INTEGRITY IN SCIENCE 
     Protection Against Retaliation 

FINANCIAL CONFLICTS IN RESEARCH 

HUMAN RESEARCH: ETHICAL FOUNDATIONS 
     Distinguishing Clinical Care from Research
     Ethical Considerations in Collaborations 

SCIENTIFIC COMMITTEE REVIEW 
     Designating a Responsible Investigator 
     Reporting Concerns about Human Subject Protections
     Approval of Research Protocols 
     Full Review 
     Expedited Review 
       Criteria for Expedited Review 

EXEMPTION FROM REVIEW 
       Criteria for Exemption from Review 

USE OF INVESTIGATIONAL DRUGS OR DEVICES OUTSIDE
CONTROLLED CLINICAL TRIALS 
     Emergency Use Without Prior IRB Approval 
     Obtaining an Emergency IND 
     FDA Contacts for Emergency Drug Shipment 
     Exception from Informed Consent Requirement with an Emergency IND
     Off-label Use of Approved Drugs
     Off-label Research with Approved Drugs 
     Treatment Uses of Investigational Drugs Requiring Prior IRB Approval
       Open Label Protocol or Open Protocol IND
       Treatment IND 
       Group C Treatment IND 
       Parallel Track 

GENERAL REQUIREMENTS FOR INFORMED CONSENT 
     Basic Elements of Informed Consent 
     Additional Consent Requirements 

EXCEPTIONS FROM CONSENT REQUIREMENTS 
     Exemption from Review Versus Waiver of Consent 
     Short Form Consent
     Informed Consent Without Documentation 
     Waiver of Consent 
     Emergency Medical Research 
     Waivers When Studying Usual Care 

INFORMED CONSENT FOR SPECIAL SUBJECT CLASSES 
     Minors 
     Persons Lacking Decision-making Capacity 
     Waiver of Consent for Emergency Medical Research 
     Jail Detainees 
     Employees 

GUIDELINES FOR OBTAINING INFORMED CONSENT 
     Who May Obtain Informed Consent?
     Informed Consent Is an Interaction, Not a Piece of Paper 
     Consider the Setting
     Translated Consent 
     Making Consent Forms Understandable 
     Documenting Consent 

RECRUITING RESEARCH PARTICIPANTS 
    Advertising for Volunteers 
    Recruiting for a Study Versus Clinical Referrals 
    "No" Means No 
    Payments to Subjects 

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH 
    Inclusion of Pregnant Women 

INCLUSION OF CHILDREN IN RESEARCH 
    Justifications for Exclusions 

MAINTAINING CONFIDENTIALITY 

PREPARING THE RESEARCH PROTOCOL 
     Safety Monitoring in Clinical Trials 
     HIV/AIDS Related Research 
     Determining Appropriate Sample Size 
     Criteria Used by the Scientific Committee to Review Protocols

PREPARING THE APPLICATION

RESPONSIBILITIES AFTER APPROVAL 
     Revisions 
     Notification of Primary Care Physician 
     Admitting to Hospital or Transferring to Another Hospital 
     Handling Experimental Drugs 
     Consent Procedure 
     Record Keeping 
     Research Personnel Qualifications 
     Scientific Quality Assurance 
     Publication Credit 

PROGRESS REPORTS 

ADVERSE EVENT REPORTS 
    Triggers for Identifying Potential Adverse Drug Events
    Determination of Causality 
    Determination of the Severity
    Documenting and Reporting Serious Events, Local Site 
    Other Investigational Drug Clinical Trial Sites 
 

GUIDELINES FOR RESEARCH INVESTIGATORS

This section describes expectations for the ethical conduct of research done at all components of the Cook County Bureau of Health Services (including Cook County Hospital, Provident Hospital, Oak Forest Hospital, the Cook County Department of Public Health, the Ambulatory and Community Health Network, and Cermak Health Services) and the Hektoen Institute, LLC.
 

Such research includes all projects:

• which will be carried out at an affiliate of the Cook County Bureau of Health Services; or
• which will be carried out by an employee of an affiliate of the Cook County Bureau of Health Services or the Hektoen Institute acting as an employee or agent of one of these institutions; or
• which will recruit or enroll patients or employees of one or more of these institutions as research subjects.

 

The rest of this section describes expectations and procedures for carrying out research on human subjects. Guidelines for carrying out ethical vertebrate animal research are given in the Animal Research Guidebook Supplement and in the assurance in  Section F.
 
 
 

INTEGRITY IN SCIENCE

As a result of political furor over a number of high-profile cases of scientific misconduct, the Public Health Service has taken a series of steps to reform its own response to the problem. Oversight for the federal misconduct policy has been moved into a central Office of Research Integrity (ORI), under the aegis of the PHS. This office is charged with monitoring policies, procedures and investigations at each institution receiving federal research funds.

The current definition of scientific misconduct adopted by the PHS is this:

"Misconduct" or "Misconduct in Science" means fabrication, falsification, plagiarism, or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducting or reporting research. It does not include honest error or honest differences in interpretations or judgments of data.

This definition of scientific misconduct is actually quite narrow. Some serious misbehavior is not "scientific misconduct". For instance, misappropriation of grant funds, failure to protect human subjects, bias in hiring, or mistreatment of animal subjects, while subject to severe sanctions via other routes, are nevertheless not considered "scientific misconduct" under federal regulations.

The ORI has been refining and extending federal oversight of scientific misconduct, but it still depends crucially on local institutions to provide the first-line monitoring and investigations. A major reason for this is that adequate investigations of potential misconduct require a deep understanding of both research methodology and the particular field of study, expertise that can only be provided by fellow scientists.

All recipients of federal research grants are now required to have an appropriate written policy to deal with potential scientific misconduct. The policy which applies to the Cook County Bureau of Health Services is given in Section F. It details the steps that will be taken when an allegation of scientific misconduct comes to the institution's attention.

If you have a concern about possible misconduct, contact the appropriate Research Integrity Officer:
 
 

Bureau Research Integrity Officer is Dr.Robert Weinstein. He can be contacted at 312-633-3237 

For Cook County Hospital, the Associate Research Integrity Officer is Keith Dookeran, MD, at 312-633-8207. 

For Provident Hospital, the Associate Research Integrity Officer is  Clyniece Watson, MD, at 312-572-2684. 

For Oak Forest Hospital, the Associate Research Integrity Officer is Henry Andoh, MD at 708-633-4193. 

For the Ambulatory & Community Health Network, the Associate Research Integrity Officer is Mary Driscoll at 312-633-8236. 

For Cermak Health Services, the Associate Research Integrity Officer  is Jean Kiriazes at 773-869-6575. 

For the Cook County Department of Public Health, the Associate  Research Integrity Officer is Steven M. Seweryn, at 708-492-2021.

Protection Against Retaliation

The Cook County Bureau of Health Services is committed to preventing retaliation against any  person who in good faith brings a concern to official attention about possible scientific misconduct. If you feel you have suffered an adverse action or retaliation as a result of raising such a concern, contact David Carvalho at 312-633-7510 within 180 days of the adverse action, or within 180 days of your becoming aware of the adverse action. If you feel the institution has not responded to your complain in a timely manner,  you may contact:

Office of Research Integrity
Division of Policy and Education
5515 Security Lane, Suite 700
Rockville, MD 20852
Telephone: (301) 443-5300
Fax: (301) 594-0042
 
 
 

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FINANCIAL CONFLICTS IN RESEARCH

By federal regulation, institutions must also ensure that the design, conduct, or reporting of research funded under federal grants, cooperative agreements or contracts will not be biased by any conflicting financial interest of those investigators responsible for the research. The Cook County Bureau of Health Services has adopted a policy (Section F) requiring that all significant financial interests in a research project, regardless of its funding source, must be reported. All applications for approval of research by a Bureau IRB or by the Cook County Hospital Institutional Animal Care and Use Committee must include a signed declaration by all investigators as to existence of any significant financial interest in the research (see Form D-III ) .

All Investigators Must Disclose Significant Financial Interests

An "Investigator" means the Responsible Investigator and any other person who is responsible for the design, conduct, or reporting of research. For purposes of determining financial interests, the Investigator's interests include those of his/her spouse and dependent children.

What Constitutes a Significant Financial Interest?

Significant Financial Interest means anything of monetary value, including but not limited to  salary or other payments for services (e.g., consulting fees or honoraria); equity interests (e.g., stocks, stock options or other ownership interests); and intellectual property rights (e.g., patents, copyrights and royalties from such rights).

Financial interests which are subject to reporting for any given research proposal include those which:

Would reasonably appear to be affected by the specific research proposed;

                                                                       and/or

Are interests in entities whose financial interests would reasonably appear to be affected by the research.
 

The term "Significant Financial Interest" does NOT include:
 

• Salary, royalties, or other remuneration from the applicant institution;
• Any ownership interests in the institution, if the institution is an applicant under the Small Business Innovation Research Program;
• Income from seminars, lectures, or teaching engagements sponsored by public or nonprofit entities;
• Income from service on advisory committees or review panels for public or nonprofit entities;
• An equity interest that when aggregated for the Investigator and the Investigator's spouse and dependent children, meets both of the following tests:   1) Does not exceed $10,000 in value as determined through reference to public prices or other reasonable measures of fair market value, and  2) does not represent more than a five percent ownership interest in any single entity;
• Salary, royalties or other payments that when aggregated for the Investigator and the Investigator's spouse and dependent children over the next twelve months, are not expected to exceed $10,000.

If a Significant Financial Interest Exists, What Actions Must be Taken?

Investigators are required to report any significant financial interests at the time of applying for institutional approval of a research proposal. A box is included next to the investigator's signature block in Form D-III and in the Animal Research Application to indicate if a significant financial interest exists. If there is a significant interest, the Financial Interest Statement (Section D-II.d) must be completed and submitted with the application for institutional approval.

The Scientific Committee (IRB) or the Institutional Animal Care and Use Committee, as part of the normal protocol review process, consider any reported interests, determine if there is a potential conflict of interest, and, if so, will determine how to manage, reduce or eliminate the conflict. If your research project does not require the use of human or vertebrate animal subjects, submit a copy of the research protocol and the Financial Disclosure Form to the Office of Research Development.

Examples of conditions or restrictions that might be imposed to manage conflicts of interest include, but are not limited to:

        1. Public disclosure of significant financial interests;
        2. Monitoring of research by independent reviewers;
        3. Modification of the research plan;
        4. Disqualification from participation in all or a portion of the research funded;
        5. Divestiture of significant financial interests; or
        6. Severance of relationships that create actual or potential conflicts.
 
 
 

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HUMAN RESEARCH: ETHICAL FOUNDATIONS

The principles underlying this legislation are contained in The Belmont Report issued in 1978 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The ongoing implementation of this legislation is carried out by a system of Institutional Review Boards which must approve every use of human subjects at institutions receiving federal research funds.

The Belmont Report found three quintessential requirements for the ethical conduct of human subjects research:
 

Respect for persons

involves a recognition of the personal dignity and autonomy of individuals, and special protection of those persons with diminished autonomy. This principle leads directly to the requirement for informed consent. For consent to be informed, it must meet the standards of information, comprehension, and voluntariness. Subjects must be given sufficient information on which to base their decisions, including information about the research procedures, purposes, risks and anticipated benefits, alternative procedures, and a statement offering the subject the opportunity to ask questions and to withdraw from the research at any time.

The information must be comprehensible, written in a format matched to the individual's capacity to understand it. Most importantly, this means that medical jargon cannot be substituted for lay language, that probing to see if the subject has understood the information may be necessary, and that even persons of limited capacity be helped to understand their participation at the appropriate level.

Voluntariness means that subjects must be well aware that they may refuse to participate, or may cease to participate at their discretion at any time, without penalty or threat of penalty. Conditions of consent must be free from coercion or undue influence.

entails an obligation to protect persons from harm by maximizing anticipated benefits and minimizing possible risks of harm. This implies that the investigators must conscientiously undertake a risk/benefit assessment of the protocol. From the viewpoint of the participant, all risks -- physical, psychological, social or other -- must be kept to the minimum possible. The risks that do exist must be balanced by clear benefits to the individual subject and/or to the general social good. Subjects must be thoroughly and completely informed of the risks entailed.

The beneficence principle also implies that the protocol will be based on scientifically sound reasoning. Neither risk nor inconvenience to subjects can be justified if the activity will not clearly advance the state of scientific knowledge.

requires that the benefits and burdens of research be distributed fairly. Selection of research subjects must be the result of fair procedures and result in fair selection outcomes. The "justness" of subject selection relates not only to the subject as an individual but also to the subject as a member of social, racial, sexual or ethnic groups. Researchers may not base selections on individual or social favor or disdain. Subjects may not be selected simply because they are readily available in settings where research is conducted or because they are easy to manipulate as a result of their illness or socioeconomic condition.

Social justice in research also implies an order of preference in the selection of classes of subjects -- adults are preferred over children, for instance -- and some classes of potential subjects, such as the institutionalized mentally infirm or prisoners, may be involved as subjects only under certain restrictive conditions.
 

Distinguishing Clinical Care from Research

Federal regulations concerning subject protection apply only to situations which clearly entail research. Often the boundary between practice and research is blurred, so that treating a patient with an experimental approach is difficult to differentiate from doing research on a subject. The Belmont Report defines practice as "interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment, or therapy to particular individuals."

Research, on the other hand, "designates an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby develop or contribute to generalizable knowledge... Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective."

Sometimes clinical practice can become research when it is prepared for dissemination as generalizable knowledge. Two examples would be studies of a single case or a small case series prepared for publication or presentation at a professional meeting. Another would be preparation of data from a quality assurance study for publication or presentation outside the institution. In both cases the activity that produced the data is not defined as research, and does not require prior IRB review, but does become "research" when prepared for dissemination. Also in both cases, the research would likely qualify for an exemption from review (see section below) as long as the data is not linked to individual identifiers.
 
 

Ethical Considerations in Collaborations

This Guidebook describes in detail the procedures all investigators within the Bureau are expected to follow to protect human subjects in research. When carrying out collaborative research, an investigator is also expected to be aware of the circumstances under which human subjects are studied at collaborators' sites. For instance, if you were to collaborate on a study by analyzing specimens obtained from patients at another institution, and if those specimens had been obtained under misleading or coercive conditions, your own ethical responsibility would not be discharged by your distance from the collection process or by the existence of human protection procedures in the Bureau. Your responsibility is to find out under what conditions the specimens were obtained, and to refrain from collaborating until there is an assurance that human subjects are protected at the collaborating institution. Most universities, academic medical centers and teaching hospitals have procedures in place for protecting human subjects -- as, for instance, an Institutional Review Board and a Multiple Project Assurance. However, most private practitioners, many community hospitals and many community clinics do not. If you would like to collaborate with a person or institution where such procedures are not in place, an assurance can be obtained for your project which makes it clear that your collaborators understand and are committed to human subjects protection. If this is your situation, contact the Office of Research Development for help in getting such an assurance.
 

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SCIENTIFIC COMMITTEE REVIEW

The following describes the oversight responsibilities of each IRB for research within the Bureau:
 

Research involving human subjects is governed by a common federal regulation (45 CFR PART 46 Protection of Human Subjects). Most federal agencies subscribe to the common rule, including the Department of Health and Human Services ( DHHS). The Scientific Committees of the Bureau report to DHHS by way of a standing assurance (See Section F), and therefore follow these standard federal regulations.

The Food and Drug Administration (FDA), which regulates clinical trials of new drugs and devices, has a set of regulations that largely concurs with this standard rule (21 CFR 50, 21 CFR 56, and other rules), but has not adopted it in its entirety. For this reason, some aspects of review and approval of protocols involving human subjects may have different requirements imposed by DHHS and FDA.

When both FDA and DHHS have jurisdiction, both sets of requirements must be met. Within the Bureau, many research protocols do fall under both sets of requirements. Both the DHHS and FDA requirements are incorporated into these guidelines.
 

DESIGNATING A RESPONSIBLE INVESTIGATOR
 

Any fully-qualified professional employed by a Cook County Bureau of Health Services affiliate (including Cook County Hospital, Provident Hospital, Oak Forest Hospital, Cermak Health Services, the Ambulatory & Community Health Network, the Cook County Department of Public Health) or the Hektoen Institute, or any person appointed to the medical or professional staff of an affiliate, may act as a Responsible Investigator for research. Ordinarily the Principal Investigator for a project will also be the "Responsible Investigator" designated on the Institutional Approval Forms. However, residents, fellows and students may not be Responsible Investigators, but may have their research sponsored by an attending physician willing to act in that capacity. In this case, the attending physician is designated the "Responsible Investigator". Likewise with other health professionals: a licensed social worker employed by Cook County Hospital, for instance, may be a Responsible Investigator or may act as Responsible Investigator on a social work student project.

For projects that are parts of larger multi-institutional studies, we ask that a qualified investigator employed by a Bureau affiliate or Hektoen be named "Responsible Investigator" to act as the locally responsible party. This means that even if the overall project has a PI from another institution, the "Responsible Investigator" as indicated on the approval forms will be one of our own employees or professional staff members.

In all cases, communication from the Scientific Committees -- such as letters of approval for projects, or notices that progress reports are due -- will be sent to the named Responsible Investigator.
 

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REPORTING CONCERNS ABOUT HUMAN SUBJECT PROTECTIONS

If you have a concern about the protection of human subjects in research in any Bureau facility, contact the Scientific Committee with oversight responsibility for the study in question. If you don't know which Scientific Committee has responsibility, call the Office of Research Development at 312-633-4940. 

In addition, for federally funded research, you may contact the Office for Protection from Research Risks: 

Office for Protection from Research Risks 
National Institutes of Health 
6100 Executive Blvd. 
Suite 3B01, MSC 7507 
Rockville, MD 20892-7507 
Tel: (301) 496-7005 

For FDA regulated research: 

Office of Health Affairs (HFY-20) 
Food and Drug Administration 
5600 Fishers Lane 
Rockville, MD 20857 
Tel: (301) 827-1685 
 
 

APPROVAL OF RESEARCH PROTOCOLS

Any research involving human subjects must be reviewed by the Institutional Review Board (Scientific Committee). Approval must be obtained before the research begins. Two levels of review are possible: Full review and expedited review. In addition, in some cases research may qualify for an exemption from Scientific Committee review, as described below.

Institutional officials may not approve a study which has been disapproved by the Scientific Committee. On occasion the Responsible Investigator may meet with the Scientific Committee to discuss any concerns or answer any questions that arise during its review. Such a meeting may be requested by either the investigator or the Scientific Committee.
 

FULL REVIEW

A Full Board Review is a review of proposed research at a convened meeting at which a majority of the Scientific Committee is present, including at least one member whose primary concerns are in nonscientific areas. For the research to be approved, it must receive the approval of the majority of members present at the meeting.
 

EXPEDITED REVIEW

An Expedited Review is a review of the proposed research by the Scientific Committee chair or a designated voting member, or group of voting members, rather than by the entire Scientific Committee. Federal rules permit expedited review for certain kinds of research involving no more than minimal risk and for minor changes in approved research.

A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed 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. For instance, the risk of drawing a small amount of blood from a healthy individual for research purposes is no greater than the risk of doing so as part of a routine physical examination.

The following table summarizes the ways in which research which may be eligible for expedited review. (When applying for an expedited review please refer to this table and cite one or more of the nine criteria listed which are applicable to your project on form D-III)
 
 

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EXEMPTION FROM REVIEW

Note that an investigator may not make the final decision that his/her research is exempt without confirmation of this status from the appropriate Scientific Committee. Use Form D-III.d for this purpose.

The following excerpt from federal regulations (45 CFR PART 46) details the criteria by which a project may qualify for exemption from review:
 

Most research conducted at Bureau affiliates that is eligible for exemption falls in Category 2 (interviews, surveys, educational testing) or Category 4 (for retrospective compilation of existing data -- note that "Retrospective" means that the data already exist at the inception of the study.). Under Category 4, information may not be linked directly or indirectly to personal identifiers such as subjects' names or medical record numbers. Under Category 2, such linkage is not allowed  in cases where such linkage could pose some risk to the subjects. 

Under Category 4, such identifiers must be removed at the time the data is compiled. Category 4 also includes data prepared for publication from individual cases or small case series and reports of quality assurance activities which after completion seem to merit general dissemination outside the institution.

If a research project seems to fall into one of the exempt categories, the research investigator must receive confirmation of the project's exempt status from the Chair of the Scientific Committee. A short form for this purpose is included is found in Section D-III.d.
 

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USE OF INVESTIGATIONAL DRUGS OR DEVICES OUTSIDE CONTROLLED CLINICAL TRIALS

As described in a following section, treatment use of FDA-approved drugs for indications other than those approved ("off-label use") may in some cases also require approval by the Chair or Co-Chair of the IRB, but not prior IRB review.
 

EMERGENCY USE WITHOUT PRIOR IRB APPROVAL

The Food and Drug Administration recognizes that treatment decisions may be made outside of research considerations. Physicians retain the authority to provide emergency medical care to their patients without prior Scientific Committee approval. In these cases, physicians must meet FDA requirements to use investigational articles for emergency purposes.

An Emergency IND Request allows the use of an investigational article outside an approved clinical protocol and without prior Scientific Committee approval in emergency situations. These are defined as:

• life-threatening situations
• in which no standard acceptable treatment is available and
• there is not sufficient time to obtain prospective Scientific Committee approval for use.

For the purposes of using investigational drugs for emergency treatment, the term "life threatening" includes conditions that are either life threatening or severely debilitating:

Life threatening means diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival. The criteria for life threatening do not require the condition to be immediately life-threatening or to immediately result in death. Rather, the patient must be in a life-threatening situation requiring intervention before such intervention can be reviewed at a convened meeting of the IRB.

Severely debilitating means diseases or conditions that cause major irreversible morbidity. Examples of severely debilitating conditions include blindness, loss of arm, leg hand or foot, loss of hearing, paralysis or stroke.

This exception to prior IRB review may not be used unless all of the conditions described above exist. It allows for one emergency use of a test article. Any subsequent use of the investigational product must have prospective IRB review and approval. The FDA acknowledges, however, that it would be inappropriate to deny emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time to convene a meeting to review the issue. On the other hand, if you have reason to believe that an investigational drug will be appropriate for emergency treatment of multiple patients, you should develop a protocol for its use and seek IRB approval.

Within 5 days of the emergency drug use, the physician must make a report in writing to the IRB for review and consideration at its next convened meeting. This report should detail:

    1)     the rationale for using the investigational item, including any evidence from prior studies that the agent might be safe and effective for the condition being treated;

    2)     the clinical context for its use, especially addressing the threat to the patient and the lack or ineffectiveness of approved alternative treatments;

    3)     if available, the FDA IND number for this agent and a copy of any ongoing protocol for its use.
 

Approval of the emergency drug request is not complete until given by the full IRB.
 

** Please note that patients treated under an Emergency IND Request may not be entered as subjects in a research project or clinical trial **

Obtaining an Emergency IND

The emergency use of an unapproved investigational drug or biologic also requires Investigational New Drug (IND) status from the FDA. If the patient does not meet the criteria of an existing study protocol, or if an approved study protocol does not exist, the usual procedure is to contact the manufacturer and determine if the drug or biologic can be made available for the emergency use under the company's IND.

The need for an investigational drug or biologic may arise in an emergency situation that does not allow time for submission of an IND. In such a case, FDA may authorize shipment of the test article in advance of the IND submission. Requests for such authorization may be made by telephone:

Exception from Informed Consent Requirement with an Emergency IND

All effort should be made to obtain informed consent from the patient or the patient's legal representative before using an investigational drug for emergency treatment. In cases where this is not possible, both the treating physician and another physician not involved in any trial of the test article must certify in writing that all four of the following apply:
 

1. The patient is confronted by a life-threatening situation necessitating the use of the test article.
2. Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the patient.
3. Time is not sufficient to obtain consent from the patient's legal representative.
4. No alternative method of approved or generally recognized therapy is available that provides An equal or greater likelihood of saving the patient's life. This written certification should be submitted to the IRB within 5 days as part of the Emergency IND Request.

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OFF-LABEL USE OF APPROVED DRUGS
 

At Cook County Hospital, when a physician prescribes an approved drug for treatmentfor unlisted indications,  IRB approval usually will not be required. A physician with a permanent Illinois license may prescribe any approved, marketed drug to treat a patient for an unlisted indication, provided he/she writes a valid order or prescription. If this off-label use comes to the attention of the Pharmacy because of an unusual dose, route, patient population or potential for an adverse effect, the Pharmacy may require the physician to justify such use from the literature. This literature will be reviewed by a clinical pharmacist, the Chairman of the Drug and Formulary Committee and the chairman (or designee) of the prescribing physician's department. If this group approves of such use, it may continue. Only if they do not agree with such use, will it be referred to the IRB for final determination.
 

If off-label use of an approved drug is questioned by the Pharmacy Department and subjected to review by the group described above, the physician wishing to use the drug may request interim approval for such use from the Chair of the IRB. If the Chair gives interim approval, the drug may be used for the purpose under question until a decision is reached by the process described above. An Off-Label Request may be approved verbally by the Chair if the situation requires, to be followed within 5 days by a written report
 

Research with Approved Drugs

Use of approved drugs in planned clinical trials is subject to the usual IRB review process. In addition, there are circumstances in which FDA oversight may also be required, especially if the principal intent of the study is to develop information about the product's safety or efficacy. FDA oversight is not necessary if the study meets all six of the following conditions:
 

1. It is not intended to be reported to FDA in support of a new indication for use or to support any other significant change in the labeling for the drug;
2. It is not intended to support a significant change in the advertising for the product;
3. It does not involve a route of administration or dosage level, use in a subject population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the product;
4. It is conducted in compliance with the requirements of IRB review and informed consent;
5. It is conducted in compliance with the requirements concerning the promotion and sale of drugs;
6. It is not emergency research for which waiver of informed consent will be sought.

TREATMENT USES OF INVESTIGATIONAL DRUGS REQUIRING PRIOR IRB APPROVAL

Investigational products are sometimes used for treatment of serious or life-threatening conditions either for a single subject or for a group of subjects. The following mechanisms expand access to promising therapeutic agents without compromising the protection afforded to human subjects or the thoroughness and scientific integrity of product development and marketing approval.
 

Open Label Protocol or Open Protocol IND

These are usually uncontrolled studies, carried out to obtain additional safety data (Phase 3 studies). They are typically used when the controlled trial has ended and treatment is continued so that the subjects and the controls may continue to receive the benefits of the investigational drug until marketing approval is obtained. These studies require prospective Institutional Review Board (IRB) review and informed consent.
 

Treatment IND

With a Treatment IND you may treat eligible subjects with investigational drugs for serious and life-threatening illnesses for which there are no satisfactory alternative treatments. A treatment IND may be granted after sufficient data have been collected to show that the drug may be effective and does not have unreasonable risks. Because data related to safety and side effects are collected, treatment INDs also serve to expand the body of knowledge about the drug.
 

There are four requirements that must be met before a treatment IND can be issued:

1. the drug is intended to treat a serious or immediately life-threatening disease;
2. there is no satisfactory alternative treatment available;
3. the drug is already under investigation, or trials have been completed; and
4. the trial sponsor is actively pursuing marketing approval.

Group C Treatment IND

The "Group C" treatment IND was established by agreement between FDA and the National Cancer Institute (NCI). The Group C program is a means for the compassionate distribution of investigational agents to oncologists for the treatment of cancer under protocols outside the controlled clinical trial. Group C drugs are generally Phase 3 study drugs that have shown evidence of relative and reproducible efficacy in a specific tumor type. They can generally be administered by properly trained physicians without the need for specialized supportive care facilities. Group C drugs are distributed only by the National Institutes of Health under NCI protocols. Although treatment is the primary objective and patients treated under Group C guidelines are not part of a clinical trial, safety and effectiveness data are collected. Although the FDA does not require local IRB review of Group C protocols, the Cook County Hospital/Bureau IRB requires prior review and approval, as well as informed consent by the patient.  Oak Forest and Provident Hospital IRBs may also elect to review Group "C" protocols  locally. Contact the IRB Chair for more information.
 

Parallel Track

The Parallel Track permits wider access to promising new drugs for AIDS and HIV-related diseases under a separate "treatment" protocol that "parallels" the controlled clinical trials that are essential to establish the safety and effectiveness of new drugs. It provides an administrative system that expands the availability of drugs for treating acquired immunodeficiency syndrome (AIDS) and other HIV- related diseases. These studies require prospective IRB review and informed consent.
 
 

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GENERAL REQUIREMENTS FOR INFORMED CONSENT

Legally effective informed consent shall:
 

• Be obtained from the subject or the subject's legally authorized representative;

 
• Be in language understandable to the subject or representative;

 
• Be obtained under circumstances that provide the subject with an opportunity to consider whether or not to participate, and that minimize coercive influences;

 
• Not include language through which the subject is made to waive any of his legal rights or which releases the investigator, sponsor or institution from liability for negligence.

 

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EXCEPTIONS FROM CONSENT REQUIREMENTS

Exemption from review versus waiver of consent

Investigators sometimes confuse the status of "exempt from review" and "waiver of informed consent". In fact these are two separate concepts. A project that is exempt from review has such minimal risk that it does not require ongoing IRB oversight, but the rights of the subjects do not change just because the project carries minimal risk.

As an example, a survey of patient attitudes about some aspect of their care may very well be exempt from IRB review. It would be completely unacceptable, however, for the interviewer to imply to the subject that he/she had to answer specific questions, or that there would be a penalty for refusing to participate. In fact, the IRB often will require a brief statement at the start of an interview or survey that the respondent is free to refuse to participate or to answer any questions, that he/she may stop at any time without penalty, that care will not be affected by participation, that the IRB may be contacted for questions or complaints, and that answers will be kept confidential. These are key elements of informed consent that are not eliminated when a project is exempt from review. Whenever appropriate, they should be standard operating procedure.

With retrospective chart surveys, the major potential violation of the subject's rights would be a breach of confidential information. When done with appropriate measures to "unlink" personal identifiers from the data, this kind of research may be done without the subject's express consent because this threat to his/her rights has been eliminated.

On the other hand, some studies which carry substantial risk, and for that reason are not eligible for exemption, may be carried out with a waiver of either informed consent itself -- as in some emergency medical research -- or of documenting the verbal informed consent.

Finally, there are circumstances in which a study may not be eligible for exemption, but may nevertheless be of such minimal risk as to allow for a modification in the consent process, such as a "short form" consent, or a waiver of the consent process altogether.
 

Short form consent

In most cases informed consent must be documented. Documentation is usually a written consent form containing all the information to be disclosed, which is signed by the subject or the subject's legal representative. In some cases, a "short form" may used in which the information is presented without benefit of a full written version of the consent document. Before a short form can be used, the IRB must first review and approve a written summary of what will be presented. 

A short form may be allowed in cases where the subject does not speak English. In this case, the short form consent document must be in the subject's own language. Since the short form is a standard document, it is not necessary to obtain a new translation of this form for each study. The study summary can be in English, and with the IRB's approval, may be the English version of the consent form. Standard short form consents in a number of languages commonly encountered in Bureau facilities can be obtained from the Cook County Hospital/Bureau IRB (312-633-7792). 

The full consent procedure must be presented orally to the subject in his/her own language. Each oral presentation must be witnessed by a third person, who must sign both the short consent form and a copy of the written summary of the presentation. When the investigator obtaining consent is assisted by a translator, the translator may serve as the witness. 

It is preferable that the translator for the consent process be a certified medical interpreter. A family member or friend of the participant should not be asked to interpret. The investigator obtaining the consent must be present during the translated consent procedure to answer questions. 

When either the short form or a full translated consent is used, copies of both an English version of the consent form and the signed translated or short form consent must be placed in the participant's medical record. 

These are the necessary steps for using a short form consent when the subject does not speak English: 
 

1. A person fluent in both English and the subject's language verbally delivers the information contained in the full consent document (which may also serve as the study summary);
2. the short form document is signed by the subject (or the subject's legally authorized representative); 
3. the summary is signed by the person obtaining consent as authorized under the protocol; and
4. both the short form document and the summary should be signed by the witness (who may also be the translator).

As discussed below under "Translated Consent", this procedure will not ordinarily be acceptable when the subject's native language is Spanish, and the investigator has reason to believe before starting the study that a substantial number of Spanish-speaking subjects will be enrolled. In this case, a full consent translated into Spanish will be required. 

The IRB may also allow a short form consent process for certain minimal risk studies in which a full documented consent is not practical. An example might be an interview study in which subjects will be contacted only over the telephone. Verbal consent can be obtained over the phone, witnessed, and a copy of the short form summary sent to the subject. 

Informed consent without documentation

When subjects are recruited because of sensitive, stigmatizing, or illegal characteristics keeping their identities confidential may be crucial in obtaining their cooperation. If the only document in which they could be identified is the written consent document, you may request IRB permission to waive written consent. This does not mean that there is no informed consent: You will still prepare and carry out a consent process as in any other study. The written documentation, however, is omitted.
 

WAIVER OF CONSENT

In a few circumstances, the consent process itself may be waived:

Emergency medical research

As described in the section, "Informed Consent for Special Subject Classes", patients who are unable to consent because of a medical emergency may be enrolled in research without consent under very restrictive conditions. If your protocol will require this kind of waiver of consent, consult with the Scientific Committee Chair.
 

Waivers when studying usual care

The IRB may elect to waive the consent process when the research is an "invisible", minimal-risk part of patient care. For such a waiver, there must be no additional risk, and no additional tests or procedures above and beyond what the patient would normally encounter. As a rule, such a waiver will not be granted unless there is ample justification for omitting consent. Such a justification would include:

(1)     that the research involves no more than minimal risk to subjects;

(2)     that the waiver or alteration will not adversely affect the rights and welfare of the subjects;

(3)     that the research could not practicably be carried out without the waiver or alteration; and

(4)     that whenever appropriate, the subjects will be provided with additional pertinent information after they have participated in the study.
 

In addition, there should be a rationale supporting the idea that the knowledge being sought is important enough to justify whatever invasion of privacy may be required to obtain information about unconsenting (or unaware) subjects. Waiving consent in these circumstances may be done only with express permission of the IRB. An additional circumstance in which the IRB may allow a waiver of consent is when some aspect the Bureau's services is being studied and obtaining consent would not be feasible. An example of a study which might qualify for this type of waiver would be an evaluation of follow-up visits as a result of emergency room referrals, undertaken prospectively, in which data will be compiled from a large number of medical records. It might not be practicable to approach all the subjects for permission to use this data, and their knowledge that their follow-up visits are being studied might invalidate the research. Since their care is not affected in any way, however, as long their privacy and confidentiality are protected, such a study might be allowed to proceed without prior consent.
 

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INFORMED CONSENT FOR SPECIAL SUBJECT CLASSES

Minors

In most cases, permission for a child to participate in research may be given by a parent or legal guardian. In research that entails risky procedures it may be necessary to obtain the permission of both parents. In all cases, permission of both parents is desirable where feasible. If one parent is not available, this fact should be noted on the consent form.

With children of an age to understand some aspects of research (usually considered to be around age seven or older), and with adolescents, you must give the subject a developmentally appropriate explanation of the research and ask for his/her assent. Children old enough to sign their names should be asked to sign an assent line in the consent form.

If child refuses to assent to research participation, in most cases, that decision must be respected. However, when the research offers the child the possibility of a direct benefit that is important to the health or well-being of the child and is available only in the context of the research, the IRB may determine that the assent of the child is not necessary. Additionally, in such circumstances a child's dissent, which should normally be respected, may be overruled by the child's parents, at the IRB's discretion. There are some circumstances, even in this category of studies, in which a child's dissent may be permitted to stand. For instance, when research involves experimental therapies for life-threatening diseases such as cancer, if the likelihood of success is marginal and the probability of extreme discomfort is high, a mature adolescent close to death may refuse the treatment and have his/her wishes respected.

Note that most categories of exempt research apply also to studies of minors, with the exception of interviews and surveys. Only observations of public behavior, in which the investigator and child do not interact, may be exempted. If there will be interaction with the child, even via paper and pencil, the protocol must be reviewed. Parental permission will also be required in most cases.

Adolescents legally defined as emancipated are permitted to participate in research without their parents' permission. Research involving older adolescents who, under applicable law, may consent on their own behalf for selected treatments (e.g., treatment for venereal disease, drug abuse, or emotional disorders) may also not require parental permission. The IRB will determine for each project requesting such an exception if it may be allowed. In these cases, investigators must:

1) explicitly request that the IRB make an exception to the requirement for parental permission; and 2) document for each case in which parental permission was not obtained why it was not possible to obtain it. In addition, when adolescents are enrolled in complex research protocols, it may be advisable to make an ombudsman available to them - an adult not involved in the research who can act as an advisor and advocate for the adolescent during his/her participation in the research.

In other research (e.g., research on child abuse or neglect), there may be serious doubt as to whether the parents' interests adequately reflect the child's interests. In these cases, alternative procedures for protecting the rights and interests of the children asked to participate must be worked out with the IRB.
 

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Persons Lacking Decision-Making Capacity

Persons recruited for research participation may lack decision making capacity due to a number of circumstances: Having either a psychiatric disorder (e.g., psychosis, neurosis, personality or behavior disorders), an organic impairment (e.g., dementia) or a developmental disorder (e.g., mental retardation) that affects cognitive or emotional functions to the extent that capacity for judgment and reasoning is significantly diminished. In addition, persons under the influence of or dependent on drugs or alcohol, those suffering from degenerative diseases affecting the brain, terminally ill patients, and persons with severely disabling physical handicaps, may also be compromised in their ability to make decisions in their best interests.

Under the Illinois Health Care Surrogate Act, decisions about medical care may be made by a surrogate decision maker when the patient is judged to be incapable of making those decisions. A surrogate decision maker is an adult with decisional capacity who is available upon reasonable inquiry and is willing to make decisions on behalf of the patient. When no there is no person with valid and effective Power of Attorney for Health Care for the patient, a surrogate may be identified according to the following priority:
 

1. The patient's guardian of the person;
2. The patient's spouse (common law spouses are not recognized in Illinois, but may qualify under category #7)
3. Any adult son or daughter of the patient;
4. Either parent of the patient;
5. Any adult brother or sister of the patient;
6. Any adult grandchild of the patient;
7. A close friend of the patient [Note: this shall refer to any person 18 years of age or older who has exhibited special care and concern for the patient and who presents an affidavit to the investigator stating that he or she: (i) is a close friend of the patient; (ii) is willing and able to become involved with the patient's health care and (iii) has maintained such regular contact with the patient as to be familiar with the patient's activities, health, and religious and moral beliefs. The affidavit must also state the facts and circumstances that demonstrate familiarity];
8. The patient's guardian of the estate, appointed by the court.

In this context, surrogate decision makers may be asked to give permission for enrolling persons lacking decision making capacity when the research holds outs some potential for personal benefit to the patient. In order to enroll a person lacking decision making capacity into a clinical study with a surrogate decision maker's permission, the investigator must take these steps:

1. Determine if the patient is competent to consent to participate in research. Note that adults may not be presumed "incompetent" to consent for themselves based on such broad factors as whether they are institutionalized or have a certain diagnosis. Rather, the investigator must determine if the person can understand and consent to the research.

This means determining if the person has the ability to understand the nature and consequences of a decision regarding research participation, and the ability to reach and communicate an informed decision in the matter. Specifically, using assessment procedures described in the protocol, the investigator will determine if the patient understands each of the following:
 

1. the nature and extent of his/her proposed research participation
2. the potential risks and benefits of participation
3. the alternatives to participation in the research
4. the right to refuse to participate and the right to withdraw from the study

2. Take steps to identify an appropriate surrogate decision maker and document that surrogates higher in priority are not reasonably available.

3. Obtain documented informed consent from the surrogate for the patient's participation in the research.

4. Obtain signed, dated documentation from a physician not involved in the study that steps 1-3 have been appropriately carried out, and that the research holds the potential to benefit the patient personally. This documentation may also be included as part of the consent form, or may be attached to it.
 

Some special considerations apply to obtaining surrogate consent when a person lacks decision-making capacity:

• The identity and relationship of the surrogate decision maker to the patient must be documented on the consent form. The affidavit required of the "close friend" surrogate must be attached to the consent form.

 
• In the consent process, the surrogate decision maker must be informed that he/she will be asked to make decisions on behalf of the patient in a manner that conforms as closely as possible to the known wishes of the patient. If the patient's wishes are unknown, the surrogate is expected to make decisions in accordance with the patient's best interests, weighing the risks and potential benefits of research participation and those of alternative available treatments.

 
• When two or more individuals are members of the highest possible surrogate priority category, they must reach consensus on the patient's research participation before the patient is enrolled. If the patient objects to a particular individual acting as the surrogate decision maker, then that person may not act as that patient's surrogate decision maker for research participation. If this individual represents the highest possible surrogate priority category, then the patient may not be enrolled.

 
• When obtaining consent from a surrogate for a person lacking decision making capacity, the investigator is expected to obtain the subject's assent, if possible. The subject must be present during the entire consent procedure and the subject's presence must be documented in the consent form. If a decisionally impaired adult refuses to assent to research participation, that decision must be respected.

 

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Waiver of Consent for Emergency Medical Research

Under some very restricted circumstances, waivers of informed consent may be permitted in emergency medical research involving patients unable to give informed consent. As an example, the window for applying an experimental treatment for severe head injury may not allow enough time to obtain permission from an unconscious patient's next of kin. Such a waiver can only be used if several strict criteria are met, and only after consultation with and notification of the population of potential subjects to be studied. Please consult the Chair of the Scientific Committee about these procedures.
 

Jail Detainees

Detainees and prisoners can only be asked to participate in research which could potentially benefit the persons themselves or a group to which they belong. No research with prisoners or detainees may be exempted from review. Consent procedures must include clear language that there will be no repercussions to the potential subject should he/she decide not to participate, and no special consideration (such as early release) will be given should they decide to participate. Procedures for maintaining strict confidentially should also be used, and described in the consent form.

Research with Jail detainees also requires that the convened IRB meeting at which it is considered include a prisoner advocate. For this reason, you may not enroll Jail detainees in an approved protocol unless recruiting from this population was specifically requested and approved. Responsible Investigators are responsible for instructing research personnel about this restriction, and remind them that detainees are usually distinguishable from the general patient population by the presence of a Sheriff's deputy, the use of restraints, and with outpatients, a Department of Corrections uniform worn by the detainee.
 

Employees

Consent procedures used for employees must include clear language that there will be no repercussions to the potential subject should he/she decide not to participate, or once enrolled, decide to discontinue participation. Procedures for maintaining strict confidentially should also be used, and described in the consent form.
 
 

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GUIDELINES FOR OBTAINING INFORMED CONSENT

Who may obtain informed consent?

Obtaining informed consent is the responsibility of investigators trained to carry the process out correctly. For this reason, informed consent may only be obtained by persons who:
 

1. Are named as investigators on the application for IRB approval;
2. Are professionally trained (e.g., physicians, nurses, social workers);
3. Have been trained to obtain and document informed consent according to these guidelines;
4. Are knowledgeable about the study for which the consent is being obtained;
5. Are able to communicate with the prospective subject, either directly or through a qualified interpreter;
6. For the purposes of the study in question, are supervised by the named Responsible Investigator.

Studies which employ persons who do not meet these criteria to obtain consent will be considered non-compliant and subject to suspension or termination by the IRB.
 

Informed Consent is An Interaction, Not a Piece of Paper

The written document is only a guide to what you will say to the prospective subject, as well as a record of what was communicated. The information in the consent document must be presented in a face-to-face dialog, with abundant opportunities for the prospective subject to ask questions and for the investigator to amplify the explanation as needed. Information on the consent form must be presented in such a manner that a person with a second grade education can understand it.  The consent form should reflect the content and language actually used when talking with the subject. 
 

Consider the Setting

Obtaining informed consent for research should be a meaningful interaction. It should not be carried out as if it were pro forma or just another piece of necessary paperwork. To this end, the person obtaining consent should find a setting in which distractions and interruptions are minimized and privacy is maximized. This is especially important when a medical condition of the prospective subject is to be studied.
 

Translated Consent

Although the IRB does not require that all consent forms be translated to languages other than English, if you anticipate recruiting from a population with a substantial number of non-English speakers, translated consent forms are required. You should especially consider whether there are likely to be many Spanish-speaking subjects in the recruitment pool. Exclusion of potential volunteers because of an easily-anticipated language barrier might violate the principle of inclusiveness in research.

At Cook County Hospital, the IRB has adopted a guideline that any study planning to recruit 100 or more subjects at Cook County Hospital is likely to recruit a substantial number of Spanish-speaking subjects, and therefore will have to provide a Spanish language consent document. When a full translated consent is required, investigators are expected to have the work done by a professional translator. If you need recommendations for such services, call Funeka Sihlali, Scientific Quality Coordinator, at 312-572-3506.

For projects which will not take place at Cook County Hospital, the appropriate IRB will judge the need for Spanish or other language consent forms according to the populations to be recruited for each protocol.

For non-English-speaking subjects, when a full translated consent has not been prepared,  the consent procedure may be translated verbally by an interpreter, with that person also signing the consent form and a short form consent document in the subject's own language. 

For both short form and translated consent procedures, it is preferable that the translator for the consent process be a certified medical interpreter. A family member or  friend of the participant should not be asked to interpret.  The investigator obtaining the consent must be present during the translated consent procedure to answer questions.

When either the short form or a full translated consent is used, copies of both an English version of the consent form and the signed translated or short form consent must be placed in the participant's medical record. 

Making Consent Forms Understandable

The average reading skills of Americans are no higher than an eighth-grade equivalent Most already-prepared handouts, questionnaires, and consent forms are written at 10th grade level or higher. This means that the majority of subjects in any setting are unlikely to be able to read and understand these materials. When preparing written materials, providers should pitch them at the lowest possible level of reading difficulty, generally fifth grade level or lower. In addition, clinicians should consider using non-written materials to communicate. Effective communication requires an exchange that includes probing to see if the information is understood.

William L. Freeman, MD, MPH, of the Indian Health service has discussed the problem of limited literacy in obtaining informed consent for medical research. The IHS has developed a number of general principles and guidelines for obtaining consent from subjects with limited literacy:
 

Write the consent form to be a script for your face-to-face discussion with the prospective subject.
 

Always keep in mind that informed consent is a process, with face-to-face discussion the most important part. The consent form is only a documentation of that process. If you write the consent form to be the same as the information you will give verbally, you will more likely use simple, direct language that anticipates and answers the prospective subject's needs for information.

In particular, you need to avoid an information overload which leads prospective volunteers to stop paying attention or to feel overwhelmed by the detail. Much scientific detail can be reworded or eliminated without compromising the needed information.

This means avoiding long words and complex phrasing. It also means using the active voice instead of the passive voice; using common words; making clear the links of logical sequences and of cause and effect (even if it makes the sentence longer); and repeating key or new ideas.

Ask yourself, "What questions am I trying to answer? What background information does h/she not have, but needs, to understand this?" Asking those questions may help to eliminate jargon, specialty terms and ideas not essential to making an informed decision. Also, avoid euphemisms. Research should be called "research", not "study" or "project", all the more so because many prospective subjects are suspicious of research and need to feel that the investigator is being completely open about his/her intentions.

In particular avoid using the same word with different meanings. An example is "benefit", which in the context of a consent form could be used to speak of a potential good outcome from the experimental treatment, or could be used to refer to ongoing standard health care. The former is a good thing that might happen if the subject participates, the latter is something that the patient is assured of getting regardless of his/her decision to participate in the research. Use the word "benefit" to refer to one or the other, but not both.

• Use headings and indentations to clearly mark sections of the form
• Use bolding or underlining to emphasize key words
• Use extra spacing between topics
• Repeat important or difficult-to-understand points
• Avoid using all uppercase letters
• Keep the type size reasonable
• Use large margins and plenty of empty space

 

When a prospective subject's literacy skills are very limited

    Finally, a number of strategies may be used to enhance the consent process with persons whose literacy skills are limited:

• "Next day consent": Carry out the initial discussion a day before the person actually gives consent and is enrolled. This gives him/her a chance to mull over the explanation, think of questions, reread the documentation and consult with family members.
• Use of flip-cards -- large format cards with key points and relevant graphics and diagrams -- to accompany the discussion.
• Use of patient-centered videotape or audiotape.
• Community-based methods to inform people before they are asked to participate, e.g., by publicizing and discussing the protocol repeatedly in the media.

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Documenting Consent
 

Sample consent forms are included in Section D-V. They are also available on the disk.

These are intended as examples only, to suggest wording and format for acceptable consent forms. You may rewrite, reformat or edit these examples to suit your study. All consent forms must, however, include all the essential elements of informed consent listed in a previous section.

Likewise with consent forms provided by study sponsors: you may and often should rewrite them to include only the truly essential points in a more understandable format.

Consent forms must be reproduced on institutional letterhead. As part of the project explanation given to the subject, the subject must be informed that s/he will receive a copy of the consent form.

Informed consent must be obtained by a licensed physician or a qualified professional listed as an investigator on the research project. The consent form must be signed by the subject, as well as the investigator. When a short form consent is used, a witness to the verbal explanation must also sign the document. The person witnessing the consent must have no professional or personal interest in the research to be carried out. The ORIGINAL signed copy must be attached to the subject's chart, the subject or the subject's representative receives a copy, a copy must be retained by the Responsible Investigator, and a copy must be forwarded to Pharmacy Services when applicable. The Responsible Investigator must retain copies of the signed consent forms for at least three years after the end of the study. Scientific Committee members, the staff of the Office of Research Development, and appropriate federal regulators have the right to access all study documents which are kept in the files of the Responsible Investigator(s).

The consent form must contain the names and telephone numbers of persons to contact should the subject have any questions or complaints about: 1) the research itself; 2) medical questions; and 3) human subject protections. The contact person for categories 1 ans 2 may be the same person, but it must be clear in the consent form that both types of questions should be referred to him/her.  For the third category, this should be the phone number for the responsible Scientific Committee 
 
 
 

RECRUITING RESEARCH PARTICIPANTS

Advertising for Volunteers

Posters, flyers, mailings and newspaper ads are all legitimate methods to inform people of studies they might be interested in joining. Such advertising must be done carefully, however, to avoid being misleading or possibly coercive. Advertising materials must also be reviewed and approved by the IRB.

Remember that direct recruiting advertisements are considered to be part of the informed consent and subject selection processes. IRB review is necessary for advertising materials to ensure that the information is not misleading to subjects. This is especially critical when a study may involve subjects who are likely to be vulnerable to undue influence. When direct advertising is to be used, the IRB reviews the information contained in the advertisement and the mode of its communication, to determine that the procedure for recruiting subjects is not coercive and does not state or imply a certainty of a favorable outcome or other benefits beyond what is outlined in the consent form and protocol.

The IRB must approve the final copy of printed ads. It will evaluate not only the verbal content, but the relative size of type used and other visual effects. When ads are taped for broadcast, the IRB should review the final audio or video tape. No claims should be made, either explicitly or implicitly, that the drug, biologic or device is safe or effective for the purposes under investigation -- remember that this usually is the experimental question under study, so no forgone conclusions may be implied.

Claims also cannot be made that the test article is known to be equivalent or superior to any other drug, biologic or device. Such claims would not only be misleading, but would also be a violation of the FDA's regulations concerning the promotion of investigational drugs or devices. Advertising for recruitment into investigational drug, biologic or device studies should not use terms such as "new treatment", "new medication" or "new drug" without explaining that the test article is investigational. A phrase such as "receive new treatments" implies that all study subjects will be receiving newly marketed products of proven worth. Advertisements should not promise "free medical treatment" when the intent is only to say subjects will not be charged for taking part in the investigation.

Generally, any advertisement to recruit subjects should be limited to the information the prospective subjects need to determine their eligibility and interest. When appropriately worded, the following items may be included in ads:

• The name and address of the clinical investigator and/or research facility;
• The condition under study and/or the purpose of the research;
• In summary form, the criteria that will be used to determine the eligibility for the study;
• A brief list of participation benefits, if any (e.g., no-cost health examination);
• The time or other commitment required of the subjects;
• The location of the research and the person or office to contact for further information.

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Recruiting for a Study versus Clinical Referrals

The Scientific Committee (IRB) requires that all organized recruitment of potential research subjects at Bureau facilities be reviewed and approved prior to recruiting subjects. Organized recruitment would include contacting patients whose names have been extracted from medical records; stationing recruiters in clinic waiting rooms or other hospital areas; posting flyers or handing out recruiting leaflets.

This is in contrast to an individual physician telling a patient during a clinical interaction about a research study available at another institution. As long as only descriptive information is given to the patient ( i.e., a summary of the research, and the name and phone number of the physician conducting the trial), without any stated or implied endorsement of the research, the IRB considers this interaction to be a clinical referral, not organized recruitment.

Sometimes care providers are asked by colleagues from other institutions to provide lists of names and addresses or phone numbers of patients who may meet inclusion criteria for a study being conducted at that institution. Releasing the names and addresses of your patients to someone not employed by the Bureau, who does not have any clinical reason to know this information, is a violation of patient's rights to privacy and confidentiality. Only employees with a clinical reason to know about patients' conditions should contact them about possibly participating in research. That means you may speak to, call or write your own patients and ask permission to forward their names to your colleague, without breaching the confidentiality of your relationship. Likewise, someone under your direct oversight -- a resident or a nurse for example -- could make this initial contact. Until the patient gives permission to be recruited, however, your off-site colleague and/or his employees should not be given this information. When subjects are recruited this way, it is considered organized recruitment and must have IRB approval.
 

"No" Means No

Prospective subjects who have declined to participate in a research study may not be approached again for that study. It is an infringement of a person's autonomy not to accept that person's decision, and any further approaches could be seen as coercive.
 

Payments to Subjects

Ads may state that subjects will be paid, but should not emphasize the payment or the amount to be paid. In general, the IRB recognizes that the legitimate costs to subjects for participating in research -- car fare, lost wages, child care, food -- may be appropriately reimbursed without creating a coercive situation. In some cases payments which compensate subjects for additional discomforts might be considered, but this determination will be made for projects on a case-by-case basis. Given the financial situation of many of our subjects, thought must be given to whether the offer of a large payment for participation reduces a participant's ability to freely say no to the research.

In addition, with studies lasting more than a few days, it is not appropriate to make full payment contingent upon completion of the study. It is appropriate to hold a small portion of the payment until the completion of the study as long as this "bonus" is not so large as to be coercive. Incentive payments and the payment schedule must be described in the consent document.
 

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INCLUSION OF WOMEN AND MINORITIES IN RESEARCH

Both the National Institutes of Health and the Food and Drug Administration have guidelines intended to ensure that federally-supported or federally-regulated biomedical and behavioral research involving human subjects will elicit information about individuals of both genders and of diverse racial and ethnic groups and, in the case of clinical trials, to examine differential effects on such groups. The Cook County Bureau of Health Services is also committed to inclusiveness in all its research. For that reason, you will be asked, when making yearly progress reports to the Scientific Committee, to report on the gender, racial and ethnic makeup of samples of subjects enrolled in your research.
 

Inclusion of Pregnant Women

The desire to safeguard the developing fetus as well as to serve the needs of the mother has in the past led to a presumption of exclusion from research for pregnant women. That is, pregnant women were routinely excluded from volunteering for research unless there was a compelling reason for them to participate (as when the condition being studied is related to pregnancy itself).

This presumption, meant to protect vulnerable research subjects, has also led to a nearly complete lack of knowledge about the effects of many medical treatments on pregnant women and on fetuses. When clinical situations arise which might call for a particular treatment, and the patient is pregnant, practitioners have no way of knowing or even estimating the risks of the treatment. In addition, sweeping rules intended to protect pregnant women in research raised barriers to conducting even the most innocuous studies of them. For instance, the curent law does not allow an exemption from review for research using minimal risk surveys of pregnant women.

In a move to encourage more and better research on pregnant women, the Department of Health and Human Services has proposed to change its research policy, from a presumption of exclusion to one of inclusion of pregnant women. With this policy change, pregnant women may not be categorically excluded from clinical trials based solely on the pregnancy. If there is evidence that either the woman or fetus may be harmed by participation in a trial, then pregnant women may be excluded. An explicit rationale for exclusion will be required in the proposal for research.

As of the publication of this guidebook this policy change has not yet taken place. To check on the current status of the DHHS inclusion policy for pregnant women, call the Office of Research Development.
 

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INCLUSION OF CHILDREN IN RESEARCH

Therefore, proposals for research to be funded by NIH involving human subjects must include a description of plans for including children. If children will be excluded from the research, the application or proposal must present an acceptable justification for the exclusion.
 

Justifications for Exclusions

It is expected that children will be included in all research involving human subjects unless one or more of the following exclusionary circumstances can be fully justified:

1. The research topic to be studied is irrelevant to children.

2. There are laws or regulations barring the inclusion of children in the research.

3. The knowledge being sought in the research is already available for children or will be obtained from another ongoing study, and an additional study will be redundant.

4. A separate, age-specific study in children is warranted and preferable.

5. Insufficient data are available in adults to judge potential risk in children (in which case one of the research objectives could be to obtain sufficient adult data to make this judgment).

6. The study design is aimed at collecting additional data on pre-enrolled adult study participants (e.g., longitudinal follow-up studies that did not include data on children).

7. Other special cases justified by the investigator and found acceptable to the review group and the Institute Director.

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MAINTAINING CONFIDENTIALITY

In some studies, where subjects are selected because of a sensitive, stigmatizing, or illegal characteristics (e.g., persons who have sexually abused children, sought treatments in a drug abuse program, or tested positive for HIV) keeping the identity of participants confidential may be as or more important than keeping the data obtained about them confidential.

In many observational and retrospective studies, data is recorded without any individual identifiers, and thus may be exempt from IRB review. Persons performing such a study must confirm its exempt status with the Chair of the Scientific Committee. If subject's names will be recorded by the investigator for follow-up (either for further record reviews or for personal contact) this research requires IRB review. In such instances, the IRB must determine whether subject's consent must be sought before the researcher gains access to the records.
 
 
 
 

PREPARING THE RESEARCH PROTOCOL

In many cases, a protocol that fits these guidelines will have been developed as part of a grant application.  If so, please submit the narrative of your grant application as the description of the protocol.
 

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Safety Monitoring in Clinical Trials

When a new drug or treatment is being tested, there should be a mechanism to monitor the safety and efficacy of the trial at intervals throughout. Most multisite trials sponsored by a federal agency or pharmaceutical company will have a central Data Safety Monitoring Board which will periodically check to see if unexpected patterns of adverse reactions can be discerned, or if the differences between treatments are so large that it is more ethical to stop the trial than to continue it. Even with trials which are locally designed and carried out, periodic safety monitoring can be built into the protocol without jeopardizing experimental control. For instance, the pharmacy department might be asked to provide, at certain accrual points, an unmasked code to an independent investigator (not the Responsible Investigator or other person directly carrying out the trial) who could use interim results and adverse event information to make a recommendation as to whether the trial should continue. If your protocol includes such a safety monitoring mechanism, be sure to describe it.
 
 
 

HIV/AIDS RELATED RESEARCH

For research on Human Immunodeficiency Virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS), the following elements must be included in the protocol:
 
 

A. The study is to be designed with administrative, management and technical safeguards to control use and disclosure of information and to protect against unauthorized disclosure. Where identifiers not required by design of the study, they are not to be recorded. If identifiers are records, they should be separated, if possible, from data and stored securely, with linkage restored only when necessary to conduct the research. No lists should be retained identifying those who elected not to participate. Participants must be given a fair, clear explanation of how information about them will be handled.

B. As a general principle, information is not to be disclosed without the subject's consent. The protocol must clearly state who is entitled to see records with identifiers both within and outside the project. This statement must take into account the possibility of review of records by the funding agency, and by FDA officials if the research is subject to FDA regulations (21 CFR 50).

C. The protocol should contain information setting forth how to respond to requests by third parties who have authorization for disclosure of information signed by subjects. (Particular attention should be given to handling blanket authorizations that purport to authorize disclosure of all the data relating to a given person.)

D. Careful consideration must be given to circumstances under which participants may be recontacted for follow-up studies. New informed consent procedures will be employed if additional studies not addressed by the first informed consent process are to be performed involving materials or data collected in the original study. (New informed consents must have the Scientific Committee's prior approval.)

E. It is the policy of the Public Health Services (PHS) that when HIV testing is conducted or supported by PHS, individuals whose test results are associated with personal identifiers must be informed of their own test results and provided with the opportunity to receive appropriate counseling. Individuals may not be given the option "not to know" the result, either at the time of consenting to be tested or thereafter. This policy does not apply to testing situations in which subjects consent to be tested but specimen results cannot be linked to individual subjects by anyone other than the subjects themselves.

There are exceptions under special circumstances set forth in the policy of the PHS. Investigators may contact the Scientific Committee for these exceptions. However, proposed exceptions must have the prior approval of the Scientific Committee, the Agency Head of PHS, and the Office from Protection from Research Risks.
 
 
 

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DETERMINING APPROPRIATE SAMPLE SIZE
 

If the proposed research design cannot yield useful data, there is no ethical justification for asking subjects to take on the risks, or even the inconvenience, of participating. One way in which a design may be fatally flawed is by having a sample size too small to detect meaningful differences between experimental treatments. Even if the study is descriptive, as in a survey of patient attitudes, too small a sample size means that range of the responses will not adequately describe the true nature of the variables being studied. For these reasons, the IRB asks that you justify your proposed sample size, either with a power analysis when differences between groups are to be tested, or with other information when the study is descriptive.

When calculating sample sizes for tests of differences between or among groups, you have to determine four values: the Type I error rate acceptable (also known as the alpha value-- most often set at .05 -- with the result reported as "p" for probability), the Type II error rate acceptable (this indicates the power of the test), the estimated variability in the data, and the estimated size of the differences between or among groups. This last is often based on a judgement about what size difference between treatments would be clinically meaningful. Many basic statistical programs provide routines to calculate sample sizes for a variety of experimental designs.

Some good sites which will calculate sample size interactively online are:

• The UCLA Power Calculator (http://calculators.stat.ucla.edu/), which will calculate either power or sample size for a variety of designs and distributions;

 
• With Designing Clinical Trials (http://hedwig.mgh.harvard.edu/size.html) you can calculate power for several types of clinical trials;

 
• For analysis of variance designs you can go to Power Analysis for ANOVA Designs (http://www.math.yorku.ca/SCS/Online/power/).

 

• A "Supercourse" on epidemiology, found at http://www.pitt.edu/~super1/main/index.htmincludes several tutorials for statistical treatment of both epidemiological and clinical research. This site includes a lecture on determining sample size for surveys.

 
• The electronic British Medical Journal has an online book, "Statistics at Square One" which is a good basic overview of the use of statistics in clinical research. It can be found at: http://www.bmj.com/statsbk/

Pilot Studies

When the treatment, procedure or intervention being tested is so new that you cannot estimate either the variability or the size of the difference between groups, you may be advised to carry out a pilot study with a small number of subjects before undertaking a full-scale test. This is particularly advisable if there are questions about the feasibility of the approach. If you have planned a pilot or feasibility study, indicate that your research is at this stage to justify a small sample size.
 

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CRITERIA USED BY THE SCIENTIFIC COMMITTEE TO REVIEW PROTOCOLS:
 

A. The acceptability of the study will depend upon its relative merits of, and the need for, the specific investigation.

B. The description of the protocol must:
 

1. Highlight the need for the study, document any pertinent work in the field and any conflict in the area under investigation.

2. Carefully define the end point in the study and the circumstances under which the study may be interrupted (e.g. frequency of expected adverse effects and level of statistical significance necessary to terminate the investigation).

3. Define the patient population, sampling methodology and criteria for inclusion/exclusion to reduce any possible group bias.

4. Make clear any likely risks and benefits to individual subjects and to the class(es) of patients being studied.

5. Use of placebo designs must be fully justified. Placebo studies may be appropriate where there is no known therapy for a particular condition. When a proven effective therapy exists, however, withholding that therapy for the sake of making a comparison of an new drug to a placebo is not justifiable.

The Scientific Committee may ask consultants outside its membership to review any studies for which additional expertise is needed. It may also designate a "Review Subcommittee" to monitor certain studies for which there is special concern about risks or feasibility.
 
 
 

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PREPARING THE APPLICATION

For the Cook County Hospita/Bureau IRB, five copies (one original, four copies--collated sets) of the completed forms, budget and protocol must be submitted to the Scientific Committee. Upon receipt of the project with the appropriate forms, the Chairman of the Scientific Committee will refer it directly to one or more members of the Scientific Committee for report and recommendation.

The reviewing Scientific Committee member(s) may discuss the merits of the project directly with the investigator(s). The reviewing member(s) may ask questions and request changes or corrections in the project and consent form. Such changes or corrections must be made by the investigator(s) before the review process proceeds to the next step.

After the reviewing member(s) have completed their review of the research project, it is presented at the next convened meeting of the Scientific Committee. The reviewing member(s) will report their findings and recommendations. Recommendations are voted upon by the entire Scientific Committee. Occasionally, investigator(s) may be asked to present and discuss the project before the Scientific Committee.

At Cook County Hospital, after a research project requiring full review has been approved by the entire Scientific Committee, it is forwarded to the Executive Medical Staff (EMS) for approval. No subjects may be entered into a new study until the protocol has been approved by the EMS. If necessary, the President of the EMS can give interim approval of a protocol prior to confirmation at the next regularly scheduled EMS meeting. This restriction does not apply to protocols receiving expedited review or which have been exempted from review.

When the Oak Forest or Provident Hospital IRB has responsibility, the study can begin upon receipt of written IRB approval. 
 
 
 

RESPONSIBILITIES AFTER APPROVAL

Revisions

Any changes in the protocol or consent form are to be approved by the Scientific Committee before they go into effect. All changes in key personnel (e.g., co-investigators) are to be reported to the Scientific Committee. If you wish to enroll more subjects than your study was originally approved for, or if you want to enroll subjects from a special population not included in the original protocoll, this is considered a revision and must receive IRB approval.
 
 

Notification of primary care physician

The investigator must inform the patient's primary care physician of the desire to enter the patient in a study protocol prior to discussing the project with the patient. The primary care physician's approval is not necessary for patient enrollment. However, communication with the primary care physician is necessary. The subject should also be encouraged to discuss the research study with his/her primary care physician.
 

Admitting to hospital or transferring to another hospital

When a patient who is enrolled in clinical research is admitted to the hospital, those involved in his/her care need to be fully aware of that person's participation in the research, what experimental drugs if any the patient is taking, and any expected side effects of those drugs. The investigator is responsible for ensuring that any other physicians who will take responsibility for the patient's care are informed about the patient's research participation and that a copy of the signed consent form is in the patient's medical record. Of course, if the condition which necessitates hospitalization is judged to be an adverse event, a report must be filed with the IRB.

When the patient will be transferred to another hospital, the IRB which originally approved the study must be notified. Appropriate staff of the receiving hospital (e.g., attending physician, nursing supervisor, pharmacist), must be notified that an enrolled patient is being transferred, and should receive copies of the protocol and signed consent form. A copy of the consent form must also be put in the chart at the receiving hospital, and appropriate staff be informed about how to contact the investigator should the patient experience an adverse event, or if the patient requires a change in medications or treatment.
 

Handling experimental drugs

A. If experimental drugs are used, the investigator is responsible for:
 

1. obtaining the necessary subject's consent before the drug is administered;
2. insuring that the drug is used under his/her supervision;
3. maintaining a proper record of results;
4. adhering to the procedure for reporting adverse reactions from a drug or experimental medical device;
5. providing involved personnel with a copy of the approved protocol and other information related to the drug;
6. notifying the Pharmacy Services of who will participate and administer the drug.

B. All drugs approved for use in an approved research project must be delivered to, stored in, and dispensed by Department of Pharmacy. The Drug and Formulary Committee will consider exceptions to this regulation if submitted to them in writing.

C. It is the Department of Pharmacy' responsibility to insure drug security, drug control, and accountability records. The Department of Pharmacy will provide the investigator(s) with the investigational and/or the control drug labeled for the subject, at the time of administration and in a form ready to administer.
 

Consent procedure

Informed consent must be obtained by a licensed physician or other qualified professional listed as an investigator on the research project. Each subject is to have a copy of individual consent form in his/her chart written in his/her native language or certified as translated by an individual capable of such translation. Each subject is to be given a copy of this consent form to keep.
 

WHEN USING A SHORT FORM CONSENT, THE WITNESS SIGNING THE FORM IS TO WITNESS THE ORAL EXPLANATION OF THE PROJECT TO THE PROSPECTIVE SUBJECT.
 

Record keeping

Each investigator is required to maintain accurate, complete, and current records. Each investigator is required to keep an up-to-date log containing a list of subjects entered into a research study. This record must be made available to the Scientific Committee at its request for purposes of review.
 

Research personnel qualifications

The investigator(s) must carry out the agreed upon activities and not delegate them to other previously unspecified staff. Any persons working on a research project on the premises of a Cook County Bureau affiliate must be properly credentialed with current ID badges.
 

Scientific Quality Assurance

The Cook County Bureau of Health Services has established a program of scientific quality assurance to help investigators maintain high standards, especially in protecting human subjects. A Scientific Quality Coordinator, reporting to the Director of Research Development, is assigned to carry out research site visits and report back to the IRB responsible for the project.

Such surveys include review of charts and project records and interviews with research staff for evidence of:

1. appropriate informed consent;
2. appropriate subject eligibility, recruitment and assignment to group;
3. adequate notification of Scientific Committee (IRB) of revisions, study progress, renewal of protocol approvals, adverse events, or other information requiring IRB notification;
4. maintenance of patient confidentiality and privacy;
5. completeness of data entry;maintenance of blinding procedures;
6. consistency in carrying out study protocols; and any other scientific quality issues as requested by the Scientific Committee.

County investigators are urged to consult with the Scientific Quality Coordinator if they have any questions about the appropriate procedures and standards to be followed. Investigators, their staffs and collaborators are expected to cooperate fully with any site visit or survey activities carried out as part of the scientific quality assurance program.
 

Publication Credit

The Responsible Investigator(s) and associates agree to credit the appropriate Cook County Bureau affiliate in all publications and presentations deriving from the project.
 

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PROGRESS REPORTS

The type and frequency of formal re-reviews by the IRB are related to the risks inherent in the research. Projects which entail more potential risk, or which involve particularly "vulnerable" participants may be reviewed more frequently than the required minimum yearly review period.

About two months before the anniversary date of the approval of your project, you will receive the first of three notices that a Progress Report is due. This report must be received, reviewed and approved by the IRB by the date indicated. No grace period is allowed for filing progress reports.

If no progress report has been submitted and approved by the expiration date, the IRB is required by federal regulations to suspend the research. When a protocol is suspended, all research activity must cease until it has been reapproved. The only exception is when abrupt cessation of an experimental treatment might adversely affect the health of enrolled subjects.

When you close pout a study, you will be asked to complete a final progress report so we have a record of the number of subjects enrolled and any results or problems encountered. Investigators who fail to submit a final progress report may have their future research approvals delayed until prior final progress reports are submitted.

If a research protocol is suspended for any reason the IRB may be required to notify both the federal Office for Protection from Research Risks and any federal funding agency for that project.

The form for Progress Reports can be found in Section D-IVa.
 
 
 

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ADVERSE EVENT REPORTS

The Food and Drug Administration criteria for reportable adverse events are that such events are "serious" and "unexpected". Whether an event is judged "serious" depends largely on the clinical judgement of the investigator, often in consultation with the Chair of the Scientific Committee (IRB). In the following sections, a suggested framework is given for judging severity of an event. The final weight assigned to an adverse event, however, will stem from your close clinical knowledge of the subject and the context of the event.

Whether an event is "unexpected" can be judged by referring to the information compiled at the start of the study: Is this an event that was noted in the investigator's brochure supplied by the study sponsor? Is it an event that was mentioned as a possible risk in the original consent form?

Any program of human research is a reiterative process. As our knowledge base about new agents expands, we have an obligation to revisit the risk/benefit equation, and to revise protocols, consent forms and subject information as necessary. This has the advantage of not only maintaining an ethical relationship between investigator and subject, it also has the effect of enlisting the subject as an observer and reporter of what could be valuable information.

The following outline for evaluating and reporting potential adverse events in drug trials is adapted from one devised by Roohollah Sharifi, MD, University of Illinois Chicago.
 
 

Triggers for Identifying Potential Adverse Drug Events:

If one or more are present, the clinical investigator should undertake a determination of causality and severity as outlined below.
 

A.     Any new or worsening symptom or sign on follow-up visit that was not present on baseline physical exam or medical history.

B.     Any medical condition causing hospitalization or physician visit.

C.     Any new medication started during the study.

Determination of Causality: Is the Investigational Drug Causing this Adverse Event?

Signs in the chart below indicate the suggested weight to be given to each factor in determining the likelihood that the investigational drug is causing the event. Note that the strongest evidence comes from a rechallenge with the drug after discontinuation. This strategy is often too risky with a serious event, however, so investigators often must rely on combined information from the other key characteristics.
 
 
 

Under FDA regulations, events deemed to be unrelated to the drug or of unknown etiology do not require reporting. Some investigators, however, err on the side of caution and report all serious adverse events, regardless of judged relationship to the investigational agent.
 
 

Determination of the Severity of Adverse Drug Event

The next table shows suggested weights to be given to determine the severity an adverse event. Note that starting drug treatment, interruption of routine activities, or subject seeking medical help might be deemed either moderate or severe events, but all other listed events are considered severe, and must be reported if the investigational agent cannot be ruled out as a possible cause.
 
 
 

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Process for Documenting and Reporting Serious Adverse Drug Events (ADE) that Occur at the Local Site
 

A.     All serious and unexpected ADE need to be reported to the drug company and the IRB if the investigator cannot rule out the investigational agent as a possible cause of the event. (A form for this purpose is provided in Section D-IV.b)

B.    Information which should be provided to the drug company and the IRB:
 

1. Full description of ADE:

Name of ADE

Onset of ADE

Clear description of symptoms and signs (from medical history and PE)

Lab tests or other tests performed to diagnose ADE (date and test results)

Medications or other treatments for ADE (start and stop dates)

Outcome of the ADE

If hospitalized, admission and discharge dates

If died, date of death, cause of death, copy of death certificate

2.     Determination of causality (see above)

3.     Assessment of severity (see above)

4.     For the IRB, include recommendations for monitoring other subjects in the study so as to be able to perform an early diagnosis of the problem. Revise consent form as necessary.

5.     The drug company and the IRB should be contacted within 24 hours for a serious and unexpected ADE that results in death, or within 3 days for other serious and unexpected ADE.

6.     Advise as to the approach taken by the National Study Center based on the ADE.
 
 

Process for Handling ADE Reports from Other Investigational Drug Clinical Trial Sites
 

Note:   For NIH-sponsored clinical trials the investigator may not receive individual ADE reports from other sites, but rather a summary report from the study's Data Safety Monitoring Board. Copies of these summary reports must be forwarded to the IRB.
 

A.     If the event is both serious and unexpected send a copy of the report to the IRB with recommendations for monitoring other subjects in the study in the future.

B.     If necessary, revise the consent form to reflect any new information about the ADE or any additional tests which may be called for.

C.     If necessary, verbally inform already-enrolled subjects about the new ADE; perform any additional tests which may be called for.

D.     Advise as to the approach taken by the National Study Center based on the ADE.

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