Human Subjects in Research

 

 

Expedited review procedures may be used for certain research activities described in the federal regulations. Expedited reviews are done by one or more experienced reviewers designated by the chairperson from among members of the IRB. Projects approved by the expedited review process are subject to the same regulatory requirements as those approved on a full board review and must be periodically reviewed by continuing review before the expiration date set on approval (no longer than one year since approval). Informed consent forms associated with projects reviewed by expedited review will be stamped by the IRB with the approval and expiration dates. IRB-stamped documents are posted in IRBNet after approval and must be used when obtaining the informed consent of research participants.

Protocols eligible for expedited review are evaluated on a rolling basis as they are submitted to IRBNet. Review times for expedited reviews vary depending on the total IRB submissions load at any given time and may take, on average, about two weeks from the time of complete submission.

1. Clinical studies of drugs and medical devices only when condition (a) or (b) is met.
   (a) Research on drugs for which an investigational new drug application (21 CFR Part 312) is not required. (Note: Research on marketed drugs that significantly increases the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review.)
   (b) Research on medical devices for which (i) an investigational device exemption application (21 CFR Part 812) is not required; or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.
2. Collection of blood samples by finger stick, heel stick, ear stick or venipuncture as follows:
   (a) from healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 ml in an eight-week period and collection may not occur more frequently than two times per week; or
   (b) from other adults and children, considering the age, weight and health of the subjects, the collection procedure, the amount of blood to be collected and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an eight-week period and collection may not occur more frequently than two times per week.
3. Prospective collection of biological specimens for research purposes by noninvasive means. Examples:
   (a) hair and nail clippings in a nondisfiguring manner;
   (b) deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction;
   (c) permanent teeth if routine patient care indicates a need for extraction;
   (d) excreta and external secretions (including sweat);
   (e) uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gumbase or wax or by applying a dilute citric solution to the tongue;
   (f) placenta removed at delivery;
   (g) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor;
   (h) supra- and subgingival dental plaque and calculus, provided the collection procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques;
   (i) mucosal and skin cells collected by buccal scraping or swab, skin swab or mouth washings;
   (j) sputum collected after saline mist nebulization.
4. Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.) Examples:
   (a) physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subject’s privacy;
   (b) weighing or testing sensory acuity;
   (c) magnetic resonance imaging;
   (d) electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow and echocardiography;
   (e) moderate exercise, muscular strength testing, body composition assessment and flexibility testing where appropriate given the age, weight and health of the individual.
5. Research involving materials (data, documents, records or specimens) that have been collected or will be collected solely for nonresearch purposes (such as medical treatment or diagnosis).
   (NOTE: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR 46.101(b)(4). This listing refers only to research that is not exempt.)
6. Collection of data from voice, video, digital or image recordings made for research purposes.
7. Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation or quality assurance methodologies.
   (NOTE: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR 46.101(b)(2) and (b)(3) . This listing refers only to research that is not exempt.)
8. Continuing review of research previously approved by the convened IRB as follows:
   (a) where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; or
   (b) where no subjects have been enrolled and no additional risks have been identified; or
   (c) where the remaining research activities are limited to data analysis.
9. Continuing review of research not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified.

 

Review of non-exempt research that does not qualify for expedited review or that may present more than minimal risk to the subjects must be reviewed at a convened meeting of the University’s IRB. At the University of Delaware (UD) the IRB meets once every month and investigators proposing new protocols are usually invited to attend the IRB meeting to present their research and address any questions the Board members may have. Students having protocols reviewed at a convened meeting and presenting to the IRB must be accompanied by their faculty advisor.

The meeting dates for the IRB as well as the submission deadline for protocols to be considered for full board review at each month’s meeting are set well in advance and can be found in the Research Office Calendar of Events. The number of protocols to be reviewed at each meeting may be limited due the constraints of time and the complexity of other items on the agenda. Protocols will be accepted for review in the order received. If the board is not able to review a protocol in a particular month, it will be given priority for review in the following month.

Investigators submitting new projects are normally invited to attend the IRB meeting to present their project to the Board and answer any questions or concerns IRB Members may have. The results from the meeting are later communicated to the PI and any conditions the IRB may have set, before approval can be effective, will be addressed then. If a student-led new project is to be reviewed by the full board the academic advisor responsible for the student and project must accompany the student to the meeting.

Projects approved at a convened full board meeting must be periodically reviewed by continuing review before the expiration date set on approval and no less than once a year. Informed consent forms associated with projects reviewed at a full board will be stamped by the IRB with the approval and expiration dates. IRB-stamped documents are posted in IRBNet after approval and must be used when obtaining the informed consent of research participants.

 

In addition to the types of review listed above the IRB may provide administrative reviews when appropriate. Administrative reviews are used in cases in which the University of Delaware needs record of research with human subjects in which UD is engaged but for which review and approval are not issued by the UD IRB. This is the case, for example, when UD investigators are part of a research team performing research at another institution. Depending on the nature of the research and the collaboration arrangement, UD IRB may rely on the review and approval from the other institution’s IRB. UD keeps record of that reliance via an administrative review.

All UD investigators engaged in collaborative research with human subjects must consult with the UD IRB office and submit that proposed effort to the UD IRB regardless of other IRB reviews being sought after.

 

If ANY changes need to be made to an IRB approved protocol, investigators must seek IRB approval of those changes prior to their implementation. Examples of changes that would require the submission of an approval are: changes to the research team members, modifications in the recruitment strategies and/or advertisement materials, any changes to the research instruments already approved, elimination of previously approved procedures and/or data collection measures, new approaches to data processing or storage, edits to the approved informed consent language, etc. Amendments are reviewed as they are submitted and may take on average up to two-weeks to be completed.
Amendment submission packages must contain:

• the amendment form properly filled out,
• the tracked changes and clean versions of any documents affected by the amendment (e.g., edits to the previously approved protocol form and informed consent document, advertisement materials, etc.) Tracked changes version of any edited document must show all the markups including what is being added and/or removed.

If the amendment does affect the informed consent document, a clean version (changes accepted) needs to be submitted so a newly IRB-stamped informed consent can be issued upon approval. The approval of an amendment normally has no effect on the previously set expiration date.

 

Protocols approved by the IRB, whether under expedited or full board review, are required to undergo continuing review at least once per year, on or before the expiration date set at the time of approval for as long as recruitment and data collection is to take place, and/or private identifiable data is kept. In some cases, the IRB may require more frequent continuing reviews. Expiration reminders are automatically sent from IRBNet to the Principal Investigator (PI) and all others with whom the project has been shared, and granted full access to, in IRBNet. Reminders are sent 60 and 30 days before the project is set to expire. In addition, an expiration alert is sent on the expiration day if no approval has been secured before that day. Applications for continuing review must be submitted with enough time to allow for IRB review prior to the expiration date. In order to maintain the expiration anniversary date, continuing review applications are reviewed no earlier than 30 days before the expiration date (because of this, a 30-day expiration notice will always be received even when the application for review has been submitted early). Once a continuing review is approved a new one-year approval period starts and informed consent documents are stamped with the new approval and expiration dates.

Unless eligible for expedited continuing review, protocols originally reviewed and approved by the convened IRB meeting (full board) must undergo a full board continuing review. IRB meeting dates and deadlines must be considered when submitting a continuing application to be reviewed at a full board as to avoid lapses in IRB approval. Continuing review submissions must contain the continuing review form properly filled in and all other current documents relevant to the project (at a minimum the most current previously approved protocol form and a clean version of the informed consent). If any changes are added at the time of continuing review, the tracked changes version of the protocol form and informed consent document(s) need to be added to the continuing review application.

Lapses in IRB Approval: It is the responsibility of the investigators to provide in a timely manner the information needed by the IRB to perform its continuing review functions. When continuing review of a research project is not completed prior to the end of the approval period specified, the IRB approval will expire. All research activities involving human subjects (i.e., participant recruitment and/or data collection) must stop after IRB approval expires and cannot be restarted until approval has been secured. Expired projects for which the IRB office has not been notified of the intent for continuation will be closed. Once closed, a project cannot be re-opened and will have to be resubmitted as ‘new’ for review and approval before any research related activities can be re-initiated.

 

Investigators must report to the IRB Office any instances of unanticipated problems (UP), and/or adverse events (AE) related to the research within three days of the incident.

Unanticipated problems, in general, include any incident, experience or outcome that meets the following criteria:

1. unexpected (in terms of nature, severity or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
2. related or possibly related to participation in the research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience or outcome may have been caused by the procedures involved in the research);
3. suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic or social harm) than was previously known or recognized.

Adverse Events

An adverse event is any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research. Adverse events encompass both physical and psychological harms. They occur most commonly in the context of biomedical research, although on occasion, they can occur in the context of social and behavioral research.

Unanticipated problems and adverse events must be reported to the IRB by submitting the appropriate form via IRBNet. Depending on the nature and of the event reported and on a case by case basis the Director of Research Compliance and the IRB Chair will decide if review by the convened IRB of the submission is needed and when a for cause audit of the research project may be required.

 

Auditing will be performed routinely by the IRB office staff to ascertain general compliance with the protection of human subjects requirements and IRB-approved protocol and procedures. In addition, for cause audits will be conducted as deemed appropriate by the Director of Research Compliance, and/or the IRB Chair, to investigate reports of unanticipated problems, adverse events and/or non-compliance.

• Routine Audits: Projects are selected randomly among those active and approved via expedited and convened IRB review. The principal investigator responsible for the project is contacted to schedule a visit from the IRB office staff member conducting the audit. Prior to the scheduled visit the investigator is sent an outline of the review process. A report is generated after the audit and sent to the investigator for review. Non-compliance and other findings resulting from a routine audit are shared with the IRB. If a non-compliance finding is determined by the IRB to be serious or continuing it will be further investigated and reported to the UD Signatory Official.
• For cause Audit: Adverse events and/or unanticipated problems involving risk to participants reported to the IRB office may be followed up with an investigation. For cause audits may also be performed to investigate non-compliance with IRB-approved protocols. Depending on the nature of the investigation, for cause audits may be scheduled or unannounced. Reports from a for cause audit will be reviewed by the IRB. Depending on the outcome of a for cause audit and the IRB review of the report, an incident may have to be reported to the UD Signatory Official. The UD Signatory Official has the authority to decide if, as per the stipulated guidance, further reporting to OHRP and the funding agency is needed.

 

Protocols approved by the IRB under an expedited or full board review must receive continuing review at least once per year until closed. A project can be closed when all the following conditions are true:

• Enrollment and all data collection for the study have been completed; private identifiable data is no longer being stored, accessed or worked on
• the link (access code), if any, between the research data and the identifiers has been destroyed. More details on data storage and retention can be found in the data management section below.

A closure submission should be done as soon as the conditions above are met by creating a new submission package in IRBNet and including the closure form. If no continuing review application nor closure request is submitted by the investigator, projects will be closed by the IRB Office upon expiration. Once a study has been closed it cannot be re-opened. Any future work related to the study (e.g., long- term follow up with participants, additional enrollment and data collection, etc.) will require for a new project to be reviewed and approved by the IRB before the work can start.

 

A human subjects research project is considered “active” from the time IRB approval is issued until the time personal identifiers linked to the research data no longer exist and the project is closed. Records for active IRB approved research projects must be stored in some form (paper and/or digital form) in secure locations on campus. For research performed off-campus, the data should be secured and returned to campus as soon after collection as it is practicable. Particular care should be taken to protect data on laptop computers, external hard drives and other portable devices. Study information containing personal identifiers stored on these devices should be encrypted (see link for UD’s guidelines on encryption) to prevent unintentional breaches of confidentiality in the event the storage device is lost or stolen. Similarly, paper records identifying research participants, including consent forms, should be kept in a secure location with access restricted to key study personnel. The level of protection for the data should be commensurate with the sensitivity of the data. Basic levels of storage are as follows:

Paper Records (e.g., consent forms, data files, medical records, etc.): Paper files related to human subjects participation in research must be securely stored on campus. Access to files should be restricted to key personnel and supervised by the principal investigator(s) of the study. Locked file cabinets ought to be used and preferably located in secured locations (i.e., locked office or laboratory). In the event that research activities are not carried on campus AND it is necessary to maintain the consent forms at the research site, copies of the signed consent forms should also be stored on a secure University location (either as a paper copy or in digital form).

Digital Records (e.g., electronic files, digital recordings, etc.): Digital files containing human subjects research data must be stored in password protected files, preferably on University maintained servers with regular and secured back-up. Sensitive data should also be encrypted, stored, and securely erased when appropriate, according to the UD guidelines for protecting Personally Indentifiable Information (PII).

IRB approval for expedited and full board-reviewed protocols must be renewed annually on or before the approval expiration date. Continuing review must be obtained for as long as recruitment and/or data collection activities are ongoing, and/or private identifiable data are stored (that is, the identifying link between the data files and the participants’ identity still exists and is accessible to the researcher(s)):

IRBNet will send automatic reminders 60 days and 30 days before the expiration date, and an expiration alert the day an approval is set to expire. Please plan to submit your continuing renewal application with enough time to allow for its review and approval. No recruitment, data collection or private identifiable data analysis activities shall be carried on under an expired protocol.

If no continuing review application is submitted for review, projects will be closed after expiration. Further data collection and/or identifiable data analysis will require a new submission for IRB review and approval.

 

Approved human subject research projects should be closed at the time all data have been collected and identifying information is no longer needed. De-identified data for which no identifying key exists can be kept for further analysis and do not require continuing review and approval by an IRB.

Compliance with 45 CFR 46.115(b) requires that all records relating to IRB approved research be retained for three years after closure of the project.

Records to be maintained include: copies of all research proposals reviewed, scientific evaluations (if any), consent documents, progress reports, reports of injuries to subjects and other unanticipated problems, and copies of all correspondences between the IRB and the investigator(s). Records may be preserved in hard-copy, electronic or other media form, and must be accessible for audit purposes. Records for completed projects should be stored in secure locations on campus with the same care used when the project was active.

If a researcher (faculty, staff or student) leaves UD, a copy of the research records must remain on campus. Students should coordinate storage of research records with their faculty advisor(s) and/or departments.

 

Destruction of human subjects research records should be performed in a fashion that protects the confidentiality of the research subjects. It is recommended that paper records be shredded, that physical tapes (audio and video) be erased and physically destroyed, and that electronic media used to store data be scrubbed after the files are deleted.

Researchers may retain de-identified data for future analysis in the context of the project for which the data were collected. Data are considered to be completely de-identified when ALL links between individual identity and the data are destroyed. Research data are not considered de-identified simply because names have been removed if they still contain information that might identify the participants such as date of birth, address, etc.

 

For further guidance, please contact the IRB Office at 302-831-2137. 

1. The FDA Amendments Act of 2007 (FDAAA) requires “Applicable Clinical Trials” involving drugs, biological products and devices subject to the FDA regulations to be registered in ClinicalTrials.gov, regardless of the funding source for the study.
2. The NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information (“NIH Policy”) is complementary to the reporting requirements of FDAAA and establishes the expectation that all investigators conducting clinical trials funded, in whole or in part, by the NIH will ensure that these trials are registered and that results submitted to ClinicalTrials.gov.
3. The International Committee of Medical Journal Editors (“ICMJE”) policy (adopted by over 1,000 journals) requires, and recommends that all medical journal editors require, registration of clinical trials in a public trials registry at or before the time of first patient enrollment as a condition of consideration for publication.
4. In addition, an investigator may voluntarily decide to register a study not subject to any of the requirements above (e.g., an observational study with no intervention assignment and not intended to be published in a ICMJE journal) as a way to publicly advertise the research (i.e., recruitment of research subjects). ClinicalTrials.gov supports and encourages the registration of all research studies with human subjects, even if an explicit requirement does not apply.

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For questions, send email to: clinicaltrials@udel.edu.

 

I am the PI of a clinical trial. What do I do?

Once determined that a clinical trial will need to be registered in www.ClinicalTrials.gov the steps to follow are:

 

1. If it is my first time registering a study: How do I obtain an account with ClinicalTrials.gov?Obtaining a username and password: If you do not have an account with ClinicalTrials.gov (i.e., no username and password), proceed to https://clinicaltrials.gov/:
   1. Click “Submit Studies” and then click “How to apply for an account.”
   2. Toward the bottom of the page, click the link, “PRS Administrator Contact Request Form.” Complete the contact request form for the appropriate organization (University of Delaware).
   3. You will receive an email from clinicaltrials.gov with the email address for the University of Delaware Protocol Registration System (PRS) Administrator account, clinicaltrials@udel.edu. Email the UD PRS Administrator account and request a username and password.
      
      University of Delaware has a PRS Administrator account – do not create PRS “individual account” when registering with ClinicalTrials.gov.
   4. If you do not know if you have an account or have forgotten your username, use the steps above to verify your username.
2. How Do I Register a Trial?
   1. Prior to registration in ClinicalTrials.gov a UD research study must have received UD IRB approval. Pursuant to FDA Guidance, and NIH Policy, the following exact statement must be included in the informed consent documents of studies to be registered in ClinicalTrials.gov:
      
      “A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time”
   2. Once a username and password has been obtained, proceed to the ClinicalTrials.gov “PRS Login Page,” and enter the organization (UDelaware), username and password.
      
      For basic help with using PRS, review the “Quick Start Guide” and the “PRS User’s Guide” found in the “Help” section of the PRS top main menu, which is accessible after logging with your username and password.
   3. Complete all fields with information related to the trial. Once all of the information has been entered in the PRS record, marked as complete and released, an automated email will be sent to the UD PRS Administrator. Upon completion of the administrative review, which typically takes 3-5 business days, a UD PRS Administrator will approve and release the record to ClinicalTrials.gov, where the PRS team will review the record for quality control purposes prior to posting on the ClinicalTrials.gov website.

 

How do I Submit Trial Results?

1. Enter organization (UDelaware), your username, and your password on the “PRS Login Page.”
2. Update the “Protocol Section” and release (submit) the record.

    

   a. Ensure that the information in the Protocol Section is up-to-date before starting the Results Section (e.g., overall recruitment status, study start date, primary and study completion dates, actual enrollment, and arm and intervention information.)b. Begin results submission after the updated record has been published on ClinicalTrials.gov.

3. Enter the required and optional results data elements. Scientific information is submitted as four separate modules: the modules allow for the entry and display of information in a series of data tables with supporting notes, but without narrative conclusions about the results. The scientific information instructions section provides detailed information on how to prepare the submission of each module and it includes links to instructional online presentations:

    

   Participant Flow	Summary of the progress of participants through each stage of a study, by study arm or comparison group. It includes the numbers of participants who started, completed and dropped out of each period of the study based on the sequence in which interventions were assigned. The module accommodates a wide range of study designs and allows for the description of key events following study enrollment but prior to group assignment.
   Baseline Characteristics	Summary of the data collected at the beginning of the study for all participants, by study arm or comparison group. These data include demographics, such as age and gender, and study-specific measures (e.g., systolic blood pressure prior to exercise treatment).
   Outcome Measures and Statistical Analyses	Summary of outcome measure values, by study arm or comparison group. It includes tables for each prespecified Primary Outcome and Secondary Outcome and may also include other prespecified outcomes, post hoc outcomes and appropriate statistical analyses.
   Adverse Events	Summary of all anticipated and unanticipated serious adverse events and a tabular summary of anticipated and unanticipated other adverse events exceeding a specific frequency threshold.

4. Preview, inspect and release (submit) the record. For a description of criteria that should be addressed before releasing (submitting) the record, see “ClinicalTrials.gov Results Review Criteria.”
5. When the record is released, an automated email will be sent to the UD PRS Administrator. Upon completion of the administrative review, which typically takes 3-5 business days, the UD PRS Administrator will approve and release the record to ClinicalTrials.gov, where a ClinicalTrials.gov staff member will review the record for quality control purposes prior to posting the results on the ClinicalTrials.gov website.
6. Resources for the submission of results:

    

   a. “Basic Results Data Element Definitions” contains descriptions of each required data item. b. Results data preparation checklists, simple results templates for each module, required data and a view of data elements in a tabular form are listed in the “Scientific Information” section of the “How to Submit Your Results” guidance on ClinicalTrials.gov. c. “Helpful Hints” contains tips on entering results data, including three examples of common study models (parallel design, crossover design and diagnostic accuracy studies) and measure types.

 

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For questions, send email to the University of Delaware Research Office.

 

Additional Information

• There is a link at the bottom of each page on clinicaltrials.gov to submit a ticket for help: “CONTACT NLM HELP DESK.”
• ClinicalTrials.gov may be contacted with questions or for guidance via email at register@clinicaltrials.gov.
  1. If the question is about a specific study record, please provide the NCT Number or the Unique Protocol ID (if an NCT Number has not yet been assigned).
  2. Be detailed in your request. ClinicalTrials.gov generally responds to all emails within one business day.

 

Please see ClinicalTrials.Gov Guidance & Procedures here.

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For questions, send email to: clinicaltrials@udel.edu.