of human research subjects. Over the years, review boards have assumed many more responsibilities as the meaning of “rights and welfare” has evolved, resulting in

    “IRB mission creep.” 12 This means that the IRB work often extends beyond just the protection

    of human subjects; there is a commitment to the investigator and the institution. Examples of the extended mission of the IRB at many institutions include the evaluation of the scientifi c merit of the research, assessment of research methodology and use of appropriate statistical and analytical procedures, evaluation of plans to protect the integrity of the data collected, adherence to HIPAA regulations, and determining if investigator or institutional confl icts of interest exist.

    Given these complexities, it is essential that the investigator determine the policies of their local IRB and follow the correct submission procedures. Each IRB has its own submission guidelines. Investigators should check with their IRB offi ce or website frequently to make sure that the most current submission requirements are being followed. CATEGORIES OF REVIEW

    There are three major categories of research defi ned in 45 CFR 46; exempt, expedited, and full board review, which relate to the type of research being conducted and the level of risk. While the FDA regulations permit expedited review, there is no provision for exempt research in these regulations. While most IRBs provide investigators some guidance as to how their research will be categorized, the IRB remains the fi nal authority for making this determination. Some IRBs require that all studies be submitted for full board review. While this requirement avoids the potential problem of inappropriate use of exempt or expedited review procedures for the IRB, it may result in delays in getting a project started. It can be frustrating for the investigator who is certain that the proposed project qualifi es for an exemption, yet IRB policies call for full committee approval. From the IRB perspective, however, not applying these regulations correctly may result in the institution receiving a “letter of determination” and possible sanctions. Despite years of experience with these regulations,

questions about their use continue to occur. 13 , 14

    Research Exempted from IRB Review Table 12-1 lists the categories of research in the 45 CFR 46 that qualify for exemption from

    IRB review. In medical research, the two most common exemption categories are the use of

    anonymous surveys (exemption two) and the use of existing data or specimens (exemption

    four). Investigators often err in assuming that all surveys are exempt.

    “IRB mission creep” can include:

    ? Evaluation of the scientifi c merit of the research

    ? Assessment of research


    ? Use of appropriate statistical and analytical procedures

    ? Evaluation of plans to

    protect the integrity of the data collected

    ? Adherence to HIPAA


    ? Determining if confl icts of interest exist

    Categories of research defi ned in 45 CFR 46: (1) exempt,

    (2) expedited, and (3) full board review.

    The two most common exemption categories in medical

    research are the use of anonymous surveys (exemption two)

    and the use of existing data or specimens (exemption four). Investigators often err, however, in assuming that all surveys are exempt.

    Human research participants and the information they provide receive additional protections established in internationally accepted codes for research conduct, laws enacted at the federal and state levels, and regulations promulgated by a variety of governmental agencies. Criner_12.indd 211 2/13/2010 8:15:54 PM


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    This can occur if survey responses are collected in a way where they can be linked to individual patients or to their medical information. With the use of existing data, problems typically arise in one of two areas. The fi rst relates to the information being collected and how it will be handled. The regulations require that the investigators maintain confi dentiality of the information they collect. This is further complicated by HIPAA regulations that insist that the data be identifi ed. The second problem that often develops is if most of the information of interest is available in the medical record, the investigator needs to get some additional information that might not be routinely collected, such as the patient’s hair color or

    whether they are left or right handed. If there is a need to contact the patient to obtain this information, obviously not all data exists at the time of IRB approval. Therefore, this study would no longer qualify for an exemption.

    Expedited Review

    Table 12-2 describes the types of research that may qualify for expedited IRB review. Expedited review is appropriate only for studies that present no more than minimal risk or for ongoing research undergoing continuing review. Research submitted for expedited review is typically evaluated by the IRB chairperson or delegated to an IRB member who is familiar with the application of these regulations. The reviewer can require modifi cations of the research in order to obtain approval under expedited review regulations, but cannot reject or disapprove a proposed study. These cases would be referred to a convened meeting of the IRB. The studies reviewed under this provision of the regulations are all prospective. Given The IRB reviewer can require

    modifi cations of the research in

    order to obtain approval under

    expedited review regulations, but

    cannot reject or disapprove a

    proposed study.

    Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as (1) research on regular and special education instructional strategies, or (2) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods

    Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior, unless: (1) Information obtained is recorded in such a manner that human subjects can be identifi ed, directly or through identifi ers linked to the subjects; and (2) any disclosure of the human subjects’ responses outside the research could reasonably place the subjects at risk of

    criminal or civil liability or be damaging to the subjects’ fi nancial standing, employability, or


    Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under paragraph (b)(2) of this section, if: (1) The human subjects are elected or appointed public offi cials or candidates for public offi ce; or (2) federal statute(s) require(s) without exception that the confi dentiality of the personally identifi able information will be maintained throughout the

research and thereafter

    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 identifi ed, directly or through identifi ers linked to the subjects

    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 benefi t or service programs; (2) procedures for obtaining benefi ts or services under those programs; (3) possible changes in or alternatives to those programs or procedures; or (4) possible changes in the methods or levels of payment for benefi ts or services under those programs

    Taste and food quality evaluation and consumer acceptance studies, (1) if wholesome foods without additives are consumed or (2) 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 (FDA) or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture

    Adapted from Title 45 on Public Welfare. Code of Federal Regulations, Part 46.101(b) TABLE 12-1


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    this, investigators should expect, and the regulations require, that informed consent be obtained from the research participants. There are provisions in the regulations to waive informed consent under certain circumstances. Investigators should consult with their local IRB for guidance in this area.

    Full Board Review

    Any study that is greater than minimal risk must be reviewed at a convened meeting of the full IRB.

    The composition and functions of the board are detailed in the Code of Federal Regulations. The reader is again directed to the Library of Congress report for an overview of these requirements. 11 The materials that must be provided by the investigator are discussed in the section below. In addition to the written materials, the IRB may invite the principal investigator to the meeting to provide an overview of the research activity and how it will be conducted. Investigators should take full advantage of this opportunity, if offered. However, the investigator should be well prepared to answer the questions posed by IRB members. Any study that is greater than

    minimal risk must be reviewed

    at a convened meeting of the

    full IRB.







    Clinical studies of drugs and medical devices only when condition (a) or (b) is met Research on drugs for which an investigational new drug application (21 CFR Part 312) is not required (note: research on marketed drugs that signifi cantly increases the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review)

    Research on medical devices for which (1) an investigational device exemption application (21 CFR Part 812) is not required; or (2) 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 fi nger stick, heel stick, ear stick, or venipuncture as follows: 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/week

    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 or 3 mL/kg in an 8 week period and collection may not occur more frequently than 2 times/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 (studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications) 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: Where (1) the research is permanently closed to the enrollment of new subjects; (2) all subjects have completed all research-related interventions; and (3) the research remains active only for the long-term follow-up of subjects

    Where no subjects have been enrolled and no additional risks have been identifi ed 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 two (2) through eight (8) do not apply, 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 identifi ed

    Adapted from Title 45 on Public Welfare. Code of Federal Regulations, Part 46.110

TABLE 12-2



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    Once it is determined that a project is human research, it needs to be submitted to the IRB for review. It makes no difference if the project is a randomized controlled trial, or a retrospective chart review; all human research must be approved by the IRB. If the IRB is responsible for compliance with the HIPAA regulations as related to research, this will infl uence the materials that must be supplied for review.

    IRB decisions are based on the materials provided by the investigator. On the surface, having to state this fact seems unnecessary. Yet it is not unusual for questions to arise in the committee due to defi ciencies in the background materials provided, unclear study procedures, or omission of essential information. It is not the responsibility of the IRB to fi gure out the investigator’s intent. The goal should be to provide all of the needed information in the

    initial submission. This information falls into four general areas: (a) an institution-specifi c submission form, (b) the research protocol, (c) informed consent document, and HIPAA authorization, (d) other materials. The amount of information required by the IRB is usually a function of the category of research being conducted and the associated risks. No human research project is free from risks. Even a retrospective chart review may result in the loss of confi dentiality of patient data. Given this, it is important for the investigator to provide the details necessary to fully evaluate research risks and thus avoid IRB requests for additional information. 15 Providing guidance for developing a research protocol is beyond the scope of this chapter. The reader is directed to three excellent texts that can assist in this process. 16 - 19 The following sections provide an overview of typical IRB requirements for each of the four groups of materials mentioned above.

    Institution-Specifi c Submission Form

    There is very little standardization in the amount and types of information the local IRB requires in submitting a research proposal. To further confuse things, some IRBs have multiple submission forms depending on the type of research being proposed. The rule of thumb is, “if you know how to make a submission to one IRB, you know how to submit to one

    IRB.” Before putting the materials together for any study, visit the IRB website or offi ce to

    make sure that the correct submission procedures and the most up-to-date forms are being used.

    Once the correct forms have been obtained, investigators will be faced with a simple twopage form, or forms of over twenty pages fi lled with dozens of mind-numbing questions. In either case, carefully provide all of the required information. From the IRB perspective, there are no unimportant questions. Investigators tend to focus on the protocol, which is also a major concern of the IRB. However, the IRB also needs to make sure that the investigative team is properly qualifi ed and adequately staffed, the research facilities can accommodate the demands of the study, if vulnerable groups of participants will be included, the amount

    and timing of compensation for participating in the trial, and provisions for the acute care of the study participants are available if necessary. For sponsored trials, information about the sponsor, the clinical research organization or site management organization, and even the study monitor may be requested. Most IRBs will also request confl ict of interest statements from principal and subinvestigators.

    The Research Protocol

    The objective of the protocol is to provide a document that describes in adequate detail what is known about the condition being studied; what questions remain unanswered and the clinical relevance of this information; a testable hypothesis; eligibility criteria; study methodology; an assessment of risks and benefi ts; a sample size estimate and how data will be analyzed; and supporting references. The information provided in the study protocol needs to follow a logical progression with suffi cient attention to detail. The IRB members reviewing the protocol are not likely to be experienced in the condition being studied or the No human research project is free

    from risks.

    Before putting the materials

    together for any study, visit the

    IRB website or offi ce to make

    sure that the correct submission

    procedures and the most

    up-to-date forms are being used.

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    Title of the research The title of the research project appears on many other documents such as the initial review form and consent form. Make sure that the title is

    the same on each document

    Research objectives Describe the major goals or aims of the research in a few sentences. What will be learned from this study?

    Background What is the current state of knowledge related to the condition being studied? What is unknown? How will the information derived from this

    study improve patient care?

    Research hypothesis What is being tested? Identify the primary outcome parameter Study methodology Briefl y state the study methodology (randomized, double blind, placebo controlled)

    Eligibility criteria Defi ne the patient population that will qualify for participation in the trial. Provide specifi c information. A term like normal renal function is of little meaning to the IRB or the investigator. Does it mean a serum creatinine

    of less than 1.5 mg/dL or is it an estimated creatinine clearance of

    greater than 80 mL/min? Also exclude patients based on contraindications

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