Introduction

Crouse Hospital encourages the conduct of research in each of its departments, and in collaboration with other educational institutions, agencies, and organizations. In this regard, Crouse is firmly committed to adhering to the basic ethical principles underlying the acceptable conduct of research involving human subjects, as set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. These three principles, respect for persons, beneficence, and justice are particularly relevant to the protection of human subjects in biomedical and behavioral research, and are the accepted requirements for the ethical conduct of such research.

Respect for persons involves a recognition of the personal dignity and autonomy of individuals, and special protection of those persons with diminished autonomy.

Beneficence entails an obligation to protect persons from harm by maximizing anticipated results and minimizing possible risks of harm.

Justice requires that the benefits and burdens of research be distributed fairly.

Moreover, the principle of respect for persons underlies the need to obtain informed consent; the principle of beneficence underlies the need to minimize risks; and the principle of justice requires that subjects be fairly treated. Crouse Hospital has set standards for the conduct of research which mandate well-conceived and well-conducted research. To assist in maintaining those standards, an Institutional Review Board (IRB) has been established, and this Policy and Procedure Manual for Research with Human Subjects has been prepared for distribution to the Crouse community. The manual provides detailed information to support institutional initiatives for guaranteeing compliance with federal regulations governing the protection of human subjects and to guide principal investigators in procedures relevant to the development of research protocols that include human subjects. Throughout this manual, humans whose physiologic or behavioral characteristics, or whose understanding of their experiences, and responses are the object of study are referred to as subjects; however, Crouse in no way intends to demean the humanity and individualism of such persons. Recognizing that regulations and policies and procedures are no guarantee of ethical conduct, it is the responsibility of individual researchers to make ethical considerations central in the conduct of research and to have a clear understanding of their duties to human subjects.

Research Covered by and Exempt from Review

To comply with the federal guidelines covering the protection of research subjects, and to ensure appropriate ethical management of research programs conducted by Crouse faculty, staff, and students, all funded and unfunded research proposals involving any risk to human subjects falls within the jurisdiction of the IRB. The IRB Chairman will be responsible for determining whether the research should be reviewed or is exempt.

Research Covered by Review

Research which has potential risk to subjects includes, but is not limited to, the following:

• Research which involves the administration of drugs or other substances to subjects
• Research involving pregnant women and/or fetuses in utero
• Research involving subjects with life-threatening physical conditions
• Research involving physically intrusive procedures
• Research which previous experience (by the particular investigator or other investigators) has shown to create a potential of risk to subjects
• Research which potentially could put the subject at risk for legal or civil liability or invade a subject's privacy in regard to sensitive aspects of his/her behavior (e.g., illegal conduct, drug use, sexual behavior, alcohol use).

Research Exempt from Review

Research which is regarded as not having potential risk to subjects includes the following:

• Research in which the risks of harm reasonably anticipated are not greater than those ordinarily encountered in daily life or during the performance of routine procedures in education and/or in the practice of psychology and medicine
• Research on the effectiveness of educational, classroom, and/or instructional strategies, provided that these strategies are familiar, and nonintrusive in their implementation
• Research using educational tests (cognitive, diagnostic, aptitude, achievement) if subjects' identities are thoroughly protected
• Research using survey procedures or interview procedures where subjects' identities are thoroughly protected and their answers do not subject them to criminal and civil liability
• Research involving the collection or study of existing data, documents, records, specimens, or other products, if these sources are publicly available or the information is recorded by the investigator in such a manner that the subjects cannot be identified directly or indirectly.

Moreover, the IRB will conduct continuing review of research being undertaken with human subjects by faculty, staff, and students in accordance with the policies and procedures outlined in this manual at intervals appropriate to the degree of risk, but not less than once per year for the life of the project.

In the event research is undertaken without the intention of involving human subjects, and subsequently the researcher wishes to involve human subjects in the research, the research must be reviewed by the IRB in accordance with the policies and procedures outlined in this manual.

Criteria for Approval of Research

In order to approve research covered by the policy contained in this manual, the IRB will determine that all of the following requirements are satisfied:

• Risks to subjects are minimal
• Risks to subjects are reasonable in relation to anticipated benefits
• Selection of subjects is reasonable
• Informed consent will be sought from each prospective subject or the subject's legally authorized representative
• Informed consent will be appropriately documented
• When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects
• When appropriate, adequate provisions exist to protect the privacy of subjects and to maintain the confidentiality of data

Additional safeguards have been included in the study to protect the rights and welfare of vulnerable populations, such as children; prisoners; pregnant women; mentally disabled persons; or, economically or educationally disadvantaged individuals.

Full Review

A full review of proposed research shall take place at convened meetings at which a quorum of the members of the IRB one of whom must be non-scientist must be present. In order to approve research, the IRB shall determine that all criteria for approval are satisfied. In order for the research to be approved, it shall receive the approval of a majority of the members present at the meeting. Most research follows the full review and approval process.

Expedited Review

Expedited review allows Crouse Hospital to use an abbreviated review procedure for research proposals and teaching involving human subjects. To qualify for expedited review, two criteria must be met.

• The research or teaching must involve no more than minimal risk to the human subjects, and
• The research or teaching must consist entirely of one or more of the following specific activities:
  • Collection of hair and nail clippings in a nondisfiguring manner; deciduous teeth; and permanent teeth if patient care indicates a need for extraction
  • Collection of excreta and external secretions including sweat, uncannulated saliva, placenta removed at delivery, and amniotic fluid at the time of rupture of the membrane prior to or during labor
  • Recording of data from subjects 18 years of age or older using noninvasive procedures routinely employed in clinical practice. This includes the use of physical sensors that are applied either to the surface of the body or at a distance and do not involve input of matter or significant amounts of energy into the subject or invasion of the subject's privacy. It also includes such procedures as weighing, testing sensory acuity, electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, diagnostic echography, and electroretinography. It does not include exposure to electromagnetic radiation outside the visible range (for example, x-rays, microwaves)
  • Collection of blood samples by venipuncture, in amounts not exceeding 450 milliliters in an eight-week period and no more often than two times per week, from subjects 18 years of age or older and who are in good health and not pregnant
  • Collection of both supra-and subgingival dental plaque and calculus, provided the procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques
  • Voice recordings made for research purposes, such as investigations of speech defects
  • Moderate exercise by healthy volunteers
  • The study of existing data, documents, records, pathological specimens, or diagnostic specimens
  • Research on individual or group behavior characteristics of individuals, such as studies of perception, cognition, game theory, or test development, where the investigator does not manipulate subjects; behavior and the research will not involve stress to subjects
  • Research on drugs or devices for which an investigational device exemption is not required.

IRB Review Process For New Protocols (full Board & expedited)

To apply for IRB approval, the following should be submitted to the IRB office:

• One original copy of the complete IRB application, which includes the application form, summary of research protocol (5 pages or less), and consent document.
• One copy of the complete study protocol and one copy of the Investigator Brochure. (if applicable). NOTE: All studies using investigational drugs under an FDA IND (investigational new drug) will need an investigator brochure. This may be requested from the sponsor.
• One copy of the Report of Prior Investigations (if applicable). NOTE: All studies using investigational devices under an FDA IDE (investigational device exemption) will need a report of prior investigations of the device (21 CFR 812.45). This may be requested from the sponsor.
• One copy of the grant application (if applicable). When a new project is submitted to the IRB, it is assigned a unique IRB study number.

Applications requiring full board review will be added to the IRB meeting agenda upon receipt of the above materials by the deadline. The application will be reviewed by the IRB at its monthly meeting and the Principal Investigator will be notified of the Board's decision.

Applications that qualify for expedited review are reviewed for approval by the chair or vice-chair. If the chairman or vice-chairman feels that changes are needed, this will be communicated to the Principal Investigator. The chairman/ vice-chairman does not have the authority to disapprove the research. A research proposal may only be disapproved by the full board.

The board meets on the third Tuesday of every month.

The IRB shall review and have the authority to approve, tentatively approve pending receipt of additional information, or disapprove the subject research according to the following.

Approve

The protocol is approved as submitted.

Pending

A protocol is considered pending when the problems identified in the protocol are not serious and generally fall into two categories: 1) the investigator needs to clarify an aspect of the study or provide additional information, or 2) minor changes need to be made in the informed consent document. In these cases, approval can be given after the investigator rewrites the informed consent and/or submits to the Chair a written response to the IRB's questions and concerns. The Chair will then poll IRB members to receive final approval.

Tabled

A protocol is considered tabled when it needs substantial revisions or clarifications to the protocol or consent document. Such protocols will need to be re-reviewed by the full IRB.

Disapprove

The IRB will disapprove the proposed research if it places the subjects at risks which far outweigh the benefit or value of the knowledge to be gained, or it raises such serious ethical questions as to be unacceptable. In the event a disapproval is foreseen, the investigator will be invited to attend the meeting of the IRB to discuss the protocol. A research activity may be disapproved only after a full IRB review has been conducted.

Written notification of actions taken at the full Board meeting is mailed to the Principal Investigator after each meeting.

NOTE: At This Point the assigned IRB Number Should Be On All Correspondence.

IN CASES WHERE A STUDY IS DISAPPROVED, the IRB will provide its rationale for the action taken. The investigator may request an appearance before the Board to present arguments for reversal of the decision or propose a change in the protocol based on the advice and counsel of the Committee. Once a project is approved, no protocol or consent form changes, amendments, or addenda may be made without re-review and approval.

Attached to the standard approval letter is the final approved version of the consent form with the IRB approval stamp and expiration date affixed on the bottom of each page. This stamped consent may be copied but must not be changed in any way (including reducing the size). The consent form is valid until the expiration date. If a consent form is revised and approved by the IRB, during this period, it is stamped with the IRB approval stamp, expiration date and the date of the revision. NOTE: The expiration date remains the same. There are sponsors of clinical trials who require the inclusion of specific language in approval letters. This language will not be added to a standard approval letter or acknowledgement letter unless the investigator informs the IRB Office of the need to include special statements in the correspondence.

Continuing Review Process for Approved Research Protocols

Continuing review is a federally mandated requirement. All protocols approved by the IRB must be reviewed at least annually. The expiration date is stamped on each page of the consent document. As a courtesy, a notice that the continuing review report is due will be sent to the Principal Investigator at least one month prior to the study expiration date; however, there may be problems with the IRB database which cause a renewal notice not to be issued. Therefore, an investigator should not depend solely on IRB notification as a prompt for submitting a request for renewal. It is the responsibility of the Principal Investigator to complete the continuing review form and return all requested items at least 4 weeks prior to the expiration date in order to ensure that the review process is completed on time.

In certain circumstances, determined at the time of initial review, the Board may stipulate that continuing review should take place more frequently than once a year (for example, high risk protocols or protocols with a high risk: potential benefit ratio). If special reporting requirements are set as a condition of approval, the investigator must submit the required information in a timely manner that will permit determination of whether changes have occurred in the risk: benefit ratio. In addition, the IRB may request additional information from sources other than the principal investigator in order to assess the completeness and accuracy of information submitted and to verify that no material changes have occurred since the last IRB review. These situations may include the following: complex projects involving unusual levels or types of risks to subjects; projects conducted by investigators who previously have failed to comply with requirements of the HHS regulations or the requirements of the Crouse IRB; and projects where concern about possible material changes occurring without IRB approval have been raised, based upon information provided in continuing review reports or from other sources.

As part of the continuing review process, the IRB requires an investigator to report the experience to date in implementing the protocol (progress report). If this information is not provided, the review will be delayed until the information is provided.

If the trial has a Data and Safety Monitoring Board (DSMB), any reports received during the year should be submitted. It is the PI's obligation to continuously monitor the overall risk-benefit ratio associated with participation in the study, thus promoting the safety and interest of the subjects in the study. The Committee reviews DSMB reports as part of its process of continuing review. One board member is assigned to conduct an in depth review of each project and makes a recommendation regarding continuation. Re-approval is only granted at a convened meeting of the full Board, unless the project is eligible for expedited review.

The following should be submitted to the IRB office with the continuing review report.

• One copy of the completed Continuing Review Report.
• One copy of the current approved consent document with IRB stamp (no subject names or signatures).
• One clean copy of the consent document for the IRB to stamp with new approval dates.

Please note that the number of subjects enrolled, as it is reported on the Continuing Review Report, should be consistent from year to year. For example, if 10 subjects were enrolled in a study in the first year and five in the second year, the total listed on the Continuing Review Report for year two should be 15. This number should reflect only the patients enrolled in the study through Crouse Hospital. For example, if you are enrolling patients into a study at both University Hospital and Crouse Hospital, include only the patients enrolled at Crouse. Check previous reports for accurate reporting to avoid delays in the review process.

Do not send changes or amendments to protocols with the continuing review report; this should be done separately as needed. NO GRACE PERIOD OR EXTENSIONS ARE ALLOWED [45CFR46.109( e)]. If a study does not receive approval prior to the expiration date, the study is closed, without exception.

Fifth Year Renewal Procedures

A study may only be renewed 4 times by the continuing review process described above. After the fourth continuing review, if the study is to continue, it is necessary to re-submit the study as described in section 6. Although the IRB number will remain the same, all other procedures will be the same as for new protocols. A notice that the study has received 4 continuing reviews and needs to be re-submitted will be sent to the Principal Investigator at least one month prior to the study expiration date; however, there may be problems with the IRB database which cause a renewal notice not to be issued. Therefore, an investigator should not depend solely on IRB notification as a prompt for submitting a new application. Under no circumstances may the study proceed without the completion of the review process and approval granted.

Making Changes/ Amendments to Approved Research Protocols

Once the IRB has approved a project, it must be carried out exactly as planned. Any changes, including (but not limited to) subject population, recruitment plans, research procedures, study design, study instruments, study sites, or research personnel, must be approved by the IRB prior to implementation.
Researchers planning a change should submit the following to the IRB office:

• Cover letter explaining the change( s) and the rationale for the change/ amendment.
• Copies of any correspondence from sponsor regarding the change/ amendment.
• One copy of the revised corporate protocol (if applicable).
• One marked copy of the revised protocol (with all changes underlined) and one clean copy (for investigator initiated studies).
• One marked (with all changes underlined) and one clean copy of the revised application (if applicable).
• If change to the protocol makes it necessary to change the consent document, the following should also be submitted:
  • One marked copy of the revised consent document, with all changes underlined.
  • One clean copy of the revised consent document for the IRB to stamp with revision and expiration dates (note: the expiration date remains the same).

Minor protocol/ consent changes are often approved by expedited review. These would be changes that do not adversely alter the overall risk: benefit profile of the study; would not affect the willingness of current subjects to remain in the study; and do not alter the scientific validity of the study design. Changes to study design, which may increase risk to subjects, may require full board review. Changes that are perceived to significantly affect the risk/ benefit ratio for subjects must be reviewed by the full Board.

Implementation of any change must not occur prior to IRB approval unless the change is required to eliminate an immediate hazard to the subjects. In this case the IRB should be notified as soon as possible of the change.

Changing the Principal Investigator

If a researcher leaves Crouse permanently, the IRB should be notified of any interim investigators and of the final replacement.

Requirements for Notification of Adverse Events

All adverse event notices received from study sponsors, cooperative group offices or coordinating centers should be forwarded to the IRB office. In addition, all adverse events occurring at Crouse and affiliated institutions, for which the Crouse IRB is responsible (defined as "local events") must be reported within 10 days of the Principal Investigator becoming aware of the event. This will permit appropriate oversight needed for the safety of research study participants.

Applicable Events
1. Any adverse event which occurs in non-therapeutic research.
   An adverse event is any untoward occurrence in a research subject which may or may not have a causal relationship with the study intervention/ treatment.
2. Any serious (including death) or unexpected adverse event, which occurs in therapeutic research.
   A serious adverse event is any untoward medical occurrence that:
   • results in death
   • results in an event during which the subject was at risk of death
   • results in hospitalization or prolongation of existent hospitalization*
   • results in persistent or significant disability
   • results in a congenital anomaly/ birth defect
   * For cooperative group oncology trials, certain hospitalizations (such as admissions for uncomplicated fever with neutropenia) do not necessarily need to be reported to the IRB.
3. Any unexpected adverse event which occurs in therapeutic research.
   An unexpected adverse event is any adverse experience that is not identified in nature, severity or frequency in the current investigator brochure; or, if an investigator brochure is not required, that it is not identified in nature, severity or frequency in the risk information described in the general investigational plan (protocol) or elsewhere in the current research application. Generally, all events in the above three categories occurring within 30 days of last treatment or study intervention are reportable; however, delayed events that may be related to study treatment should also be reported.

Recruitment of Research Subjects

Many investigators will play the role of both physician and investigator when enrolling from their own patient population. In this situation the investigator may be faced with a conflict between what is best for the subject and what is best for the research study. Both the American Medical Association and the American College of Physicians recommend that physician-investigators handle their dual role by always placing the health and welfare of their patients first, before their value as study subjects.

In order to recruit other physicians' patients, the investigator should enlist the assistance of the potential subjects' own physician. Investigators should not initiate direct contact with potential subjects with whom the investigator does not have a physician-patient relationship. This could be viewed as an invasion of privacy or a breach in doctor-patient confidentiality.

It is usually not appropriate to seek consent at the time of a procedure, diagnosis or other stressful moment. A subject may require time to decide whether or not to participate, to ask questions and to confer with family or other personal advisors.

Recruitment Incentives for Enrolling Research Subjects

Recruitment incentives are often offered by study sponsors to investigators or other persons on the research team for enrolling or accelerating the enrollment of subjects. Referral fees are given to doctors or other practitioners for referring their patients to another investigator's study. The practice of accepting financial incentives (bonuses) for subject enrollment and referral fees, (sometimes referred to as "finder's fees") may compromise the integrity of the study and may generate an unethical conflict of interest. Therefore, Crouse does not allow investigators or their staff or their departments to accept recruitment incentives, including finder's fees.

If subject recruitment incurs additional costs, such as advertising expenses, it is appropriate to accept additional monies from the sponsor to cover these specific additional expenses.

Requirements for Recruiting Research Subjects through Advertisements

Advertisement is a common method used for recruiting research subjects. There are many types of advertising including posted notices, newspaper and magazine ads, radio announcements and Internet web sites. All advertising requires IRB approval. The IRB is charged with reviewing the information contained in the advertisement, as well as the mode of its communication, to determine whether the procedure for recruiting subjects affords adequate protection. IRB review is necessary to ensure that the information is not misleading to potential research subjects. Advertisements to recruit subjects should be limited to: (1) the name and address of the clinical investigator, (2) the title of the study, (3) the purpose of the research (may include a summary of the eligibility criteria used to admit subjects to the study), (4) description of incentives for participation (such as payments or free treatment), and (5) location of the study site and the person to contact for further information.

For IRB review of an advertisement, please submit a copy of the ad to the IRB office referencing the IRB study number and a brief description of where the ad will be used.

Noncompliance by Researchers or Research Personnel with Protocol Requirements and/ or IRB Guidelines & Policies

Noncompliance will be reviewed by the board.

Suspensions or Terminations of Approved Research Studies

If the IRB determines that a research project should be suspended or terminated for cause, the action will be reported to appropriate institutional officials, the head of any supporting Federal Department or Agency (if applicable), the Office of Human Research Protections at DHHS, and the corporate study sponsor (if applicable). If the project that is suspended or terminated involves a drug, device, or diagnostic regulated by the Food and Drug Administration, the FDA shall also be notified of the suspension/ termination.

Medical Devices

Studies that propose to evaluate a significant risk device must be conducted under an Investigational Device Exemption (IDE) granted by the FDA. The determination that an IDE is necessary is generally made by the sponsor of the study. Non-significant risk devices may be studied without the need for an IDE. Whenever the IRB reviews an application for a study involving a medical device for which the sponsor/ investigator has not obtained an IDE, the IRB will carefully evaluate the claim that the device is a non-significant risk device. The application should include a description of the device, a picture of the device and a report of prior investigations with the device. In addition, the IRB will evaluate the potential harm that may arise in the context of the actual use of the device, taking account of the risks associated with any surgical procedures that may need to be performed. The IRB will conduct its review in compliance with published guidance from the FDA concerning the evaluation of experimental medical devices. Guidance regarding device regulations can be found at: http://www.fda.gov/oc/ohrt irbs/devices.html (FDA Guidance).

Research Using Human Biological Materials

Research involving human biological material constitutes research that is subject to federal regulations. In this context a sample refers to any human biological material. This includes, but is not limited to, molecular material such as DNA, cells, tissues (blood, bone, muscle, etc.), organs (liver, bladder, heart, etc.), gametes, embryos, fetal tissue, waste (hair, nail clippings, urine, feces, etc.) and other materials of human origin.

Four levels of identification of research samples are recognized. These are differentiated by the amount of information that is available about the subject from whom the sample was obtained.

The levels include:
1. Unidentified Samples (Anonymous): These samples are/ were obtained and stored without any identification that may link the specimen to a specific patient.
2. Unlinked Samples (Anonymized): Unlinked samples are those that may have been acquired from identified human sources, but all identifiers or codes have been removed and destroyed such that the ability to identify particular individuals, via clinical or demographic information, would be extremely difficult for the investigator, the repository or a third party.
3. Coded Samples: Coded samples are those from which the source of the specimen can be identified by reference to a code rather than a name or other personal identifier.
   When such samples are obtained from a tissue repository, the repository retains information linking the code to a particular human specimen. Information is sufficient such that the investigator, repository or third party could link the biological sample or information derived from the research using the sample with a particular person or small group of identifiable individuals.
4. Identified Samples: These samples are collected or supplied to investigators with personal identifiers sufficient to allow identification of the donor of the material.

Identifiers are information that can be used to link a sample or scientific result with a specific person or group of people. Examples of identifiers include name, social security number, hospital number or other unique identifier. It should also be noted that using current information technology, a combination of descriptive data may be sufficient to allow identification of the donor and thereby collectively may be considered identifiers (e. g. zip code, birth date or profession may be sufficient to identify a specific individual).

Exemption from IRB Review:

Some research using existing (already on the shelf) pathological specimens, or diagnostic specimens, may be eligible for an exemption from IRB review if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects. (See procedure for requesting an exemption from IRB review).

Consent Requirements:

The necessity of obtaining informed consent from the subject applies to research involving human biological material. As a general rule, the Committee expects the investigator to obtain such consent from the sample source. In the case of research involving existent identified or coded samples, the Committee recognizes that it may not be feasible to obtain such consent.

However, federal regulations in 45 CFR 46.116( d) provide for the waiver of this requirement when the following conditions are met :

1. the research involves no more than minimal risk to the subjects;
2. the waiver or alteration will not adversely affect the rights and welfare of the subjects;
3. the research could not practicably be carried out without the waiver or alteration; and
4. whenever appropriate, the subjects will be provided with additional pertinent information after participation.

You may request a waiver of consent based on the above conditions in the application for IRB review.

NOTE: There are specific consent document guidelines for studies in which samples will be collected and stored for future research or commercial purposes and there are specific consent document guidelines for studies in which genetic testing is included.

Research using "waste" and "extra" material

Research that is conducted on "waste" or "extra" human tissue or fluids must be submitted for review by the IRB. "Waste material" is material that is collected originally for clinical or diagnostic purposes only but is no longer needed. "Extra material" is material that is collected above and beyond what is needed for a clinical or diagnostic procedure. It is collected during the same procedure, but solely for investigational purposes. The IRB may determine that research on waste or extra material qualifies for expedited review; however, the requirement for informed consent still applies.

Emergency Use of Test Articles

The use of an unapproved investigational drug or biologic requires an IND (investigational new drug application). If the intended subject does not meet the inclusion criteria of an existing clinical study, or if an approved clinical study does not exist, the usual procedure is to contact the manufacturer and determine if the drug or biologic can be made available for 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, the FDA may authorize shipment of the test article in advance of the IND submission. Requests for such authorization may be made by telephoning the FDA. (For drug products: 301-827-4573. For a biologic: 301-827-3518. Nights & Weekends: 202-857-8400.)

The emergency use of a test article (not approved by FDA) is defined as the use of an investigational drug, biologic or device with a human subject in a life threatening situation in which there is no acceptable treatment available and in which there is insufficient time to obtain IRB approval. The emergency use provision in FDA regulations is an exemption from prior review and approval by an IRB. This section is intended to comply with 21 CFR 56.

Emergency Use of an Investigational Drug or Biologic [21CFR56.104( c)]

1. As stated above, the emergency use exemption may be used only when all of the following apply:
   1. It is a life-threatening situation,
   2. There is no other acceptable treatment available, and
   3. There is not sufficient time to obtain IRB approval.
2. The emergency use exemption allows for one emergency use of a test article without prospective IRB review. FDA regulations require that any subsequent use of the investigational drug or biologic at the institution have prospective IRB review and approval. The FDA acknowledges 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. Also, because the emergency use was initiated prior to approval of the protocol by the IRB, the emergency care may not be claimed as research, nor may the outcome of the emergency use be included in any report of a research activity.
3. The physician who will be using the investigational drug or biologic must notify the IRB Chairperson within 24 hours that an Emergency Use of an investigational product has occurred or will occur.
   1. Notification does not constitute IRB approval.
   2. Notification initiates tracking to insure the investigator files the required reports with the IRB.
4. Within 5 working days after notification of the emergency use of the investigational product, the physician shall submit a written report to the IRB office noting the administering physician's name and department, name of the investigational product or procedure, date of notification, date of actual use, name of patient, description of rationale for emergency use, results of emergency use, and a protocol with any manufacturer information regarding use of the investigational product.
5. FDA regulations do not provide for expedited IRB approval in emergency situations. Therefore, the terms "interim", "compassionate", "temporary", or any other terms implying an expedited approval process are not authorized and do not apply for use of investigational drugs or biologics.
6. Even for emergency use, the physician is required to obtain informed consent of the subject or the subject's legally authorized representative unless both the investigator and a physician who is not otherwise participating in the clinical trial certifies in writing to all of the following:
   1. The subject is confronted by a life-threatening situation necessitating the use of the test article.
   2. Informed consent cannot be obtained because of inability to communicate with, or obtain legally effective consent from the subject.
   3. Time is not sufficient to obtain consent from the subject'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 subject's life.

Inclusion of Women & Minorities in Study Populations

NIH policy requires the inclusion of women and minorities in research study populations so that research findings can be of benefit to all persons at risk of the disease, disorder, or condition under study. Principal Investigators of NIH funded grants and cooperative agreements falling under the scope of the NIH policy must report annually on the number of subjects planned and enrolled to date by ethnic origin and gender.

It is the policy of Crouse to extend these requirements to all studies involving human subjects. It is expected that investigators will use all available resources to ensure the diversity of research populations.

Special Classes of Subjects

Special consideration must be given by all researchers to protect the welfare of particularly vulnerable subjects, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons [45 CFR 46.111]. The U. S. Department of Health and Human Services regulations set forth specific provisions on research involving fetuses, pregnant women, and human in vitro fertilization, prisoners, and children. Some of the requirements are described below.

Pregnant Women

For research activities directed toward pregnant women as subjects, the federal regulations provide that no pregnant woman may be involved as a subject unless either: (1) the purpose of the activity is to meet the health needs of the mother, and the fetus will be placed at risk only to the minimum extent necessary to meet such needs; or (2) the risk to the fetus is minimal.

Children (less than 18 years of age)

Federal regulations (45CFR46 Subpart D) require the IRB to classify research involving children into one of four categories and to document the discussion of the risks and benefits of the research study. The four research categories involving children that may be approved by the IRB, based on degree of risk and benefit to individual subjects, are as follows:

1. Research not involving greater than minimal risk. Research in this category may be approved provided: Adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.
2. Research involving greater than minimal risk, but presenting the prospect of direct benefit to an individual subject. Research in this category may be approved provided: (a) the risk is justified by the anticipated benefit to the subject; (b) the relationship of risk to benefit is at least as favorable as any available alternative approach; and (c) Adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.
3. Research involving greater than minimal risk with no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or conditions. Research in this category may be approved provided: (a) the risk represents a minor increase over minimal risk; (b) the intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; (c) the intervention or procedure is likely to yield generalizable knowledge about the subject's disorder or condition that is of vital importance for the understanding or amelioration of the subject's disorder or condition; and (d) Adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.
4. Research that is not otherwise approvable, but which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. Research in this category may be approved provided: (a) the IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and (b) The secretary of the Department of Health And Human Services, after consultation with a panel of experts in pertinent disciplines and following opportunity for public review and comment, has determined that the research may be conducted.
   In all cases, the IRB will determine that adequate provisions have been made for soliciting the assent of children and the permission of their parents or guardians. When children or minors (under the age of 18) are involved in research, the regulations require that assent (a child's affirmative agreement to participate in research) of the child or minor be obtained and the permission (the agreement of parent( s) or guardian( s) to the participation of their child or ward in research) of the parent( s) be obtained, in place of the consent of the subjects. Given that children have not reached their full intellectual and emotional capacities and are legally unable to give valid consent, involving children in research requires the permission of their parents or legally authorized representatives.
   While children may be legally incapable of giving informed consent, they nevertheless may possess the ability to assent to or dissent from participation. Out of respect for children as developing persons, children should be asked whether or not they wish to participate in the research, particularly if the research: (1) does not involve interventions likely to be of benefit to the subjects; and (2) the children can comprehend and appreciate what it means to be a volunteer for the benefit of others.

NOTE: The lack of active objection shall not be considered to be either consent or assent; both require a positive action by the potential subject and when appropriate the parent/ guardian.

Prisoners

To include the prison population in a research proposal, the IRB must have a prisoner representative. At this time, Crouse Hospital’s IRB does not have a prisoner representative. If you wish to include prison population in your research proposal, please contact the IRB.

Informed Consent

Informed consent is one of the primary ethical requirements underpinning research with human subjects; it reflects the basic principle of respect for persons. Since the central requirement for human subject research is that people participate voluntarily, the consent process is one of the most important parts of planning a research proposal. Informed consent assures that prospective human subjects will understand the nature of the research and can knowledgeably and voluntarily decide whether or not to participate.

Obtaining Informed Consent

The consent process must assure that the potential subject understands the study and its risks and benefits and can certify his or her willingness to participate. This obligation is the responsibility of the Principal Investigator. Consent is an ongoing process, it starts before the consent form is signed and continues until the subject's participation is complete. The informed consent process involves meeting with a potential subject, finding out whether he or she is capable of giving consent, and discussing the purpose, risks, and benefits of participation.

A subject may require time to decide whether or not to participate, to ask questions and to confer with family or other personal advisors. It is not appropriate to seek consent in a rush or at the time of a procedure, diagnosis or other stressful moment. Information given to potential subjects or their representatives must be in language that is understandable to the subject or representative.

Documentation of Informed Consent

Informed consent must be documented by the use of a written consent form (except as noted below) reviewed and approved by the IRB (signified by the presence of an IRB approval stamp and expiration date) and signed by the subject or subject's legally authorized representative. It is strongly recommended that the subject or the subject's legally authorized representative date the signature as well. A copy of the consent form must be given to the subject or person signing the form.

The consent process may not involve the use of exculpatory language through which the subject or representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, sponsor, institution, or agents from liability for negligence [45 CFR 46.116].

It is assumed that the consent form is only part of the total consent process in which the investigator, perhaps using the written consent form as an outline, describes all facets of the study and answers the subject's questions. The investigator is responsible for insuring that research subjects understand the research procedures and risks. Failure of the subjects to ask questions should not be construed as understanding on the part of the subject. The Federal regulations require that certain information be provided to each subject [45 CFR 46.116( a)] in the consent form:

• A statement that the study involves research,
• An explanation of the purposes of the research and the expected duration of the subject's participation,
• A description of the procedures to be followed, and identification of any procedures which are experimental,
• A description of any reasonably foreseeable risks or discomforts to the subject,
• A description of any benefits to the subject or to others which may be reasonably expected from the research,
• A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject,
• A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained,
• For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained,
• An explanation of whom to contact for answers to pertinent questions about the research and research subjects rights, and whom to contact in the event of a research related injury to the subject,
• A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

The regulations further provide that the following additional information be provided to subjects, where appropriate [45 CFR 46.116( b)]

• A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable,
• Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent,
• Any additional costs to the subject that may result from participation in the research,
• The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject,
• A statement that significant new findings developed during the course of the research which may be related to the subject's willingness to continue participation will be provided to the subject,
• The approximate number of subjects involved in the study.

The Crouse IRB expects that all consent documents be drafted using the format of the relevant consent document template. Sample consent documents from study sponsors should be modified accordingly. In addition, the consent document must:

• Be written in the second person (" You are").
• Font size must be at least 12 pt.
• Have a 1 inch margin at the bottom of each page.
• Include a version date (updated each time a change is submitted).
• Have page numbers
• Be simply written at an 8th grade or lower reading level (no technical jargon, all abbreviations must be defined at least once)
• Include "Crouse Hospital" at the top of the 1st page.
• Refer to research subjects as "subjects" not "patients".
• Begin, "You are being asked to participate in a research study to" (followed by the purpose of the study).

Requirements when a Study Sponsor Includes Compensation for Research-Related Injury Statements

Some sponsors offer subjects compensation for research-related injuries. In these cases, both the Crouse section regarding injuries ("In Case of Injury") and the sponsor section regarding compensation ("Compensation for Research-Related Injuries") must be included. In addition, the following disclaimer must follow the sponsor's statement.

"Neither the researchers nor Crouse Hospital make any representation, warranties or guarantees with respect to the above policy, including either its continued existence or its applicability to yourself should any adverse side effects occur."

IF the sponsor's statement will only compensate subjects for research-related injuries which are a direct result of the study drug/ procedures, then the following two disclaimers must follow the sponsor's statement.

"The above paragraph states the policy of (corporate sponsor). (Corporate sponsor) will make the final determination as to whether any injury suffered during this study is a "direct result" of the study drug/ procedures. Your physician will provide supporting information to (pharmaceutical), but cannot guarantee reimbursement."

"Neither the researchers nor Crouse Hospital make any representation, warranties or guarantees with respect to the above policy, including either its continued existence or its applicability to yourself should any adverse side effects occur."

Payments to Research Subjects for Participation

The practice of paying research subjects to participate in research is not prohibited. However, the IRB will review the specific procedures and amount of payment for each research study in order to minimize the possibility of coercion or undue influence and to determine whether the payments offered for participation constitute undue inducement. The consent document should include the details of the payment plan, including when the payment(s) will be received and the conditions under which a subject would receive partial payment (for example, if the subject withdrew before the end of the study). Free parking, travel expenses, childcare expenses or meal allowances should also be detailed. This should be included in the "Costs/ Payments" section of the consent document and NOT in the "Benefits" section.

Waiver of Documentation of Informed Consent

Documentation of informed consent is required in most cases; however, the IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds that

The only record linking the subject to the research would be the consent document, and the principal risk would be potential harm resulting from a breach of confidentiality. The IRB may determine that each subject be asked whether s/he wants documentation linking the subject with the research, and the subject's wishes will govern;

OR

The research presents no more that minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

In cases where the requirement of documentation is waived (e. g., use of an anonymous survey is proposed), the IRB may require an information/ cover letter be given to study participants.

NOTE: A waiver of documentation of informed consent is not a waiver for obtaining informed consent, it only allows for the waiver of the consent form.

Waiver of Informed Consent

The IRB may waive the requirements for obtaining informed consent or approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent listed above, provided that:

1. The research involves no more than minimal risk to the subjects;
2. The waiver or alteration will not adversely affect the rights and welfare of the subjects;
3. The research could not practicably be carried out without the waiver or alteration; and
4. Whenever appropriate, the subjects will be provided with additional pertinent information after participation.