Sterling Institutional Review Board

Chapter 1 - INTRODUCTION

Sterling Institutional Review Board (IRB) was established in 1991 as an independent ethical review board, whose purpose is to protect the rights and welfare of human subjects who participate in research. While the Principal Investigator is responsible for the conduct of the study, the IRB is responsible for determining that the proposed research is scientifically valid and that the anticipated benefits to the subjects as well as the knowledge that is expected to be gained outweigh the risks.

Sterling IRB operates in compliance with:

Protection of Human Subjects (DHHS), 45 CFR 46
FDA Regulations on Human Subjects Research, 21 CFR 50, 56, 312, 812
Standards for Privacy of Individually Identifiable Health Information, 45 CFR 160, 164

The IRB reviews and monitors research involving human subjects. It has the authority to approve, require modification in (to secure approval), or disapprove research. The purpose of the IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in research. To accomplish this purpose, the IRB uses a group process to review research protocols and related materials. The Board is responsible for approving what constitutes an adequate informed consent confirming that all necessary elements of informed consent are included. It also reviews the credentials and medical licenses of potential Principal Investigators. Sterling IRB has a policy of continuing education for both the Board members and Administrative Staff to ensure appropriate training in human research subject protections.

If there are any questions or concerns about the responsibilities of the Principal Investigator, please contact the CRO/Sponsor or call us at (770) 690-9491, toll-free at 1 (888) 636-1062, between the hours of 8:30am - 5:30pm EST. Please visit the Sterling IRB website at <www.sterlingirb.com> for forms, additional information, and links to other sites that will increase your knowledge and understanding of the clinical research process.

This handbook outlines the responsibilities of the Principal Investigator and should be read by the key personnel on the research team. We look forward to working with you to ensure the safeguarding of the rights and welfare of those who volunteer to participate in research studies.

Sterling IRB Mission Statement: The mission of Sterling Institutional Review Boardis to protect the rights, privacy, and welfare of human subjects who volunteer to participate in research studies.

Chapter 2 - THE BELMONT REPORT (Ethical Principals and Guidelines for the Protection of Human Subjects of Research):

The Belmont Report is the cornerstone statement of the ethical principles upon which the Federal Regulations for protection of human subjects are based. Sterling IRB recommends that all Principal Investigators and key research personnel read the introductory guidance below and the Belmont Report.

The following is taken from the OHRP IRB Guidebook.

http://www.hhs.gov/ohrp/irb/irb_guidebook.htm

On September 30, 1978, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research submitted its report entitled "The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research." The Report, named after the Belmont Conference Center at the Smithsonian Institution where the discussions which resulted in its formulation were begun, sets forth the basic ethical principles underlying the acceptable conduct of research involving human subjects. Those principles, respect for persons, beneficence, and justice, are now accepted as the three quintessential requirements for the ethical conduct of research involving human subjects.

Respect for persons involves 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 benefits and minimizing possible risks of harm.

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

The Report also describes how these principles apply to the conduct of research. Specifically, the principle of respect for persons underlies the need to obtain informed consent; the principle of beneficence underlies the need to engage in a risk/benefit analysis and to minimize risks; and the principle of justice requires that subjects be fairly selected. As was mandated by the congressional charge to the Commission, the Report also provides a distinction between "practice" and "research." The text of the Belmont Report is thus divided into two sections: (1) boundaries between practice and research; and (2) basic ethical principles. The full text of the Belmont Report, which describes each of the three principles and its application, is provided in the Guidebook in Appendix 6; a summary follows.

Boundaries Between Practice and Research

While recognizing that the distinction between research and therapy is often blurred, practice is described 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." The Commission distinguishes research as designat[ing] an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships). Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective. "The Report recognizes that "experimental" procedures do not necessarily constitute research, and that research and practice may occur simultaneously. It suggests that the safety and effectiveness of such "experimental" procedures should be investigated early, and that institutional oversight mechanisms, such as medical practice committees, can ensure that this need is met by requiring that "major innovation[s] be incorporated into a formal research project."

Applying the Ethical Principles

Respect for Persons:

Required by the moral principle of respect for persons (see definition, above), informed consent contains three elements: information, comprehension, and voluntariness. First, subjects must be given sufficient information on which to decide whether or not to participate, including the research procedure(s), their purposes, risks and anticipated benefits, alternative procedures (where therapy is involved), and a statement offering the subject the opportunity to ask questions and to withdraw at any time from the research. Responding to the question of what constitutes adequate information, the Report suggests that a "reasonable volunteer" standard be used: "the extent and nature of information should be such that persons, knowing that the procedure is neither necessary for their care nor perhaps fully understood, can decide whether they wish to participate in the furthering of knowledge. Even when some direct benefit to them is anticipated, the subjects should understand clearly the range of risk and the voluntary nature of participation." Incomplete disclosure is justified only if it is clear that: (1) the goals of the research cannot be accomplished if full disclosure is made; (2) the undisclosed risks are minimal; and (3) when appropriate, subjects will be debriefed and provided the research results.

Second, subjects must be able to comprehend the information that is given to them. The presentation of information must be adapted to the subject's capacity to understand it; testing to ensure that subjects have understood may be warranted. Where persons with limited ability to comprehend are involved, they should be given the opportunity to choose whether or not to participate (to the extent they are able to do so), and their objections should not be overridden, unless the research entails providing them a therapy unavailable outside of the context of research. [See discussions on this issue in other sections of the Guidebook, including Chapter 6, "Special Classes of Subjects."] Each such class of persons should be considered on its own terms (e.g., minors, persons with impaired mental capacities, the terminally ill, and the comatose). Respect for persons requires that the permission of third persons also be given in order to further protect them from harm.

Finally, consent to participate must be voluntarily given. The conditions under which an agreement to participate is made must be free from coercion and undue influence. IRBs should be especially sensitive to these factors when particularly vulnerable subjects are involved.

Beneficence:

Closely related to the principle of beneficence (see definition, above), risk/benefit assessments "are concerned with the probabilities and magnitudes of possible harms and anticipated benefits." The Report breaks consideration of these issues down into defining the nature and scope of the risks and benefits, and systematically assessing the risks and benefits. All possible harms, not just physical or psychological pain or injury, should be considered. The principle of beneficence requires both protecting individual subjects against risk of harm and consideration of not only the benefits for the individual, but also the societal benefits that might be gained from the research.

In determining whether the balance of risks and benefits results in a favorable ratio, the decision should be based on thorough assessment of information with respect to all aspects of the research and systematic consideration of alternatives. The Report recommends close communication between the IRB and the investigator and IRB insistence upon precise answers to direct questions. The IRB should: (1) determine the "validity of the presuppositions of the research;" (2) distinguish the "nature, probability and magnitude of risk...with as much clarity as possible;" and (3) "determine whether the investigator's estimates of the probability of harm or benefits are reasonable, as judged by known facts or other available studies."

Five basic principles or rules apply when making the risk/benefit assessment: (1) "brutal or inhumane treatment of human subjects is never morally justified;" (2) risks should be minimized, including the avoidance of using human subjects if at all possible; (3) IRBs must be scrupulous in insisting upon sufficient justification for research involving "significant risk of serious impairment" (e.g., direct benefit to the subject or "manifest voluntariness of the participation"); (4) the appropriateness of involving vulnerable populations must be demonstrated; and (5) the proposed informed consent process must thoroughly and completely disclose relevant risks and benefits.

Justice:

The principle of justice mandates that the selection of research subjects must be the result of fair selection procedures and must also result in fair selection outcomes. The "justness" of subject selection relates both to the subject as an individual and to the subject as a member of social, racial, sexual, or ethnic groups.

With respect to their status as individuals, subjects should not be selected either because they are favored by the researcher or because they are held in disdain (e.g., involving "undesirable" persons in risky research). Further, "social justice" indicates an "order of preference in the selection of classes of subjects (e.g., adults before children) and that some classes of potential subjects (e.g., the institutionalized mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain conditions."

Investigators, institutions, or IRBs may consider principles of distributive justice relevant to determining the appropriateness of proposed methods of selecting research subjects that may result in unjust distributions of the burdens and benefits of research. Such considerations may be appropriate to avoid the injustice that "arises from social, racial, sexual, and cultural biases institutionalized in society."

Subjects should 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." Care should be taken to avoid overburdening institutionalized persons who "are already burdened in many ways by their infirmities and environments." Nontherapeutic research that involves risk should use other, less burdened populations, unless the research "directly relate[s] to the specific conditions of the class involved."

The Belmont Report: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm

Chapter 3 - CATEGORIES OF RESEARCH REVIEW

A. Full Board Review:

Full Board Review: Reviewed by a quorum of Board members.

Human subject research that is not classified as exempt or expedited requires review by the full IRB at a convened meeting. Sterling IRB meetings are held twice a week but may be cancelled by the Chairman for insufficient applications, holidays, or inability to secure a quorum.

Sterling IRB uses a primary reviewer system for full Board reviews. Submission application materials are sent to the Board at least 4 days prior to a meeting. The primary reviewer leads the discussion of each project and the Board determines whether the project meets the criteria for approval and whether revisions to the protocol or informed consent are needed.

The informed consent is reviewed for accuracy, clarity, and inclusion of the required elements of consent. By a majority of those present at the meeting, each study is either: (1) approved as submitted; (2) approved pending receipt of minor revisions to study procedures, the informed consent document(s), or other written materials; (3) deferred pending review at a subsequent Board meeting after receipt of significant additional information or revisions; or (4) disapproved. Verbal notification will be made within 24 hours and approval documents will usually be mailed within 2 business days.

Written minutes of each Board meeting include: (1) attendance; (2) the number of votes to approve, disapprove, or abstain; (3) the basis for requiring changes in or disapproving the research; and (4) a summary of the controverted issues and their resolution.

B. Expedited Review:

Federal regulations recognize that certain types of research may be reviewed by an IRB through an expedited review procedure (45 CFR 46.110) (21 CFR 56.110). Both the FDA and OHRP have a published guidance on categories of research that may qualify for expedited review, as follows: Categories of Research that May be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure. See the following links for guidance:

FDA Guidance: http://www.fda.gov/oc/ohrt/irbs/expeditedreview.html
OHRP Guidance: http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm

Expedited review means that the IRB Chairman or designee is solely responsible for the review and approval. Verbal notification will be made within 24 hours and expedited review approval documents will usually be mailed within 2 business days. The Board will be apprised of studies approved by expedited review.

C. Exempt Human Subject Research:

Certain types of human subject research that present little or no risk to the participants may be classified as exempt from the federal regulations (45 CFR 46.101(b)) (21 CFR 56.104). The Chairman or designee will determine whether the research meets the exempt criteria, based on review of the correspondence concerning the request, protocol, and associated documents. The decision will usually be communicated to the Principal Investigator within 48 hours of the determination being made.

Chapter 4 - PRINCIPAL INVESTIGATOR RESPONSIBILITIES

A. Study Conduct:

The Principal Investigator is responsible for the ethical conduct of the research study, and for protecting the health and welfare of all subjects enrolled at his/her site(s). The clinical research study must be conducted as stated in the protocol and in accordance with all applicable federal, state and local laws and Good Clinical Practices (GCP). The Principal Investigator agrees to abide by the Investigator Compliance Agreement as stated in the Submission Application for the Investigator/Site. (See the Sterling IRB website <www.sterlingirb.com>, Forms)

B. Training and Education:

The Principal Investigator and all key research personnel should have appropriate training in conducting clinical trials and each should be aware of the obligations to communicate with the IRB and the Sponsor during the study. (See the Sterling IRB website <www.sterlingirb.com>, Training and Education, for additional resources.)

C. Record Keeping:

The study records need to be retained as directed by the Sponsor. The Principal Investigator is responsible to maintain complete and accurate records for the following:

Source records for each subject
All correspondence with the Sponsor and IRB including, but not limited to, copies of the application, notices of approval, acknowledgements, and signed informed consent documents

D. Audits and Inspections:

All records of human subject research are subject to inspection by regulatory agencies, the Sponsor and Sterling IRB. The Principal Investigator is responsible for being prepared at all times for an audit or inspection.

E. Form FDA 1572:

The Principal Investigator is responsible for completing and submitting the Form FDA 1572 prior to the start of the study, if applicable. This is a contract between the Principal Investigator and the FDA which outlines the responsibilities that the Principal Investigator agrees to assume in order to conduct the study. All copies of the original and revisions to the Form FDA 1572 need to be forwarded to Sterling IRB.

F. Referral Fees, Incentives, and Bonus Payments for Recruitment:

1. Referral Fees: Sterling IRB does not support the recruitment of research subjects by payment for referrals to research subjects or other persons - including, but not limited to - the Principal Investigator, Sub-Investigator or Clinical Coordinator(s) for research under its review. This is in accordance with the American Medical Association (AMA) Code of Medical Ethics which states, �Offering or accepting payment for referring patients to research studies (finder�s fees) is also unethical.� E-6.03 Fee Splitting Referrals to Health Care Facility

2. Incentives and Bonus Payments for Recruitment: The Principal Investigator should report to Sterling IRB any proposed incentives, gifts, or bonus payments to the Principal Investigator or study staff other than the original contractual agreement for review. These will be reviewed on a case by case basis. Sterling IRB is concerned that these practices may cause undue influence on the research staff. E-8.0315 Managing Conflicts of Interest in the Conduct of Clinical Trials

G. Summary of Requirements of the Principal Investigator:

The Principal Investigator is required to provide to Sterling IRB the following information and reports for continuing review of the research study following approval. These requirements should be reviewed by all individuals involved in the research activities. If you have any questions, please call Sterling Institutional Review Board at 888-636-1062 and a member of our staff will be glad to assist you.

Amendments: Once a study has received initial IRB approval, any change to the study is considered an amendment. All amendments must be submitted to Sterling IRB for review and approval prior to implementation.

Informed Consent: All changes to the informed consent are considered an amendment to the study and must be reported to Sterling IRB. Approval must be granted by Sterling IRB prior to use of the revised informed consent.

Advertisements and Recruitment Material: These items are reviewed in accordance with FDA guidelines, and must be approved by Sterling IRB prior to use. Approved submissions will be stamped �approved.� Once an Investigator has received initial IRB approval, any advertisements and recruitment materials submitted for approval thereafter are considered amendments and must be accompanied by a completed Recruitment Materials Submission Form. Forms can be found at <www.sterlingirb.com>, Forms.

Revisions to 1572: Revisions to the FDA 1572 Form must be submitted to Sterling IRB. If the revised 1572 is due to a change of site/additional site, the revised FDA 1572 must be accompanied by a completed Additional Site Submission Application. Forms can be found at <www.sterlingirb.com>, Forms.

Change in Risks: Unanticipated problems involving risks to the subject or others must be reported immediately.

Serious Adverse Event Report: Sterling IRB requires that the Serious Adverse Event Report be submitted if the event is unexpected, and serious. A serious event is one which occurs to a subject while participating in the study that: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; is a congenital anomaly/birth defect; results in persistent or significant disability/incapacity; requires intervention to prevent one of the aforementioned outcomes; or should be (in the Investigator�s opinion) considered by the IRB. Note: questions regarding whether an event is considered an SAE can often be resolved by referring to the description of an SAE in the Protocol or consulting with the Sponsor. An unexpected event is an event, the nature or severity of which is not consistent with the potential risks in the Informed Consent Document(s), Protocol, Investigator�s Drug Brochure (IDB), or Investigation Plan. The serious unexpected event should be reported within 10 business days of the Investigator�s knowledge of the event. All fatal or life threatening events should be reported to Sterling IRB immediately. Forms can be found at <www.sterlingirb.com>, Forms.

Significant Protocol Deviation Report (and Exceptions): Sterling IRB requires that all significant protocol deviations are to be reported promptly when the site becomes aware of the study event. Sterling IRB defines significant deviations as those that: (1) affect the scientific design/integrity of the study; (2) affect the rights, safety, or welfare of study subjects; (3) change the risk/benefit ratio; or (4) violate an ethical principle. Non-significant deviations do not need to be reported to the IRB unless the Sponsor/site SOPs require the Investigator to do so. All Protocol exceptions are to be reported when granted, and submitted with documentation of the Sponsor�s approval. Forms can be found at <www.sterlingirb.com>, Forms.

Unanticipated Problems (Other): There may be other unanticipated problems (that do not fall within the classifications for SAEs, External SAEs or Significant Protocol Deviations) but which: (1) involve risk(s) to the research subject(s) or others; (2) affect the rights, safety or welfare of study subjects; (3) affect the scientific design/integrity of the study; (4) change the risk/benefit ratio; or (5) violate an ethical principle. Significant Protocol Deviations may include problems that affect privacy (e.g., an unauthorized person gaining access to confidential study records), or safety (e.g., the disappearance of study medication). All Unanticipated Problems should be reported within 10 business days of the site becoming aware of the problem. Forms can be found at <www.sterlingirb.com>, Forms.

Continuing Review Reports: All reports minimally include the current study status, the number of subjects consented and their status, a current risk-benefit assessment based on study results, audit and monitoring report information, change in community attitudes, and any new information since the IRB�s last review. Forms will be sent with the approval packet and a reminder will be faxed prior to the date due. Additional forms can be found at <www.sterlingirb.com>, Forms.

Site Interim Status Update: An Interval Report should be filed for the interval that was established by the IRB at the time of approval (if applicable).

Site Continuing Review Status Report: An Investigator must receive continuing review approval prior to the �study expiration date� listed on the initial approval documents. The Investigator should submit the Site Continuing Review Status Report not less than one month prior to the last Sterling IRB meeting preceding the expiration date. Federal regulations do not allow the IRB to grant extensions or grace periods, so timely submission of the Site Continuing Review Status Report is important to avoid unnecessary interruptions in the study.

Site Final Report: After the last subject has completed the study and the Sponsor/CRO has indicated that the study is completed at the site, the Site Final Report must be submitted to ensure proper closeout. This report should include the date that the final subject completed the study. A Site Final Report should also be filed in the event of cancellation or termination of a study.

Investigator Noncompliance: The IRB will report any instance of serious or continuing noncompliance by the Investigator with the requirements of the FDA (and other agencies, if applicable) as set forth in the Federal Regulations, Good Clinical Practices, and/or Sterling IRB Operating Procedures by notice to the sponsor and the regulatory agency.

Investigator to Withdraw from Study: Notification of the Investigator's decision not to conduct the study or to withdraw from the conduct of the study must be submitted to the IRB. A Site Final Report will need to be filed unless a new Investigator has been approved to continue with the study site.

Chapter 5 - SUBMISSIONS TO THE IRB

A. New Study Submissions:

Principal Investigators are required to submit the Submission Application for the Investigator/Site (and attachments) along with the requested items listed on the Submission Guidelines. Instructions for completing the form are self-contained. All forms and guides are located on the Sterling IRB website <www.sterlingirb.com> and can be filled in electronically. If there are any questions, our staff will be glad to assist you.

B. Change in Principal Investigator:

When there is a change of Principal Investigator for an already approved study, the following is required to be submitted to Sterling IRB for review of the new Principal Investigator:

Submission Application for Change of Principal Investigator
- Note, this form may be used only if the new Principal Investigator will continue to conduct the study using only the procedures already approved, at only the site(s) already approved, using only the research personnel already reviewed (however, this form may still be used if there is a change in subject compensation). Otherwise, a Submission Application for the Investigator/Site is required to request a change of Principal Investigator.
Copy of the revised Form FDA 1572, if applicable
CV of the new Principal Investigator
Copy of the new Principal Investigator�s medical license (wallet card is acceptable)

C. Change in Site or Adding Additional Sites:

When there is a change in site location or additional sites are added, the following is required to be submitted to Sterling IRB:

Additional Site Submission Application for each site that has changed or been added to the study
Copy of the revised Form FDA 1572, if applicable

D. Translations for Subject Information and Informed Consent:

Informed consent must be presented in a language understandable to the subject. If the subject does not speak English, Sterling IRB requires a certified translation of the IRB approved informed consent. Some Sponsors require back translations for accuracy. All revisions of the informed consent must go through the same process.

Sterling IRB can arrange to have the informed consent and any other study related document translated into any language. As an alternative, the site or study sponsor can submit a document that has already been translated along with a certification statement for verification to Sterling IRB.

E. Advertisements and Recruitment Materials:

Advertisements and recruitment materials may be submitted to Sterling IRB for review by regular mail, fax, or e-mail: . Advertisements and recruitment materials submitted for review after the Investigator has received initial approval are considered amendments and must be accompanied by a completed Recruitment Materials Submission Form. Include the IRB ID# on all documents.

Advertising or recruiting for study subjects is considered to be the start of the informed consent process. The information contained in the advertisement/recruitment materials and the mode of communication must be reviewed by the IRB and approved before they are used. All submitted materials must comply with applicable state and local laws.

Sterling IRB requirements for advertisements and recruitment materials:

Straightforward and honest approach
Clearly stated purpose
Does not include testimonials
Includes the word �research� when referring to study type
Must define the word �placebo�
Does not state or imply a certainty of favorable outcome or other benefits
Does not include information outside the scope of the Protocol or the Consent Form(s)
Advertisement should not be misleading concerning its purpose
The institution is identified
Name of contact person and contact information should be included
Benefits are included but not guaranteed
Compensation is balanced by description of commitments expected during the study and is not emphasized
Does not make claims, explicitly or implicitly, that the test article is known to be equivalent/superior to any other drug, biologic, or device
Does not make claims, explicitly or implicitly, that the test article is safe/effective for the purpose under investigation
Does not include coercive language, tone, or exculpatory language
Does not use the terms: �free,� earn,� �new,� �state of the art,� �cutting edge,� �breaking technology,� or �improved�
Ages for eligibility must be specified
Advertisements and recruitment materials for pediatric studies are adult-directed

For print advertisements, please submit a copy of the print ad in the format that it will appear, so that Sterling IRB can review the layout of the advertisement as well as the text.

If participating in a large, multi-site study, the Sponsor may prepare a package of recruitment materials/advertisements for you to use once approved by the IRB. Each site choosing to use these recruitment materials should include their site specific information, such as the clinic name, telephone/contact information and compensation information, taking care not to alter the layout, type font or size of the approved advertisement. These recruitment materials/advertisements are considered approved, and do not need to be re-submitted to Sterling IRB.

Radio and television advertisement scripts must be submitted to Sterling IRB for approval. It is recommended that scripts are reviewed and approved prior to production of cassettes/CDs/MP3s for radio and videotapes/DVDs for television ads. All recruitment media (cassettes/CDs/MP3s for radio and videotapes/DVDs for television) must be approved before advertising begins.

Recruitment materials/advertisements provided with the original submission will be reviewed with initial review. Sterling IRB will notify you if any revisions are required before approval can be granted. Approved recruitment materials/advertisements will be provided in the initial approval documents, and will be marked with an "Approved" stamp.

Recruitment materials/advertisements submitted after the Investigator�s initial review must be accompanied by a completed Recruitment Materials Submission Form. These items usually will be reviewed by expedited review within 2 business days. Sterling IRB will notify the Principal Investigator or designee if any revisions are required before approval can be granted. Approval documents and the recruitment materials/advertisements that have been stamped �Approved� will be sent to the site.

Sterling IRB must review any revision made to previously approved recruitment materials/advertisements. These include text changes, and other image changes such as pictures, font type or size. Please contact Sterling IRB if there are any questions regarding changes to participant recruitment materials/advertisements.

F. Telephone Screenings:

Sterling IRB requires that a telephone screening script include the following information:

The prospective subject must provide their permission for the screening to proceed and for the screener to collect confidential medical information (otherwise, the call should be ended)

The prospective subject will be told that the information gathered from the screening procedure will be kept confidential

The prospective subject will be told what will happen to the information collected (i.e stored in a database)

The prospective subject will be told what will be done with the information if he/she does not qualify for this study (i.e. will the information be destroyed, or, with the permission of the prospective subject, will the information be kept in a database and used for another study. In the later case, the prospective subject must give his/her permission for the information to be stored)

The prospective subject must be told that he/she does not have to answer any questions they do not want to respond to, and may choose to end the phone call at any time

Below is suggested telephone screening script confidentiality language:

�We are conducting a research study in which you may be eligible to participate. If you are interested, I will ask you some confidential questions regarding your medical history and present condition. You do not have to answer any questions that you do not want to respond to, and you may end this phone call at any time.

All information collected today will be kept confidential. I am using a paper survey, which will be destroyed if you decline participation. If you choose to participate in this study, this survey will be kept with other research records for this study. These records are accessible to our research staff and will not be shared with anyone else without your permission.�

�Are you interested in participating in this study?�

If answer is �no�, person should be thanked and call ended

If �yes�, proceed to next question:

�Do we have permission to proceed in obtaining the confidential medical information about your medical history and present condition?�

If answer is �no�, person should be thanked and call ended

If �yes�, proceed to the next question

�May we keep the information we obtain in a data base in order to contact you regarding future studies?� (If applicable)

If �yes�, information may be retained in a database for future studies

If �no�, information may not be retained in a database for future studies, although if the prospective subject qualifies, they may still participate in this study.

Note: See Chapter 7 Informed Consent; J. Informed Consent Requirements When Determining Eligibility for Research, for additional information.

HIPAA RESPONSIBILITIES: This is applicable to non-covered entities as defined in the Privacy Rule.

If Protected Health Information (PHI) is to be recorded into a database, the Principal Investigator will need to complete and submit an Application for Partial Waiver of Authorization - For Recruitment Purposes. See the Sterling IRB website <www.sterlingirb.com>, Forms. The completed Application should be submitted along with the telephone screening script for approval.

G. Notification of Approvals and Acknowledgements:

Full Board Review of a New Study: Sterling IRB will contact the CRO/Sponsor and/or Principal Investigator within 24 hours of the meeting with a verbal notification of the Board�s decision. Approval documents will usually be sent within 2 business days.

Expedited Review: Approval documents will usually be sent within 2 business days of approval.
Amendment to Add a Principal Investigator: Approval documents will usually be sent within 2 business days of approval.

Advertisements and Recruitment Materials: (see �E� above)
Serious Adverse Events: Acknowledgements will usually be sent within 15 business days of Sterling IRB�s review.

Significant Protocol Deviations and Exceptions: Acknowledgements will usually be sent within 15 business days of Sterling IRB�s review.

Unanticipated Problems: Acknowledgements will usually be sent within 15 business days of Sterling IRB�s review.

External Adverse Events (INDs): Acknowledgements will usually be sent monthly.

Site Continuing Review Status Report: Approval documents will usually be sent within 7 business days of Sterling IRB�s review.

Site Interim Status Update: Acknowledgments will usually be sent within 15 business days of Sterling IRB�s review unless the IRB requests clarification or additional information.

Site Final Report: Acknowledgements will usually be sent within 15 business days of Sterling IRB�s review.

(All documents are sent through the U.S. Postal service unless otherwise requested. Overnight delivery service will be billed at cost, if requested.)

H. Amendments to the Protocol:

Sterling IRB offers two options for submitting Protocol amendments for IRB review:

Option 1

Submit a completed Modifications and Amendments to Previously Approved Research Submission Form (see the Sterling IRB website <www.sterlingirb.com>, Forms), along with the following attachments:

Copy of Protocol
Copy of informed consent detailing proposed changes, if any
Copy of �Summary of Changes� or tracked version of protocol showing changes
For device studies, a copy of the FDA IDE letter approving the amendment, if applicable
Copy of questionnaires or surveys to be used with the study, if changed
Copy of advertisements/recruitment materials, if changed

Option 2

Submit a cover letter detailing the request for an amendment to the protocol or an addition of another arm or treatment group to the protocol, along with the following:

Copy of Protocol
Copy of informed consent detailing proposed changes, if any
Copy of �Summary of Changes� or tracked version of protocol showing changes
For device studies, a copy of the FDA IDE letter approving the amendment, if applicable
Copy of questionnaires or surveys to be used with the study, if changed
Copy of advertisements/recruitment materials, if changed

Protocol amendments must receive IRB review and approval before they are implemented, unless an immediate change is necessary to eliminate an apparent hazard to the subjects. The IRB should be notified of this occurrence. If an amendment requires changes to the informed consent document, please follow the directions listed in section �I�, Revisions to the Informed Consent Document, below.

I. Revisions to the Informed Consent Document:

Sterling IRB offers two options for submitting revisions to the Informed Consent Document(s) for IRB review:

Option 1

Submit a completed Modifications and Amendments to Previously Approved Research Submission Form (see the Sterling IRB website <www.sterlingirb.com>, Forms), along with copies of both the already-approved document and the proposed revised document. These should be submitted with changes clearly marked by red lining, highlighting, or tracking both the already approved document and the proposed revised document.

Option 2

Submit a cover letter requesting a revision to an already-approved informed consent document, along with copies of both the already-approved document and the proposed revised document. These should be submitted with changes clearly marked by red lining, highlighting, or tracking both the already approved document and the proposed revised document.

Consent revisions will be reviewed by the full Board unless the changes fall under the expedited review category.

Any IRB approval of a revised informed consent document that might relate to the subjects� willingness to continue participation in the study will necessitate the re-consent of all current subjects (active or follow-up) in the clinical study. Subjects who have completed the study and those in follow-up may be mailed a copy of the changes to the consent document. The FDA and Sterling IRB do not require the re-consenting of subjects that have completed their active participation unless information that has been received affects the risks to research subjects that have already completed the study.

J. Changes to the Clinical Investigator Brochure:

The Sponsor may update the Clinical Investigator Brochure (CIB) during the course of the study. Changes to the Clinical Investigator Brochure should be submitted to the IRB. If this is a multi-site study, the Sponsor will usually submit the revision on behalf of all the Principal Investigators participating in the study. Receipt of the revised Clinical Investigator Brochure will be acknowledged.

K. Forms:

All Sterling IRB Forms are located on our website at <www.sterlingirb.com>. Sterling offers two ways to complete the forms for submission. The forms can be printed and manually completed or the electronic version can be completed online, saved and printed. All forms must be submitted with an authorized signature. The electronic version is compatible with Microsoft Word 2000 and above.

The Submission Application for the Investigator/Site is completed when a Principal Investigator/Site first seeks IRB approval. If additional research sites are submitted concurrently with the first Principal Investigator/Site, a Supplemental Site Form must be completed and submitted for each additional research site.

Once a Principal Investigator has been approved, any subsequent changes/additions in research sites must be submitted for approval by completing an Additional Site Submission Application (accompanied be the revised FDA 1572).

For a change in Principal Investigator for an already-approved site, submit a completed Submission Application for Change of Principal Investigator. Note: the Submission Application for Change of Principal Investigator can only be used if the new PI will continue to conduct the study using only the procedures already approved, at only the site(s) already approved, using only the research personnel already reviewed (though the form may be used if there is a change in compensation). Otherwise, a completed Submission Application for the Investigator/Site should instead be submitted.

Chapter 6 - CONTINUING REVIEW

Continuing review of IRB approved research is required under 45 CFR 46.109(e) and/or 21 CFR 56.109 (f).

The Continuing Review, Interim, and Final Reports require information about the number and status of subjects involved in the study. The categories are defined below:

Total Consented: The number of prospective subjects that have signed the consent form. (Subjects must sign the consent form prior to screening, with the exception of verbal consent for telephone screenings).

Screen Failures: The number of consented subjects who will not be able to participate in the study because of information gathered, including test results that were obtained, during the screening process.

Total in Screening/run-in: The number of prospective subjects that have been consented and are currently in the inclusion/exclusion phase of the study.

Total Active: The number of randomized subjects (those that have passed the screening process) who are currently active in the study.

Total Completed: The number of subjects who have completed the study.

Total Subjects Withdrawn/Terminated Early: The number of randomized subjects that withdrew or were withdrawn prior to completion.

Total Consented should equal Total Screen Failures + Total in Screening/run-in + Total Active + Total Completed + Total Withdrawn/Terminated Early.

Site Continuing Review, Interim and Final Report forms are included in the initial or continuation approval package; additional copies are located on the Sterling IRB website <www.sterlingirb.com> under Forms.

A. Continuing Review Status Report: (Application for Continuation)

Sterling IRB is required to review all non-exempt research projects at intervals appropriate to the degree of risk, but not less than once a year. If a research study was initially reviewed via expedited review procedures and risks to the subjects remain minimal, the continuing review may be expedited. If a research study initially received full Board review, the project generally requires full Board continuing review. It is the responsibility of the IRB to perform a substantive continuing review and consider the same issues as during initial review.

It is the Principal Investigator�s responsibility to submit the Site Continuing Review Status Report in sufficient time to permit review and approval prior to the study expiration date. The regulations make no provision for any grace period extending the conduct of research beyond the expiration date of IRB approval. Continuing review and reapproval of research must occur on or before the one year anniversary of the initial IRB approval date. To assist in this Principal Investigator obligation, Sterling IRB will send faxed reminder notices. It is important to remember that the IRB needs to receive the Continuing Review Report in sufficient time for review and re-approval of the research prior to the study expiration date.

If the Principal Investigator does not submit a Site Continuing Review Status Report in time for Sterling IRB review prior to the expiration date, he/she will be notified by memorandum that the IRB approval has lapsed. This memo details that research procedures must stop, except for those that are necessary for subject safety. Failure to submit for renewal may result in Board action, including, but not limited to, suspension and/or termination of IRB approval.

Sterling IRB will send renewal approval documents with the continuing review forms for the coming year to the study site.

B. Interim Status Update:

The Board will determine intervals for review based on risk. These report forms will be included in your approval package with the due date, which will also be noted in the approval letter.

It is the Principal Investigator�s responsibility to submit the Site Interim Status Update prior to the due date. To assist in this Principal Investigator obligation, Sterling IRB will send faxed reminder notices.

If the Principal Investigator does not submit a Site Interim Status Update in a timely manner, a memo will be sent to the Investigator notifying him/her that failure to submit a report may result in Board action.

Following review, an acknowledgement will be sent to the investigator/site. (Effective 04/17/08)

C. Final Report:

After the last subject has completed the study and the Sponsor/CRO has indicated that the study is completed at the site, the Principal Investigator must submit a Site Final Report to the IRB to ensure proper closeout. This report should include the date that the final subject completed the study. This report must also be submitted when/if the study is cancelled or terminated.

Following review, an acknowledgement will be sent to the investigator/site.

D. Protocol Deviations (Including Exceptions):

Protocol deviations and exceptions are study events whereby the Sterling IRB-approved research protocol has not been followed. The IRB has the authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB�s requirements, or that has been associated with unexpected harm to subjects.

The Principal Investigator is responsible for reporting all significant deviations and exceptions to the IRB, however data collection and communication of such events may be delegated to appropriate clinical site research personnel. All significant protocol deviations should be reported promptly when the site becomes aware of the study event, using the Significant Protocol Deviation Report Form (Including Exceptions) available on the Sterling IRB website at www.sterlingirb.com, Forms. All protocol exceptions should be reported when granted, using the Significant Protocol Deviation Report Form (Including Exceptions). Documentation of the Sponsor�s approval of the exception should be attached. The Principal Investigator or Sub-Investigator will sign the Significant Protocol Deviation Report Form (Including Exceptions) prior to submission to Sterling IRB.

DEFINITIONS:

Deviation: An unanticipated instance when the protocol, as currently approved, is not followed. Deviations can be separated into two categories, significant and non-significant (as defined below).

Significant Deviation: A protocol deviation that affects the scientific design/integrity of the study; affects the rights, safety, or welfare of study subjects; changes the risk/benefit ratio; or violates an ethical principle.

Examples of Significant Deviations:

Enrolling a subject without obtaining informed consent
Enrolling a subject outside the inclusion/exclusion criteria without sponsor approval
Failing to send an exception report when enrolling a subject outside the inclusion/exclusion criteria with sponsor approval
Deviations in the administration of study procedures (i.e. dosing/intervention errors)
Willful or knowing misconduct on the part of the investigator(s) or study staff
Breach in confidentiality/privacy pertaining to information about a subject
Study drug missing at site or not returned by subject
Study materials stolen (i.e. study drug, laptop containing study-related information)
Subject on exclusionary, disallowed or concomitant medications without sponsor approval
Failure to send an exception report when a subject is taking exclusionary, disallowed or concomitant medications with sponsor approval
Failure to collect/perform labs or tests (i.e. chemistry, pregnancy, urine, ECG, EKG)
Pregnancy
Study drug given to incorrect subject
Performing tests on a subject prior to consenting that subject
Enrolling a subject before their screening lab(s) is/are received
Consenting a subject with the incorrect version of the ICF
Failure to initial a page of the Informed Consent Form
Omission or delay of safety monitoring procedures, reports, or letters
Untimely reporting of events to the IRB (i.e. not reporting Serious Adverse Events within 10 business days of the investigator�s knowledge of the event, not reporting all Significant Protocol Deviations promptly, not reporting protocol exceptions as they are granted)
Storing drugs incorrectly/at incorrect temperature
Increase in enrollment not in accord with the protocol

Non-Significant Deviation: A protocol deviation that affects only logistical or administrative aspects of the study, has no substantive effect on the safety or well-being of research participants, does not affect the value of the data collected (meaning the deviation does not confound the scientific analysis of the results), and does not result from willful or knowing misconduct on the part of the Investigator(s). These deviations do not need to be reported to the IRB unless the sponsor/site SOPs require the Investigator to do so.

Examples of Non-Significant Deviations:

Subject out of window (unless by a significant amount)
Subject diaries/e-diaries not filled out/completed
Principal Investigator signed in incorrect place/incorrect time on ICF
Missed telephone calls, follow-up calls or contacts; out of window phone calls

Exception: An instance that is anticipated and which is granted an exception by the Sponsor, who will provide documentation for the approval of the protocol exception. Protocol exceptions are to be reported when granted, and submitted with documentation of the Sponsor�s approval.

Sponsor monitors often request that the site send the entire Protocol Deviation/Violation Log. Sterling requests that the site, using the above criteria, only submit significant deviations and exceptions on the Significant Protocol Deviation Report Form (Including Exceptions) that can be found on the Sterling IRB website at www.sterlingirb.com, Forms.

All Significant Protocol Deviations and Exceptions will be reviewed and acknowledged.

E. Serious Adverse Events (SAE):

The Principal Investigator is responsible for reporting unexpected Serious Adverse Events to Sponsors and Sterling IRB; however, he/she may delegate the data collection and communication of such events to appropriate clinical site research personnel. The Principal Investigator or Sub-Investigator must sign the completed Serious Adverse Event Report form prior to submission to the IRB. Sterling IRB requires that all Serious Adverse Events (SAEs) be submitted promptly (within 10 business days of the investigator�s knowledge of the event). All fatal or life threatening events should be reported immediately to Sterling IRB.

Follow-up Reports: For all initial SAE reports that do not show resolution, Sterling IRB requests a follow-up report with additional information, including date resolved. More than one follow-up report may be sent to the IRB with information as it becomes available.

For reported deaths, the Principal Investigator or designee should supply the Sponsor and IRB with any additional requested information (e.g., hospital records and autopsy reports).

DEFINITIONS:

Serious Adverse Event: An incident which occurs to a subject while participating in the study that: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; is a congenital anomaly/birth defect; results in persistent or significant disability/incapacity; requires intervention to prevent one of the aforementioned outcomes; or should be (in the investigator�s opinion) considered by the IRB. Note: Questions regarding whether an event is considered an SAE can often be resolved by referring to the description of an SAE in the protocol or consulting with the Sponsor.

Unexpected: An event, the nature or severity of which is not consistent with the potential risks in the Informed Consent Document(s), Protocol, Investigator�s Drug Brochure (IDB), or Investigation Plan.

Upon receipt and review of an SAE, Sterling IRB may request additional information from the Principal Investigator. If Sterling IRB determines, after review of an SAE that additional information should be provided to the subjects, a request will be made to the Sponsor and Principal Investigator for a revision or addendum to the informed consent.

All Serious Adverse Events will be reviewed and acknowledged.

F. Unanticipated Problems (Other):

�Other� Unanticipated Problems include any unanticipated problem that does not fall within the classifications for Serious Adverse Events, External Serious Adverse Events, or Significant Protocol Deviations, but which: involves risk(s) to the research subject(s) or others; affects the rights, safety or welfare of study subjects; affects the scientific design/integrity of the study, changes the risk/benefit ratio; or violates an ethical principle.

The Principal Investigator is responsible for reporting Unanticipated Problems to trial Sponsors and Sterling IRB; however, he/she may delegate the data collection and communication of such events to appropriate clinical site research personnel. The Principal Investigator or Sub-Investigator will sign the Unanticipated Problem Report prior to its submission to Sterling IRB. All unanticipated problems involving risk should be reported to Sterling IRB within 10 business days of the site becoming aware of the problem.

Examples of unanticipated problems involving risks may include, but are not limited to the following:

Unexpected frequency or severity of expected adverse events
Incarceration of a study subject
New findings that may influence a subject�s willingness to continue participation the study
Subject complaints
Breach of confidentiality or privacy
Unauthorized use or disclosure of Protected Health Information (PHI)
Study drug or test article accountability discrepancies
Adverse results from a Data Monitoring Committee (DMC)
Unanticipated legal risk to a subject
Unanticipated additional costs to subjects

All Unanticipated Problems will be reviewed and acknowledged.

G. External Adverse Events (IND Safety Reports*):

External adverse events involve study participants who are not enrolled at a study site approved by Sterling IRB or where the Principal Investigator (PI) is not under the oversight of Sterling IRB. The Principal Investigator typically receives notification of these external events from the Sponsor in the form of an IND Safety Report.

* The term �IND Safety Report� is used here to represent all types of external adverse events reports, including, but not limited to, IND Safety Reports, Data Safety Monitoring Board Reports, and FDA Safety Alert Letters.

IND Safety Reports should be submitted to Sterling IRB only if, in the opinion of the Sponsor/CRO/SMO or Principal Investigator, the report meets at least one of the following conditions:

Information on the report results in an increased risk to all participants in the study.
Information on the report affects the rights, safety, or welfare of all participants in the study.
The report is for a device study.
The report is being submitted per Sponsor or Site requirements.

For multi-site studies, Sterling requires the Sponsor to submit IND Safety Reports on behalf of the Investigators. Investigators should not submit any IND Safety Reports to Sterling if reports are being submitted on their behalf.

For single-site studies, it is the Principal Investigator�s responsibility to submit all IND Safety Reports that meet one of the four conditions listed above.

All IND Safety Reports concerning other sites that meet one of the four submittal conditions above should be submitted to Sterling IRB within 10 business days of receipt.

The IRB Chairman or designee will review submitted IND Safety Reports prior to the board meeting and determine if the following criteria is met for full Board review:

1) Unexpected, and

2) Related to, or possibly related to the use of the study article, and

3) Serious (defined for the purpose of reviewing external adverse event reports). A serious adverse event is defined as a medical occurrence or other event involving risk(s) to subjects or others that results in any of the following:

Death
A life-threatening event
Inpatient hospitalization or prolongation of existing hospitalization
A persistent or significant disability / incapacity
A congenital anomaly / birth defect
An event that requires medical or surgical intervention to prevent one of the outcomes above
Other medically important events that, in the opinion of the Principal Investigator, may jeopardize the subject or may require intervention to prevent one of the outcomes listed above.

All reports that are not presented for full IRB review will be available to IRB members at any time during the life of the study for review. Data Monitoring Committee reports and Sponsor monitoring reports should be made available upon request.

Chapter 7 - INFORMED CONSENT

A. The Process of Consent and Assent:

Informed consent for a research study is a process, not just a form and a signature. It includes the recruitment materials, verbal instructions, written materials, question/answer sessions, and the informed consent agreement documented by the subject�s signature. Information must be presented in a manner that provides the subject sufficient opportunity to consider whether or not to volunteer. This should occur in an atmosphere that minimizes possible coercion or undue influence. The fundamental purpose of IRB review and approval of the consent document is to protect the rights and welfare of human subjects.

Minors and individuals who are not competent to provide consent should be given the opportunity to assent (affirmational agreement) to participate in the research study. Sterling�s policy is that documented assent must be obtained from all children ages 7-11; verbal assent must be obtained from all minors. The Sponsor may increase the required age range for assent to either younger than 7 or older than 11. The assent should be written at an age appropriate level.

Informed consent must be presented in a language understandable to the subject (approximately at an 8^th grade reading level), with all required elements of consent included. No consent may include language through which the subject or the subject�s legally authorized representative is made to or appears to waive any of their legal rights. The informed consent document is the written summary of the information provided to the subject and documents the fact that the process of consent occurred. The consent document should be revised if protocol changes warrant it or new safety information becomes available that affects the risks to the participants. All informed consent revisions must be approved by Sterling IRB.

B. Elements of Informed Consent:

The basic elements of informed consent are found in 45 CFR 46.116 and/or 21 CFR 50.25. Federal regulations require that all consent forms contain the following information:

Introduction (with a statement that the study involves research)
Purpose of the study
Description of the study procedures (identifying any that are experimental)
Expected duration of the subject�s participation
Potential risks or discomforts of participation
Description of any benefits to the subject or others that may reasonably be expected from the study
Alternatives that may be available to the subject
Confidentiality of records description
Compensation for injury statement (for greater than minimal risk studies)
Contact persons for answers to pertinent questions about the study, the rights of the subject, and whom to contact in the event of a research related emergency
Statement that participation is voluntary (no loss of benefits to which the subject is otherwise entitled)
Statement of who may review their records during the course of the study: Sponsor, Regulatory agencies (DHHS, FDA), Research staff, IRB and all others that may apply
Dated signature lines to permit verification that consent was obtained prior to participation in the study

It is important to include additional elements of information if they are applicable to the study.

These include:

Unforeseen risks statement
Reasons for involuntary termination of participation (if applicable)
Additional costs to participants (if applicable)
Consequences for withdrawal (e.g., adverse health/welfare effects if any)
New findings statement (to be provided if relevant)
Number of subjects
Compensation

C. Waiver of Informed Consent:

Sterling IRB may approve a consent procedure which alters some or all of the required elements or may waive the requirement to obtain informed consent. Requests for a waiver of informed consent must be accompanied by appropriate justification. In general, Sterling IRB expects that informed consent will be obtained from all subjects. However, under certain circumstances, an IRB can waive certain requirements for informed consent if the following criteria are met:

1. ⁺Waiver of Documentation of Informed Consent: the regulations (45 CFR 46.117(c)) state that the IRB may waive the requirement for the investigator to obtain a signed consent form if it finds either:

a. the only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality: or

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

⁺Please complete a Waiver of Documentation of Informed Consent application, which is located on our website <www.sterlingirb.com> under forms.

2. ⁺Waiver of Elements of Consent: The IRB may consider waiving the requirement for some or

all of the elements of informed consent (45 CFR 46.116(d)). The regulations state that informed

consent may be waived in full or in part if the IRB determines that:

a. the research involves no more than minimal risk to the subjects; and

b. the waiver or alteration will not adversely affect the rights and welfare of the subjects; and

c. the research could not practicably be carried out without the waiver or alteration; and

d. whenever appropriate, the subjects will be provided with additional pertinent information after participation.

⁺Please complete a Waiver of Informed Consent application, which is located on our website <www.sterlingirb.com> under forms.

*Please note, with a few narrow exceptions, FDA regulations do not allow for the waiver of informed consent. The following exceptions are noted in Title 21, as follows:

a. Documentation of informed consent may be waived if the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context. (See 21 CFR 56.109(c))

b. An exception from informed consent requirements is granted for emergency research, as outlined in 21 CFR 50.24.

D. Informed Consent and State Law:

It is the responsibility of the Principal Investigator to report to the IRB any special laws governing medical research, including HIPAA, in their state or community.

E. Safeguarding Confidentiality & Protecting Privacy:

Confidentiality and loss of privacy are issues of primary importance in research. �Confidentiality� pertains to the use and disclosure of information (i.e. a subject�s Protected Health Information (PHI)). The Principal Investigator must have plans to protect the subjects� identity as well as the confidentiality of the research records. Such plans can include any or all of the following measures: (1) ensuring that all persons who will have access to subjects� PHI have been educated on the HIPAA Privacy Rule; (2) ensuring that all persons who will have access to subjects� PHI have been trained on their respective site�s policies relating to confidentiality; (3) requiring that all persons who will have access to subjects� PHI sign a confidentiality agreement or similar obligation to protect the confidentiality of subjects� PHI; (4) limiting access to subjects� PHI to only those persons who need to have access for study-related purposes; (5) using electronic safeguards (i.e. secure data network, limited access to electronic data, password protections) for PHI that is maintained electronically; (6) using physical safeguards (i.e. storage in a secure, locked area) for PHI that is maintained on paper; (7) removing names and other identifying information from research records; and (8) redacting the identities of study participants when research results are presented at meetings or in medical publications. Other methods of safeguarding confidentiality may also be used.

�Privacy� addresses the way(s) a subject is kept from the presence or observation of others and/or protected from unauthorized intrusion(s). The Principal Investigator must have plans to protect the subjects� privacy. Such plans can include any or all of the following measures: (1) limiting personal information collected from subjects to only that which is necessary for study purposes; (2) collecting subjects� personal information in a private setting/location; (3) conducting study-related activities and procedures in a private setting/location; (4) using drapes or other physical barriers for subjects who must disrobe; and (5) leaving study-related phone messages for subjects only in voice mailboxes to which the subject has sole access. Other methods of protecting privacy may also be used.

Principal Investigators may obtain a Certificate of Confidentiality if a determination is made that the research is of such a sensitive nature that protection is necessary to perform the research. Certificates of Confidentiality protect the privacy of individuals in any federal, state, local, civil, criminal, administrative, legislative, or other proceedings. Also see Chapter 10, HIPAA.

F. Subject Compensation:

Compensation for participation in research should not be offered to the subject as a means of coercive persuasion but as a form of recognition for the investment of the subject�s time and any other inconvenience incurred. In most cases, compensation should be prorated during the study, to avoid any impression that the investigator is coercing the subject to continue in the study or penalizing the subject for non-compliance with the protocol. Large lump sums at the end of the study are discouraged. These can be seen as an undue influence to the subject continuing in the study, even though they may wish to discontinue.

The Board gives special consideration to vulnerable populations where others are acting as their legally authorized representatives, that decisions to participate are not based on monetary gain.

G. Recruitment:

Advertisements and recruitment materials for study subjects are considered to be the start of the informed consent process and must have IRB approval prior to its use. Any subsequent modifications to approved recruitment materials must also be reviewed and approved by the IRB before use. The materials must be consistent with the IRB approved protocol and informed consent form for the research study and must comply with applicable state and local laws. (See Chapter 5- E. Advertisements and Recruitment Materials)

Sterling IRB does not want to discourage participation of any who may benefit from research. However, the Board wants to be assured that if special considerations and additional measures need to be taken, they will be implemented. (See Chapter 8 - Vulnerable Subjects, Additional Considerations and Protections)

H. Non-English Speaking Subjects:

The informed consent document and all subject materials need to be translated into a language that the subject can read and understand. The translation process is discussed in Chapter 5. The person obtaining the informed consent must be fluent in both English and the language of the subject. The Board recommends that the site have a staff member who is fluent in the subject�s language available to translate questions and answers between the physician and the subject during the study.

I. Subject Contact with Sterling IRB:

It is the responsibility of the Principal Investigator to explain the role of the IRB to prospective subjects. The name and telephone number of the Sterling IRB Chairman are listed in each informed consent document; a subject may contact the IRB with any questions they may have regarding their rights as a research participant or with any complaints they may have about the study.

J. Informed Consent Requirements When Determining Eligibility for Research:

For some studies, the use of screening tests to assess whether prospective subjects are appropriate candidates for inclusion in studies is an appropriate pre-entry activity. While an investigator may discuss availability of studies and the possibility of entry into a study with a prospective subject without first obtaining consent, informed consent must be obtained prior to initiation of clinical procedures that are performed solely for the purpose of determining eligibility for research, including withdrawal from medication (wash-out). When wash-out is done in anticipation of or in preparation for the research, it is part of the research. FDA Information sheets: Guidance for Institutional Review Boards and Clinical Investigators, 1998 Update.

K. Signature Requirements:

Research Participant Signature: The study participant must sign and date the consent form. In emergency, life-saving situations, consent may be waived, but the request must meet the requirements found under 21 CRF 56.109 (c) or 45 CFR 46.117 (c).

Signature of Person Who Conducted the Informed Consent Discussion: The person who conducted the consent discussion must sign and date the consent form.

Investigator Signature: Sterling IRB does not require the signature of the investigator on a consent form, but will include this signature block at the request of the Sponsor or Investigator.

Witness Signature: Sterling IRB does not require the signature of a witness on a consent form, but will include this signature block at the request of the Sponsor or Investigator. Sterling IRB requests that the Sponsor or Investigator have written procedures explaining who may be a witness, and what the witness signature signifies. If a witness signature block is included on the consent form, it must be signed for each consent form, unless the written procedures of the Sponsor or Investigator allow otherwise.

Impartial Witness Signature: If a research subject or legally authorized representative is unable to read the consent form because of blindness or illiteracy, an impartial witness should be present during the entire consent process, and should sign and date the consent form. Sterling IRB may include a signature block for an impartial witness if the sponsor or investigator indicates that the subject population includes subjects who cannot read. The impartial witness signature block should be left unsigned unless there is an impartial witness present for the consent process. The Sterling Board may request an impartial witness signature for certain studies. An impartial witness signature block should also be included if required by federal, state or local law.

Signature of Legally Authorized Representatives (LARs): A legally authorized representative is defined as an individual, or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedures involved in research. For research studies that allow the enrollment of subjects who are not legally competent, the consent form will include a signature block for an LAR. If the subject is not legally competent, an LAR must participate in the consent process, agree to the subject's participation in the research, and sign the consent form. If the research allows the enrollment of both subjects who are and are not legally competent, then the LAR signature block will be labeled when necessary. This signature block should only be signed if the subject is not legally competent.

Telephone Consent: Verbal telephone consent is not sufficient. However, it is acceptable to send the informed consent document by fax and conduct the consent interview over the telephone when the subject or LAR can read the consent as it is discussed and can provide to the investigator sufficient documentation verifying his/her identity. If the consent is signed, it can be sent back to the investigative site by fax. The consent with original signatures will be mailed or brought to the investigative site at the earliest opportunity and a copy will be given to the subject or LAR.

Initials: Sterling IRB requires that the research participant, minor subject�s parents, or legally authorized representative initial each page of the consent document.

Chapter 8 - VULNERABLE SUBJECTS, ADDITIONAL CONSIDERATIONS AND PROTECTIONS

For all vulnerable populations, please provide the IRB a detailed explanation of the additional measures taken by your site to ensure the safety and welfare of these potential research subjects. For example, subjects may be given additional time to consider participation, how capacity for consent will be determined, whether the consent of legally authorized representatives is to be sought, whether assent should also be sought, whether an advocate or consent auditor should be required and if there will be appropriate follow-up if needed.

A. Children and Minors:

Federal regulations identify four categories of research that may be allowable for children as outlined in 45 CFR 46, Subpart D and 21 CFR 50, Subpart D. The first three categories may be approved by the IRB but the fourth also requires special federal approval.

The Categories are:

Research not involving greater than minimal risk. (45 CFR 46.404; 21 CFR 50.51)
Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. (45 CFR 46.405; 21 CFR 50.52)
Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject�s disorder or condition. (45 CFR 46.406; 21 CFR 50.53)
Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. (45 CFR 46.407; 21 CFR 50.54)

When children are involved in research, the regulations require the assent of the child (who is capable) and the permission of the parent(s) or legally authorized representative (LAR). Children should always be asked if they want to participate in the research and must affirmatively agree to participate. Sterling requires a documented assent for children 7 - 11 years of age. In certain studies, the IRB may waive assent requirements.

B. Pregnant Women and Fetuses:

Federal regulations 45 CFR 46, Subpart B, require that IRBs consider additional safeguards before approving research involving pregnant women, fetuses, or in vitro fertilization.

C. Prisoners:

Prisoners, due to the lack of control of their circumstances, are considered to be at greater risk of being coerced into participating in a research study. Special care should be taken that:

The compensation is not coercive
The risks of participating would be acceptable to non-prisoner volunteers
The selection of subjects is equitable and does not affect decisions regarding parole
Adequate provisions to protect the privacy of subjects and to maintain the confidentiality of the data are taken
Adequate follow-up care will be provided, if needed

Only four categories of research are permissible under 45 CFR 46, Subpart C.

The IRB should be notified immediately if an enrolled subject should become incarcerated while participating in a research study. The protocol and consent document would need to be reviewed again with a prisoner representative present. Unless the IRB reapproves the research for the inclusion of the prisoner(s), the newly incarcerated individual must withdraw from the study.

D. Cognitively Impaired Persons:

Cognitively Impaired: Having a psychiatric disorder (psychosis, neurosis, and personality or behavior disorders), an organic impairment (dementia), or a developmental disorder (mental retardation) that affects cognitive or emotional functions to the extent that the capacity for judgment and reasoning is diminished. Other diseases, conditions and disorders that may also impact the subjects� ability to make decisions in their best interest include: substance abuse, degenerative diseases affecting the brain, terminally ill persons, and those with severely disabling handicaps.

The Principal Investigator is in the ideal position to determine if a subject has the ability to understand the implications of the decision to participate in research, and whether the subject is making a rational decision to participate and has the ability to follow the protocol.

E. Traumatized and Comatose:

Research involving subjects undergoing emergency care differs from clinical research in other settings because the patient�s ability to provide informed consent is often severely compromised, and decisions about participation must often be made quickly and the patient�s legally authorized representative may not be available. Altered mental status may arise from trauma, shock, infection, psychological response (anxiety, grief, pain) or the effects of drugs (OHRP Guidebook, Chapter VI).

The Board will consider a waiver of the informed consent when risks are no more than minimal, the research could not be reasonable carried out without waiving the requirements of informed consent, and such a waiver will not adversely affect the subject�s rights or welfare. Sterling IRB will require that information be given to the subject or legally authorized representative if and when it becomes possible.

F. Terminally Ill:

Terminally Ill: Those who are deteriorating from a life threatening disease or condition for which no effective treatment exists.

Research involving terminally ill patients presents additional concerns in that potential subjects tend to be more vulnerable to coercion or undue influence than healthy adult subjects due to their desire to seek treatment, and the research is likely to involve more than minimal risk. Special attention should be given to the informed consent process ensuring the risks and benefits are communicated clearly and in a manner that will not create false hope nor eliminate all hope.

G. Educationally Disadvantaged:

For educationally disadvantaged subjects, special care should be taken to ensure comprehension in the informed consent process. The person conducting the consent should review each section and pose questions after each section to ensure understanding.

Illiterate persons who understand English may have the consent read to them and �make their mark�, if appropriate, under state law. An independent witness (not an employee of the research site) should also be present during the presentation and signing of the informed consent to ensure the subject comprehends the concept of the study and the risks and benefits as it is explained verbally, and he/she is able to indicate approval or disapproval for participation.

H. Economically Disadvantaged:

For economically disadvantaged subjects, special consideration should be given to ensure that compensation (whether monetary or other enticements) is not presented in a manner which may be coercive. �Free care� and reimbursements can substantially affect the voluntariness of the decision to participate. Payment should not be contingent on completion of the study and should be prorated.

I. Additional Considerations - Inclusion of Women and Minorities:

Sterling IRB shall determine whether consideration has been given to the manner in which subjects are selected and assure that adequate provision has been made for the inclusion of women and minorities, whenever possible. The benefits and burdens of research should be distributed fairly within society and investigators should always seek racial and gender equity in the recruitment of subjects.

J. Additional Protections - Students, Employees and Normal Volunteers:

Students: Students who participate in research in their own student setting (university, medical school).

There can be many potential problems with student participation in research. It is important to ensure that consent is freely given and not coerced. Students may feel the need to agree to participate in research in order to receive favor with the faculty, academic credit, monetary compensation, better grades, employment, recommendations, or other reasons. Another concern with student research is confidentiality, due to the close nature of a college environment.

Guidelines should be established to ensure that confidentiality and coercion do not become areas of concern in the academic research setting.

Normal Volunteer: A healthy person who volunteers for medical research and for whom no therapeutic benefit can result from participation.

The altruistic motivation for the normal volunteer�s agreement to participate in research heightens the concern for the risks to which such participants should ethically be exposed. Monetary payments should not be so great that they constitute an undue inducement. Any compensation that is offered should be commensurate with the time, discomfort, and risk involved.

Employees: Employees of the research center.

It is important to ensure that employees who volunteer to participate in research at a research center where they are employed are not coerced in any manner. Their decision to participate, or not to participate, should have no impact on their performance evaluations, job advancement, or employment status. Guidelines should be established to handle an injury or illness of an employee who is participating in research. Due to the close nature of a research environment, strict measures should be taken to ensure the confidentiality of an employee�s study-related records. Many Sponsors do not allow employees of the research center to participate in a research study.

Chapter 9 - RESEARCH CONFLICTS AND NON-COMPLIANCE

A. Conflict of Interest:

Situations arise in which financial or other personal situations may compromise, or have the appearance of compromising, an investigator�s professional judgment in conducting and reporting research. The evaluation for assessing a potential bias to the mandate of human subject protections is very important. Sterling IRB has a financial disclosure section as a part of its Submission Application for Investigator/Site.

The Principal Investigator has the responsibility to assess conflict of interest for each study, and re-assess throughout the study. If conflict of interest becomes an issue, a report should be made to the IRB.

OHRP has published a guidance for protecting research subjects from possible harm caused by financial conflicts of interest in research studies. The guidance document entitled Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection.

The target audience includes investigators, IRB members and staffs, institutions engaged in human subjects research and their officials, and other interested members of the research community.

The guidance is located at: http://www.hhs.gov/ohrp/humansubjects/finreltn/fguid.pdf

B. Suspension or Termination of IRB Approval:

The Sponsor and appropriate regulatory agency will be notified of any determination made by the Board to suspend or terminate approval of a research study or investigative site. The Principal Investigator will be sent a letter detailing the IRB�s determination, length of suspension or termination of IRB approval. Any response from the Principal Investigator, Sponsor/CRO or regulatory agencies will be reviewed by the IRB.

C. Non-Compliance and Complaint Reporting:

The Principal Investigator bears the ultimate responsibility for the conduct of the research study.

The Principal Investigator must comply with the requirements as set forth the Investigator Compliance Agreement in the Submission Application for the Investigator or Site; the Sterling IRB Investigator Handbook; as well as all regulatory requirements on the federal, state and local level.

Information regarding non-compliance in research may come to the attention of the IRB in many different ways. These include information contained in the Submission Application for the Investigator or Site, Site Continuing Review Status Reports, Site Interim Status Update, Serious Adverse Event Reports, Significant Protocol Deviation Reports, Unanticipated Problem Reports, employees, collaborators, whistleblowers, or the research subjects.

D. Appeal of IRB Decisions:

Should Sterling IRB disapprove a protocol or disqualify the credentials of a Principal Investigator, the document forwarded to the Principal Investigator will include the notification and a statement of the reason for the Board�s decision. The Investigator will be given an opportunity to provide in writing adequate reasons for asking the IRB to reconsider its recommendations.

The response will be submitted to the full Board, and the Board members may vote to accept or reject the appeal. Neither the Principal Investigator nor the Sponsor has the authority to overrule the IRB�s rejection of a study or activity.

Chapter 10 - SPECIAL TOPICS

A. HIPAA

HIPAA stands for the Health Insurance Portability and Accountability Act of 1996. The Privacy Rule establishes the conditions under which certain healthcare groups, healthcare clearinghouses, organizations, or businesses, called �covered entities,� handle the individually identifiable health information known as Protected Health Information (PHI). Principal Investigators should be aware of the Privacy Rule because it establishes the conditions under which covered entities can use or disclose PHI for research purposes. The specific regulations for HIPAA are found in: 45 CFR 160 and 164.

Many research organizations that handle PHI will not have to comply with the Privacy Rule because they are not covered entities. The Privacy Rule will not directly regulate researchers who are engaged in research within organizations that are not covered entities even though they may gather, generate, access, and share personal health information. For instance, entities that sponsor health research or create and/or maintain health information databases may not themselves be covered entities; however, the Privacy Rule may affect their relationships with covered entities. It is recommended that research sites consult their own legal counsel to determine if they are a �covered entity�. (See the decision tool, �Am I a Covered Entity?� on the HIPAA website at: <www.hhs.gov/ocr/hipaa>).

Covered entities are permitted to use or disclose protected health information for research with individual authorization, or without individual authorization under limited circumstances as set forth in the Privacy Rule.

Authorization by Research Participant:

HIPAA specifies that a covered entity may neither use nor disclose PHI for research purposes unless the patient has provided, in advance, his or her written authorization for such use or disclosure (unless a waiver is obtained). Authorization may be combined with the informed consent document. California requires the individual authorization to be a separate document with its own signature lines. It is the responsibility of the PI to be aware of any state and local laws that raise the standard that HIPAA has set forth.

Six Required Elements:

A description of the PHI to be used or disclosed that specifically identifies the information
Name of the persons and/or entities authorized to use or disclose the PHI
Name of the persons and/or entities authorized to receive the PHI
The purpose of the requested use or disclosure of PHI
An expiration date, which may be indicated as �end of study� or �none,� for Authorization to place PHI in a research database (California requires an actual date)
Signature of the subject and date

Three Required Statements:

A statement that the subject has the right to give written notice to withdraw their authorization at any time, including any applicable exceptions to the right to withdraw authorization
A statement that once the subject�s PHI has been disclosed, it is possible that the receiver may re-disclose the information
A statement that informs the subject that they may choose to refuse to sign the authorization and this will not affect their medical treatment

General Requirement