FDA Warning Letter Regarding the Failure to Submit INDs for the Conduct of Clinical Investigations 

with an Investigational Product that met the Definition of a Combined Product.

 

Inspections of clinical trials are conducted as a part of the U.S. Food and Drug Administration (FDA)’s Bioresearch Monitoring Program.  These inspections are designed to evaluate the conduct of research and to help ensure that the rights,   safety, and welfare of human subjects have been protected.  Below you will find a short summary of a warning letter issued because of the failure to submit an investigational new drug application.

 

Warning Letter to Dr. David M. Lubeck/Arbor Centers for EyeCare

 On November 18, 2022, the FDA issued a warning letter to Dr. David M. Lubeck/Arbor Centers for EyeCare.  The FDA officials inspected Dr. Lubeck study and concluded that the investigator did not adhere to the FDA regulations governing the conduct of clinical investigations and the protection of human subjects. Specifically, the investigator failed to submit an Investigational New Drug application (IND) for the conduct of a clinical investigation with investigational new drugs that is subject to 21 CFR 312.2(a) [21 CFR 312.20(a), 312.20(b), and 312.40(a)].

The FDA argued that the investigational product used in combination with another drug comprised  both a drug and a device components and was therefore a combination product within the meaning of section 503(g) of the FD&C Act (21 U.S.C. 353(g)).

Furthermore, the FDA underlined that because the primary mode of action of the investigational combination product was attributable to the product and because the product met the definition of a drug under section 201(g) of the FD&C Act, an IND was required for any clinical investigation of the investigational combination product used in such Protocol.

Among other important issues noted in this investigation was that the investigator did not wait the 30 days to enroll subjects in the study.  An IND does not go into effect upon FDA’s receipt of the IND submission. Rather an IND generally goes into effect 30 days after FDA receives the application, or on earlier notification by FDA that the clinical investigation in the IND may begin (21 CFR 312.40(b)). The FDA emphasized that FDA regulations require a sponsor to submit, and to have in effect, an IND before initiating a clinical investigation that must be conducted under an IND in accordance with 21 CFR 312.40.

For more details about the inspection of this study and the findings of the FDA please review the Warning Letter to Dr. Davd M. Lubeck.

Developing a Mobile Health App?

Updated FTC-HHS online tool helps developers understand which federal laws apply

 

 

The Federal Trade Commission (FTC) in conjunction with the Department of Health & Human Services (HHS) Office for Civil Rights (OCR), the HHS Office of the National Coordinator for Health Information Technology (ONC), and the Food and Drug Administration (FDA) have updated the Mobile Health App Interactive Tool. This tool is designed to help developers of health-related mobile apps understand what federal laws and regulations might apply to them.   The guidance tool asks developers a series of high-level questions about the nature of their app, including about its function, the data it collects, and the services it provides to users. Based on the developer’s answers to those questions, the guidance tool will point the app developer toward detailed information about certain federal laws that might apply to the app. These include the FTC Act, the FTC’s Health Breach Notification Rule, the Children’s Online Privacy Protection Act (COPPA), the Health Insurance Portability and Accountability Act (HIPAA), the Federal Food, Drug and Cosmetics Act (FD&C Act), and the 21st Century Cures Act and ONC Information Blocking Regulations.

 

Developers and others seeking more information about how the HIPAA Rules might apply to their health apps should visit OCR’s HIPAA and Health Apps page, which contains information on how HIPAA applies to a range of example health app scenarios and offers key questions to consider in determining when HIPAA’s regulations cover a particular health app.

 

IRB Forms – Update

The following forms were updated in the IRB website:

1. Sample Cover Letter for a Survey Study.docx (09/02/2022)
2. Application Checklist for Initial and Continuing Review Full Board.docx (09/02/2022 – New Contact Information for Institutional Biosafety Committee )
3. Application Checklist – Single Patient Expanded Access .docx(9/22/2022)
4. Request for Exemption Form .doc(09/30/2022)
5. Guidance for Completing Continuation Form.docx (10/12/2022)
6. Guidance for Preparing a Chart Review Study .docx(10/12/2022)
7. HIPAA Authorization to Use and Disclose – Spanish.doc (11/7/2022)

 

The following forms were added to the IRB website:

 

• Instructions for Facilitated Review for Collaborative Research with Neighboring Facility .docx(10/12/2022)

• Request for UConn Health as a Recruitment Site -Without Engagement(12/14/2022)

 

The following educational resources were added to the IRB website:

• NIH Policy for Data Management and Sharing (effective 1/25/2023)
• NIH Guide for Writing a Data Management & Sharing Plan
• Data Storage Finder (tool from Cornell University)

 

National Institute of Health (NIH) Policy for Data Management and Sharing

Investigators Resources

 

 

The National Institute of Health (NIH) has posted a one-page handout “The Who, What, Where and When of the NIH Data Management and Sharing (DMS) Policy” summarizing the most important information for investigators regarding the NIH Policy for Data Management and Sharing.  Click on the image to go to their website and explore the info/links in the handout.

 

The University of Pennsylvania has shared the following resources on its website to aid investigators to comply with the National Institute of Health (NIH) Policy for Data Management and Sharing

 

• DMS Plan Format Page

NIH’s checklist that walks researchers through the elements of a DMSP

• NIH FAQs on the DMSP

NIH is constantly updating its FAQ page on the DMSP. Check back for your questions.

• NIH Webinars

Includes NIH webinar recordings and registration information for upcoming presentations.

• NIH Guidance for Informed Consent

Provides points to consider and sample language for informed consent documents of research studies which plan to store and share data and/ or biospecimens for future use.

• DMPTool Guide

Penn Libraries uses DMPTool to assist with writing data management plans. DMPTool is a resource researchers can use to draft data management plans. The new NIH DMSP template is available in the tool. We can provide comments on your DMSP if you need assistance. See our contact information on this page.

• NIMH Sample DMSPs

The National Institute of Mental Health (NIMH) has developed four example DMSPs that are consistent with NIMH and NIH requirements.

• NIH Institute and Center Data Sharing Policies

NIH institutes and centers may have other data sharing requirements in addition to the NIH DMS Policy. Make sure to read your applicable policy carefully.

• NIH DMS Policy: Applicable Activity Code

A comprehensive listing of all NIH activity codes that generally require applicants to submit a Data Management & Sharing Plan

• ICPSR’s Guide to Sharing NIH Data

Provides an overview of ICPSR’s NIH funded archives and recommendations for designating ICPSR for your data to meet the requirements of the NIH DMSP.

• Working Group on NIH DMSP Guidance

Created by librarians and other research support professionals, this working group has created a variety of resources that researchers can use to prepare for the NIH DMS Policy implementation. Resources include glossaries, a DMSP checklist for researchers, and an example DMSP for the 2023 expectations.

• Ten simple rules for maximizing the recommendations of the NIH data management and sharing plan

Recent article on the NIH DMSP policy that covers 10 key recommendations for creating a DMSP that is both maximally compliant and effective.

• Data Management Resources

Research Data & Digital Scholarship Data Sharing Services

NIH Repositories

 

Cornell University has excellent resources and tools on its website to aid investigators to comply with the National Institute of Health (NIH) Policy for Data Management and Sharing.

 

In addition, the NIH National Library of Medicine has posted the following resources:

 

• NIH CDE Repository
• NIH Data Sharing Repositories
• NIH Data Sharing Policies

 

 

Office of Human Research Protection (OHRP) Luminaries Lectures Series

Educational Resources for Investigators

 

The Office of Human Research Protection  Luminaries Lectures Series features videos by esteemed individuals with thought-provoking insights on diverse aspects of human research protections.

Some of the recently added videos are listed below.  These videos are covering the challenges of research during public health emergencies and research studying usual care practices, as well as thoughts from representatives in the research community on how to promote diversity and engagement in research participation:

• “The Covid Drug Wars” – What We Learned from the Front Lines
• “Unusual Practices Masquerading as Usual Care”
• “Vulnerability, Justice, Equity, and Engagement: A Conversation About Public Health and Human Subjects Research”

Click here and start watching!

 

Changes in the HSPP/IRB

  

Administrative Manager and Deputy Director of HSPP: Julia Blair has been named Administrative Manager of the HSPP, after filling the role on an interim basis since June following Deb Gibb’s retirement.  She can be reached at jblair@uchc.edu and (860) 679-7555.

 

HSPP- July, August, September, 2022 – Newsletter

Revision to Exemption Category 4 (iii)

To ensure the protection of identifiable private information (IPI) at UConn Health in compliance with The Privacy Rule, the HSPP will limit use of the exemption 45 CFR 46.104(d)(4)(iii):
Secondary research uses of identifiable private information, [when] the research involves only information collection and analysis involving the investigator’s use of identifiable health information (not biospecimens) when that use is regulated under [HIPAA].
Exemption 4(iii) applies to secondary research ‘use’ of the IPI which is protected under HIPAA, however the release, transfer or provision of access to a non-covered entity / third party would constitute a ‘disclosure’ where the IPI is no longer protected and the exemption would not apply.
Effective October 1, 2022, to ensure compliance with HIPAA and the Common Rule (45 CFR 46), the UConn Health HSPP will restrict the use of exempt category 4(iii) to studies where the Principal Investigator is UConn Health faculty (whose home/primary institution is UConn Health) and the data is not shared outside UConn Health or with non-UConn Health personnel.
New applications to the IRB seeking approval for secondary research use of identifiable private information which do not qualify for exemption under category 4 should request expedited review by the IRB. More information on exempt and expedited submissions can be found on the HSPP website or by contacting the HSPP Education Specialist, Mayra Cagganello at x8802 or cagganello@uchc.edu.

 

National Institute of Health (NIH) Policy for Data Management and Sharing

The National Institute of Health (NIH) Data Management and Sharing policy was published on October 29, 2020, and will go into effect on January 25, 2023. The two year delay in implementation was planned to give time to institutions to learn and prepare for enactment of the policy.

This policy applies to all research funded (in whole, or in part) or conducted by NIH that results in generation of scientific data. The goal of this NIH Data Management and Sharing policy is to benefit everyone, namely investigators, funding agencies, the scientific community, and, most importantly, the public. Data sharing provides more effective use of NIH resources by avoiding unnecessary duplication of data collection. It also conserves research funds to support more investigators. As stated in this policy “data sharing enables researchers to rigorously test the validity of research findings, strengthen analyses through combined datasets, re-use hard-to-generate data, and explore new frontiers of discovery.”

The NIH DMS Policy requires researchers to submit a plan to preserve, to share the data and to show compliance with said plan.

The NIH has made available multiple educational materials to inform and educate researchers about this policy at sharing.nih.gov. Below please find the links to the webinars

Webinar I: Understanding the New NIH Data Management and Sharing Policy –
o Resource Slide Deck
o Webinar Recording

Webinar II: Diving Deeper into the New NIH Data Management and Sharing Policy
o Resource Slide Deck

To access the frequently asked questions regarding this policy please click on 2023 Data Management & Sharing Policy

Uconn Health – Research Participant Feedback Form
Now available in Redcap

The Human Subjects Protection Program (HSPP) is responsible for ensuring that studies are conducted in compliance with internal policies, federal regulations and ethical standards. When research participants complete and submit a Research Participant Feedback Form, the HSPP is able to learn about the study volunteer experiences.

Participants can access the Research Participant Feedback form in two ways:
1) Download the form from the IRB website at http://research.uchc.edu/rcs/hspp/volunteers/. Forms must be completed and emailed or faxed following the instructions on the form.
2) *NEW* Research participants may submit this form electronically by accessing the REDCap form at https://redcap.link/UConnHealth-Feedback-Research from a computer or mobile device.

The IRB and HSPP encourage the research community to help research volunteers to complete this form.

IRB Forms – Update

The following updates have been made to IRB forms:

Added new contact information to the following forms:
• Application Checklist for Initial and Continuing Review Full Board.docx (09/02/2022 – New Contact Information for Institutional Biosafety Committee)
• IRB Website : Related Departments and Committees-
Institutional Biosafety Committee (IBC): Investigators must obtain approval from the IBC prior to seeking local IRB approval for research studies that deal with recombinant DNA. Investigators may contact Vijayasmitha Rayadurg in the Office of Research Safety for additional information.

Added new template language to the following form:
• Sample Cover Letter for a Survey Study.docx (09/02/2022)

Changes to the Requests for Exemption form to limit Exempt Category 4 (iii) to researchers and activities internal to UConn Health.

• Request for Exemption Form .doc (09/30/2022)

 

Continuing Review Guidance

Considerations for When the IRB Evaluates the Progress of a Research Study

According to Robert J. Amdur & Elizabeth A. Bankert. IRB Management and Function. 2nd Edition., Jones & Bartlett, 2006, “Continuing review is a monitoring mechanism that assures that continuing safeguards are in place to protect the rights and welfares of research participants.”

When a Protocol/study is submitted for renewal or continuing review the investigator is to report the study progress and findings. When conducting the continuing review, OHRP recommends that IRBs evaluate the following issues to determine whether the study’s approval should be renewed:

Consistent with the IRB-approved Protocol
The IRB should confirm that the information provided by the investigator at the time of continuing review is consistent with the research protocol previously approved by the IRB.

Total Subject Enrollment
Evaluating information about the number of subjects enrolled in the research at the time of continuing review may allow the IRB to ascertain whether enrollment is consistent with the planned number of subjects described in the IRB-approved protocol. Has accrual progressed as planned? If not, will this affect the ability of the researchers to complete the study?

A marked difference between the actual and expected rates of enrollment may indicate a problem with the research project that requires further evaluation, including whether the research project is likely to provide sufficient data to answer the scientific question(s) being posed.

Subject Withdrawals
Subjects may discontinue their participation in research at any point for various reasons (e.g., serious adverse events, conflicts with the investigators, transportation problems, etc.).
The IRB’s continuing review procedures in general should provide for review of:
• The number of subjects who discontinued their participation; and
• A summary of the reasons for the withdrawals, if known.
IRB review of this information may shed light on problems related to the conduct of the research.

To provide an accurate account of the enrollment data, UCONN Health IRB recommends that prior to completing a Continuation form in the iRIS submission system, the Principal Investigator should have the enrollment information for the study available. If this is not the first request for continuation (e.g. study has been open form more than one year), the enrollment data should build off of the previously submitted request for continuation. Investigators should use the enrollment data in the previously approved continuation form as a starting point. The Enrollment Guidance.docx should be reviewed to provide an accurate account of enrollment numbers, screen failures or withdrawals.

Office of Human Research Protection (OHRP) – Resources
Luminaries Lecture Series

OHRP continues to add new videos to help the research community learn about multiple topics.
Click here to view the latest videos of distinguished speakers from OHRP’s Research Community Forum co-sponsored with Northwell Health this past May.
New additions include:
• The COVID Drug Wars That Pitted Doctor vs. Doctor
• Improving Health Equity in Clinical Research
• Vulnerability, Justice, Equity, and Engagement, A Conversation Public Health and Human Subjects Research
• Unusual Practices Masquerading as Usual Care

HSPP Newsletter – April, May, June, 2022

 

FDA Warning Letter Regarding the Failure to Ensure IRB Continuing Review and Approval of Protocol

Inspections of clinical trials are conducted as a part of the U.S. Food and Drug Administration (FDA)’s Bioresearch Monitoring Program.  These inspections are designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected.  Below you will find a short summary of a warning letter issued because of the failure to obtain continuing review of a study and failure to perform study procedures as required by the protocol.

 

Warning letter to Sabine S. Hazan, M.D.

On February 28, 2022, the FDA issued a warning letter to Dr. Hazan.  The FDA officials who inspected the study concluded that the investigator did not adhere to the FDA regulations governing the conduct of clinical investigations and the protection of human subjects.  Dr. Hazan failed to obtain continuing review and approval for her study.  Specifically, her study IRB approval lapsed. During the course of this lapsed period, she enrolled and randomized subjects into the protocol, and administered investigational drugs to subjects. In addition, she was unable to provide a corrective action plan to prevent the recurrence of this type of violation in the future.

The FDA emphasized that the failure to ensure continuing IRB review and approval, impeded the IRB’s ability to determine the adequacy of the application to conduct the protocol.  This raised significant concerns about the extent to which subjects’ rights and welfare were protected at that site during the lapse in approval.

For more details about the inspection of this study and the findings of the FDA please review the Warning Letter – Sabine S. Hazan, M.D. February 28, 2022

 

 Warning letter to Smitha C. Reddy, M.D. / ACRC Studies, LLC

On May 27, 2022, the FDA issued a warning letter to Dr. Reddy.  The FDA officials who inspected the study concluded that the study as it was implemented raised significant concerns about the safety of subjects enrolled and the reliability of data at that site.

Dr. Reddy failed to ensure that the investigation was conducted according to the investigational plan. Specifically, the investigator did not ensure subjects randomized to an assigned treatment arm received the correct drug for that group, and there was a failure to adhere to procedures for the blinding of staff.

The FDA emphasized that the principal investigator is ultimately responsible to ensure that the study is conducted properly and in compliance with FDA regulations, both to protect the rights, safety, and welfare of study subjects and to ensure the integrity of study data.  Additionally, the FDA required corrective actions to include retraining of the investigator on study drug administration, not just study staff.

For more details about the inspection of this study and the findings of the FDA please review the FDA Warning letter to Smitha C. Reddy, M.D./ACRC Studies, LLC

Office of Human Research Protection (OHRP) – Resources

 

The Office of Human Research Protection (OHRP) has launched two interactive programs to help explain the expectations for investigators in applying the Common Rule review criteria of equitable selection of subjects in research and minimizing research risks for participants. These resources are valuable for investigators to understand and fulfill these specific requirements for protecting human participants in research.

To access these interactive programs click on links below.

Equitable Selection of Subjects : This is a 30-minute scenario which examines how investigators could apply the concept of equitable selection of subjects in research

Minimizing Risks in Research : This is a 30-minutes scenario which examines the concept of research risks and how these risks to participants could be identified and minimized.

 

Human Subjects Training – Frequently Asked Questions

 

 I am a new resident/student at UCONN Health and I completed CITI Training under my affiliation with a former institution.  Is that CITI Certificate valid at UConn Health?

If an individual is to be included in an IRB application and that person has recently become affiliated to UConn Health (e.g. a new student), that person should attach the CITI Training certificate completed under his/her former affiliation.  If the courses previously completed are comparable to the ones required by UCONN Health IRB that individual will not need to complete additional training.  If not, he/she must complete training under his/her affiliation to UConn Health.  The CITI Program will give credit for any modules he/she have completed under other institution’s affiliation and will require completion of modules that are specific to UConn Health.

To affiliate an account in the CITI Program with UConn Health, individuals should log into the CITI program, and click on “Add Affiliation” listed under the “Courses” Menu.  To

find UConn Health in the drop down box, the following words “University of Connecticut“ must be typed.  Then, select “University of Connecticut Heath Center”.  To complete the process, check the box next to the statement: “I AGREE to the Terms of Service for accessing CITI Program materials”   and check the box with the statement: “I affirm that I am an affiliate of University of Connecticut Heath Center.” Last, click on “Continue.”

To select the correct learning group and courses, follow the “Course Enrollment Questions” posted at  https://ovpr.uchc.edu/services/rics/hspp/citi-instructions/

 

Recent Articles Published by a Central IRB

 

ADVARRA IRB:  

 What do I do about Incidental Findings in Research? If you are conducting research that has a potential to uncover an incidental finding, it is best to plan ahead for how you’ll treat the result and if you plan to return that result to a participant. This article describes the plans and consideration to communicate incidental findings to research participants.

eClinical Regulatory Trends Impacting Clinical Research   For the past two years, the clinical research industry has seen an acceleration in staff shifting to a remote, work from home model. While this was initially in an effort to keep everyone safer from the COVID-19 pandemic, many organizations are permanently moving toward a remote or hybrid work model for their staff.  This article discusses how has this shaped current regulatory trends, the benefits of eClinical suite, and the consideration when adopting an eClinical suite.

 

IRB Forms – Update

Added new contact information to the following forms:

• Human Subject Research Determination Form.doc
• dbGaP Access Request Form for IRB Certification.docx
• Participant Feedback Form.doc
• Participant Feedback Form in Spanish.docx
• HIPPA Assurance of Preparatory to Research or Decedent Research .doc
• Instructions for Students Residents or Fellows Doing Research_at_Hartford HealthCare_or_CT Children’s Medical Center.docx

Added Federal required Overview section to:

• Sample Consent for Registry (05/10/2022).doc

 

Upcoming changes in at the HSPP/IRB and the OVPR

 

• Vice President for Research: Dr. Pamir Alpay has been appointed Interim Vice President for Research, Innovation & Entrepreneurship while Dr. Radenka Maric is serving as Interim President of the University of Connecticut.
• Associate VPR and Institution Official: Dr. Victor Hesselbrock has been named Interim Associate Vice President for Research Integrity and Regulatory Affairs and Institution Official following Dr. Byerly’s departure.
• Manager and Deputy Director of HSPP: Deb Gibb retired June 1, after 19 years with the HSPP.  Julia Blair will serve as interim manager of the HSPP.

 

HSPP – January, February, March, 2022- Newsletter

 

How to Write a Low Literacy Informed Consent Form

Obtaining informed consent in non-exempt research is a process required by federal regulations –the U.S Department of Health and Human Services ( HHS) at 45 CFR 46 and the U.S. Food and Drug Administration (FDA) at 21 CFR 50.   The consent process typically includes providing a written consent document containing the required information along with an oral presentation of that information to prospective participants. However, for a consent process to empower individuals to voluntarily participate in a study or not, the information in the consent document must be presented in a language they can understand.   The readability of a consent form is essential to enable potential participants to have sufficient comprehension of the elements that facilitate a decision. The language used in consent forms should not be complex.   An 8^th grade reading level is the suggested benchmark to use as the readability index.

Investigators conducting clinical trials should consider literacy of potential participants when preparing consent documents.

John Hopkins Office of Human Subjects Research  and Elizabeth Winslow offers the following guidance for preparing consent forms:

 

• Recommendations to lower the reading level of consent forms:

 Words

• Use words familiar to the non-medical reader.
• If possible, keep words to 2- 3 syllables or fewer.
• Use common, familiar words

Sentences/Paragraphs/Print Size & Type:

• Write short, simple, and direct sentences.
• Keep paragraphs short and limited to one idea.
• Use active verbs.
• Use the second person (you) not third person (the participant) to increase personal identification.
• Avoid contractions.
• Use page numbers
• Use at least 12-point font and consider a larger font based on your audience.
• Check the text to see if each idea is clear and logically sequential.
• Avoid large blocks of printed text.

 Avoid Complex Medical Terminology

• Avoid medical Terminology. If a medical term must be used, define /explain it
• Be consistent with use of all terminology, such as drug names and abbreviations.
• Use the appropriate abbreviation the first time a drug name is used in the consent.

 Abbreviations:

• Spell out abbreviated terms the first time you use them
• Abbreviation terms such as DNA, HIV and AIDS that have come to be accepted as standard by your proposed study population need not be spelled out.
• Do not use e.g. or etc., use instead, “for example,” “so forth.”
• Spell out acronyms when first used.

 Pictures

• Use photos, graphics, tables, illustrations or diagrams if they will help clarify procedures.

Numbers

• Use numerals rather than words for numbers, e.g., “10” instead of “ten,” “1 out of 4” instead of “one out of four.”

 

Tips to Describe Study Procedures

• Consent forms for projects that involve collection of blood or other fluids should include the amount(s) to be taken.  Do not use ml. or cc. as a volume measure; give a volume equivalent in teaspoons or tablespoons. Rather than abbreviating such words as teaspoon and tablespoon, please spell them out.
• Do not use symbols such as “>”; use “greater than.”
• Describe study design procedures such as “double blind,” “randomized,” and “placebo/controlled” when the concept(s) is/are first introduced. Example: “A placebo is an inactive substance that looks like the study drug, but contains no medication.”
• Do not use the words “treatment” or “therapy” to describe an investigational drug, device or procedure. Use the term “study drug” not “study medication” when the drug is investigational.  The word “medication” or “medicine” should only be used if the drug is commercially available for that particular condition.
• Do not use the term “treatment” or “therapy”” if one of the study arms will be a placebo. Instead, use words like: “study product”, “study drug or placebo”,  “study regimen” or “study procedure
• Do not describe investigational drugs, devices or procedures as “new.”For investigational drugs or devices, state they are investigational or “experimental” and describe that term (e.g., the word “investigational” means the study drug is not approved by the U. S. Food and Drug Administration (FDA) and is still being tested in research studies.) Be consistent in using “investigational” throughout the consent form.
• Use “research study,” instead of “trial.”
• Use the word “participant” in the consent form instead of “patient” since this is research.  However, you may use “patient” when referring to the person prior to his/her entering the study.
• When describing randomization for 2 groups use, “like the flip of a coin,” for more than 2 groups, use “like drawing numbers from a hat.”

To check the grade level of a consent document, the investigator can implement the following steps. 

For Microsoft Word:

1. on the “File” tab, click the “Options” button;
2. on the “Proofing” tab, under “When correcting spelling and grammar in Word”, make sure “Check grammar with spelling” is selected;
3. under “When correcting spelling and grammar in Word”, select the “Show readability statistics” check box.  Click on OK
4. Click on the “Review Tab”
5. Click on “Spelling & Grammar”

After the grammar check is complete, Word displays a message box showing you the readability grade-level.

 

D- The following websites and word substitution file are helpful for drafting consent forms:

1. a)  Glossary of medical words: (http://kidshealth.org/kid/word/)
   b)  Clinical Research Glossary: (http://www.firstclinical.com/icfglossary/)
   c)  Glossary of lay terms: (http://humansubjects.stanford.edu/general/glossary.html)

 

• The following Checklist for Low Literacy Informed Consent Forms .pdf has been posted in the UCONN Health IRB website

 

 

Checklist How to write a Low Literacy Informed Consent Form
Recommendations to lower the reading level of consent forms	Check
Words
Use words familiar to the non-medical reader
If possible, keep words to 2- 3 syllables or fewer
Use common, familiar words
Sentences/Paragraphs/Print Size & Type
Write short, simple, and direct sentences
Keep paragraphs short and limited to one idea
Use active verbs
Use the second person (you) not third person (the participant) to increase personal identification
Avoid contractions
Use page numbers
Use at least 12-point font and consider a larger font based on your audience
Check the text to see if each idea is clear and logically sequential
Avoid large blocks of printed text
Avoid Complex Medical Terminology
Avoid medical terminology. If a medical term must be used, define/explain it
Be consistent with use of all terminology, such as drug names and abbreviations
Use the appropriate abbreviation the first time a drug name is used in the consent
Abbreviations
Spell out abbreviated terms the first time you use them
Abbreviated terms such as DNA, HIV and AIDS that have come to be accepted as standard by your proposed study population need not be spelled out
Do not use e.g. or etc., use instead, “for example,” “so forth.”
Spell out acronyms when first used
Pictures
Use photos, graphics, tables, illustrations or diagrams if they will help clarify procedures
Numbers
Use numerals rather than words for numbers, e.g., “10” instead of “ten,”  “1 out of 4” instead of “one out of four.”
Tips to Describe Study Procedures
Consent forms for projects that involve collection of blood or other fluids should include the amount(s) to be taken.  Do not use ml. or cc. as a volume measure; give a volume equivalent in teaspoons or tablespoons. Rather than abbreviating such words as teaspoon and tablespoon, please spell them out.

 

Checklist How to write a Low Literacy Informed Consent Form
Tips to Describe Study Procedures	Check
Do not use symbols such as “>”; use “greater than.”
Describe study design procedures such as “double blind,” “randomized,” and “placebo/controlled” when the concept(s) is/are first introduced. Example: “A placebo is an inactive substance that looks like the study drug, but contains no medication.”
Do not use the words “treatment” or “therapy” to describe an investigational drug, device or procedure. Use the term “study drug” not “study medication” when the drug is investigational.  The word “medication” or “medicine” should only be used if the drug is commercially available for that particular condition
Do not use the term “treatment” or “therapy”” if one of the study arms will be a placebo. Instead, use words like: “study product”, “study drug or placebo”
Do not describe investigational drugs, devices or procedures as “new.” For investigational drugs or devices, state they are investigational or “experimental” and describe that term (e.g., the word “investigational” means the study drug is not approved by the U. S. Food and Drug Administration (FDA) and is still being tested in research studies.) Be consistent in using “investigational” throughout the consent form.
Use “research study,” instead of “trial.”
Use the word “participant” in the consent form instead of “patient” since this is research.  However, you may use “patient” when referring to the person prior to his/her entering the study.
When describing randomization for 2 groups use, “like the flip of a coin,” for more than 2 groups, use “like drawing numbers from a hat.”
To check the grade level of a consent document, the investigator can implement the following steps
For Microsoft Word: 1.    on the “File” tab, click the “Options” button; 2.    on the “Proofing” tab, under “When correcting spelling and grammar in Word”, make sure “Check grammar with spelling” is selected; 3.    under “When correcting spelling and grammar in Word”, select the “Show readability statistics” check box.  Click on OK 4.    Click on the “Review Tab” 5.    Click on “Spelling & Grammar” After the grammar check is complete, Word displays a message box showing you the readability grade-level.

 

 

ResearchMatch, an Online Recruitment Tool

 

ResearchMatch.org is a national online recruitment tool for health research, funded by the National Institutes of Health and maintained at Vanderbilt University. ResearchMatch connects health researchers with individuals interested in volunteering through its secure online matching tool, available in English and Spanish. UConn Health is part of the ResearchMatch Network and there is no cost to UConn Health researchers to use ResearchMatch. There are currently over 160,000 (and counting!) registered volunteers across the country.

 

To see if ResearchMatch might be useful to you, register now to conduct a feasibility analysis:

Register here: https://www.researchmatch.org/researchers/. (You do not need to be a Principal Investigator to register.) The registration process takes less than 10 minutes. Registration grants you “feasibility access” to search the current ResearchMatch volunteer population for demographic and health information of volunteers within a designated geographic area.

 Then, if you decide to use ResearchMatch to conduct participant recruitment, you will need IRB approval. Once approved, you may request “recruitment access” in ResearchMatch and upload your IRB approval letter and your IRB-approved contact message. Recruitment access will give you the ability to send your contact message to volunteers that you select. If a volunteer agrees, you will be given access to his/her contact information in order to contact about possible study participation.

 The next ResearchMatch Training is April 14, 2022 at 3:00 pm.

For questions about how to use ResearchMatch for your health research, please contact ResearchMatch Liaison, Ellen Ciesielski eciesielski@uchc.edu or visit https://ovpr.uchc.edu/services/rics/hspp/resources/researchmatch/.

 

 

Office of Human Research Protection (OHRP) – Resources

  

• OHRP New Informational Resource Flyer with its Very Own QR Code!

OHRP’s new Informational Resource Flyer includes a QR code allowing anyone with a smart phone access to a free online library of trusted resources about research and research participation. Print, display, and distribute this flyer at your centers for the benefit of prospective research participants!

Find the flyer here together with other informational materials (in English and Spanish) that you may wish to print and provide for potential research participants! These resources are free and you do not need permission to distribute them.

 

• New Interactive Training Programs on IRB Reviews!

OHRP launched two interactive training programs on considerations for reviewing and designing research involving human participants.

OHRP created these programs to enable investigators and IRB reviewers to be cognizant of the importance of diversity, inclusion, and risk minimization in research participation.

Click here to access our other scenarios!

 

• Recordings of OHRP Presentations on Human Subjects Research and Investigator Responsibilities for Protecting Participants in Research!

 

What is Human Subjects Research? A Review of the Common Rule and its Application provides helpful explanation on the complex concept of human subjects research and how to address related considerations in the NIH grant application process.

 What Investigators Need to Know About IRB Review helps investigators understand the thoughts and considerations needed for writing a successful plan to protect human research participants that would pass the muster of reviewers.

These videos will help investigators with the NIH grant application and IRB review process.

 

 

HSPP- October-November-December, 2021- Newsletter

 

FDA Warning Letter Regarding the Failure to Submit INDs for the Conduct of Clinical Investigations with an Investigational New Drug

 

Inspections of clinical trials are conducted as a part of the U.S. Food and Drug Administration (FDA)’s Bioresearch Monitoring Program.  These inspections are designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected.  Below you will find a short summary of warning letters issued because of the failure to submit investigational new drug applications.

 

Warning letter to Kaleido Biosciences, Inc

On September 7, 2021, the FDA issued a warning letter to Kaleido Biosciences, Inc.   The FDA officials inspected two of Kaleido’s studies and concluded that investigators did not adhere to the FDA regulations governing the conduct of clinical investigations and the protection of human subjects.

Kaleido investigators thought that the product used in their investigations was subject to regulations as medical food but not subject to regulations as a drug.  However, the FDA inspectors concluded that the product was intended for use as a drug, and not as a food.

The argument established by the FDA to support their conclusion is based in the definition of food vs a drug in the use of a clinical investigation.  The FDA argued that the purposes of this clinical investigation was to evaluate the efficacy of a food product as treatment of a disease and, consequently, the food in this trial was seen as a drug.   Therefore, use of the food product in the clinical trial is not exempt from the investigation new drug requirements.

For more details about the inspection of these studies and the findings of the FDA please review the warning letter to Kaleido Biosciences, Inc.

 

Warning letters  to Jon B. Cole, MD, and Lauren R. Klein, MD., MS.

The FDA regulations require a sponsor to submit, and to have in effect, an investigational new drug application (IND) before initiating a clinical investigation of a drug in human subjects, unless the clinical investigation qualifies for an exemption (see 21 CFR 312.20 and 312.40(a)).

The FDA determined that Dr. Cole  and Dr. Klein failed to comply with these requirements while using marketed drugs in two studies.

The investigators thought that an IND was not needed, and argued that the medications administered to subjects were not part of a research intervention but were provided only for clinical purposes.   In addition, the investigators stated that if their clinical investigations were subject to FDA jurisdiction, they met the criteria for exemption from the investigational new drug requirements.

Contrary to the investigators, the FDA auditors concluded that the studies were designed to study the safety and efficacy of those marketed drugs products. In addition, the FDA determined the drugs were not delivered in the course of medical practice, but for research purposes. “The FDA underlined that whenever an investigator limits his choices, his patients’ choices, and the choices of the people working for them in the treatment of patients, then he/she is conducting a clinical investigation. This is different from the practice of medicine, where the primary intent is to treat the individual patient.”

Moreover, the FDA inspectors determined these clinical investigations did not meet the criteria for exempt since these investigations increased the risks or decreased the acceptability of the risks associated with the use of the drug products.

For more details about the studies mentioned above, the FDA’s thinking regarding IND requirements for market drugs and FDA views of clinical use vs. clinical investigation, please click on the links to the warning letters seen below:

• Warning letter to Jon B. Cole, MD
• Warning letter to Lauren R. Klein, MD., MS

  

Medical Devices

 Medical device products are regulated by the FDA’s Center for Medical Devices and Radiological Health (CDRH).  Depending on the device classification and other factors, the Code of Federal Regulations, Title 21, defines the requirements to approve or clear devices sold in the United States.

Investigators planning to conduct research with medical devices should learn the FDA status of a device.  The investigator should determine whether the device has been approved, cleared for marketing, or whether it is an investigational device. When used in research it is important that the informed consent form accurately identify the type of device being used as approved, cleared, or investigational (see FDA guidance).

Reviewing the following information will allow investigators to understand the process by which the FDA classifies devices, clears devices, and approves devices. The sections below includes excerpts from the document titled Is it really FDA approved? and the FDA webpage on the Premarket Notification 510(k) clearance process.

 

Overview of Device Regulation

FDA classifies devices, or more accurately device types, in order to identify the degree of regulations for that product area.  Classification is based on two factors:  the device description/its physical characteristics, and the intended use.

FDA classifies devices into Class I, II, or III.  The class of the device generally increases with its degree of risk. Regulatory control increases from Class I to Class III. The device classification regulation defines the regulatory requirements for a general device type. Most Class I devices are exempt from Premarket Notification 510(k); most Class II devices require Premarket Notification 510(k); and most Class III devices require Premarket Approval.

A description of device classification and a link to the Product Classification Database is available at “Classification of Medical Devices.”  To learn more about how medical devices are classified, please watch the FDA educational video titled: How is my Medical Device Classified?

Note – A registration number with the FDA only means the FDA is aware of the manufacturer and device, and does not mean the device is ‘FDA cleared’ or ‘approved.’ (see more info here)

 

Cleared Devices

The FDA may clear a device for marketing through the 510(k) process, when the manufacturer demonstrates the device is substantially equivalent to a predicate device. A claim of substantial equivalence does not mean the device(s) must be identical. Substantial equivalence is established with respect to intended use, design, energy used or delivered, materials, performance, safety, effectiveness, labeling, biocompatibility, standards, and other applicable characteristics.  The 510K clearance process does not require submission of clinical data to support the claim.

A device which is “cleared” to market should not be deemed the same as a device that has been “approved” by the FDA through a Premarket Approval (PMA) application.

 

Approved Devices 

To receive FDA approval to market  devices, manufacturers must demonstrate with sufficient, valid scientific evidence (i.e., submitting clinical data to support a claim) that there is a reasonable assurance that the devices are safe and effective for their intended use.

 

Investigational Devices

An investigational medical device is one that is the subject of a clinical study designed to evaluate the effectiveness and/or safety of the device.  An application for an Investigational Device Exemption (IDE) is to be submitted by the Sponsor or investigator to use the investigational device/unapproved device in a clinical study.

Data collected during these clinical studies is to be included in a future marketing application. The IDE application enables manufacturers to ship a device from one state to another when conducting a clinical study on the device without being subject to most other provisions of the Federal Food, Drug, and Cosmetic Act.

An IDE application may also be required for a legally marketed device that has been modified and/or intended for a new use.

Clinical studies with investigational devices of significant risk must be approved by FDA and by an Institutional Review Board (IRB) before the study can begin. Studies with devices of no significant risk must be approved by the IRB only before the study can begin.

Investigators conducting research with medical devices are to include in their initial application and informed consent forms whether their devices are approved devices, cleared devices or investigational devices.

 

Inclusion of Certificate of Confidentiality Language in Consent Forms for NIH funded Studies

 

In October 2017, NIH updated its Policy for issuing Certificates of Confidentiality (Certificates or CoCs) for NIH-funded and conducted research. These Certificates protect the privacy of participants by limiting the disclosure of identifiable, sensitive information.

Informed consent forms of NIH funded studies must include the required language regarding the Certificate of Confidentiality (CoC) and the protections it offers. This requirement is already listed in the Main Consent Form Template .doc (page 8) and the Main Consent Form Checklist.doc  (Page 4)

More information about Certificates of Confidentiality is available at https://grants.nih.gov/policy/humansubjects/coc.htm

 

IRB Forms – Update

 

The submission checklists for IRB applications have been updated.

The updates include:

• Changing the point of contact for I.T. security
• Clarifying details regarding the need for letters of permission to conduct research
• Clarifying details regarding the FERPA verification form
• Clarifying details regarding the use of recruitment tag lines for on-line postings

 

HSPP- July-August-September, 2021- Newsletter

 

Informed Consent- Process & Documentation

 The informed consent process is one of the central components of the ethical conduct of non-exempt research with human subjects.  The consent process typically includes providing a written consent document containing the required information along with an oral presentation of that information to prospective participants.  The informed consent process involves the “who”, “what”, “when’, “where”, and “how” that results in a valid, and effective informed consent being obtained from a participant.

The following section presents a general overview of an effective informed consent process and its documentation. Exceptions to this process may be granted by the IRB.  Those exceptions are described in IRB policy 2011-008.2.pdf – Informed Consent – Waivers and Alterations.

 

Who can obtain consent?    

The Principal investigator or designated individuals listed on the materials approved by the IRB. Any personnel authorized to obtain consent must comply with human subjects protection training requirements.  Individuals who are approved to obtain consent must be knowledgeable of the protocol and prepared to answer questions that may be posed by the potential subjects.

Study personnel who will be obtaining consent should be familiar with the following IRB policies:

• 2011-008.0.pdf– Informed Consent – Forms
• 2011-008.1.pdf – Informed Consent – Process
• 2011-008.5.pdf – Informed Consent – Providing and Obtaining Informed Consent  

 

Who can provide consent? 

Consent is to be obtained from an individual who has authority to give consent.  If the prospective participant is an adult who has capacity to consent, it is that individual who should give consent.  When an individual is unable to consent on his or her own behalf, consent must be obtained from a person who has the authority to do so. Investigators should be aware of the provisions described in the IRB Policy 2011-008.5.pdf  regarding the conditions and requirements to obtain consent from adults, minors, and legally authorized representatives.

The study protocol and initial study application should identify who will be providing consent (i.e., adult subjects, legally authorized representative (LAR)).  If the individual to provide consent is a LAR, documentation of this status must be obtained except when the LAR is the parent of a participant who has not yet reached the age of majority, or attests to being the next of kin. One exception to the next of kin provision is that adults with intellectual disabilities who have been declared incompetent must have an appointed legal guardian provide consent to participate in research. The natural parents of the adult are not authorized to give permission unless they have been appointed legal guardian(s).

 

When Consent Process must occur?

An informed consent process must be conducted with a potential subject prior to any involvement of the subject in non-exempt research (e.g., prior to any procedures that are done solely for research purposes).  It must happen before any interaction/interventions to collect data to ensure that the subject has an appreciation for the study in which s/he may enroll.

The process of consent should continue throughout the study, for example by explaining  each visit as it occurs and ensuring the subject is still willing to participate, or by providing new information to subjects as it is learned to ensure they are still willing to participate.

 

Where Consent Process must occur?

The consent process must be conducted in a setting that affords sufficient privacy to the potential subject. Privacy refers to an individual’s desire to control who has access to him/herself. The setting where the potential participants will interact with the researcher team must be protected from access to the public.

 

What do you need to obtain Consent from a prospective participant?

The individual obtaining consent must present the subject with a written informed consent form that contains the key information that is most likely to assist a subject in understanding the research, what is expected of them, and the potential risks of harm and potential benefits, if any. The consent form must be written in a language that is understandable to the subject or subject’s LAR, and should be written in lay language using an 8^th grade literacy level as a benchmark.  The informed consent template and informed consent checklists available on the IRB website should be used to ensure the consent document contains the regulatory and local required elements of consent.

The individual obtaining consent should ensure that the most recently approved and stamped version of the consent form is used when obtaining consent.

 

 How should a consent process be conducted?

The Principal investigator must describe the proposed process of consent in the material provided to the IRB.

This process should begin with allowing the potential subject time to review the consent document, and then a discussion of the key elements of a research study in the subject-preferred language.

The process must be free of any coercion (e.g. a threat of something bad happening if the subject declines participation), and free of undue influence (e.g. a sense of pressure to say yes, because the person obtaining consent is also the clinical provider).  The subject must receive the following information:

• that consent is being sought for research and participation is voluntary;
• the purpose of research;
• expected duration of participation and procedures to be followed;
• the risks or discomforts and the potential for benefits to the prospective subject or to others; and
• the appropriate alternatives procedures or courses of treatment, if any, that might be advantageous to the prospective subject.

The consenter should provide ample time for questions, and may ask the subject questions about the research to assess his/her understanding of the study.

In most cases, unless the IRB has waived the requirement to document consent, at the conclusion of the consent process and after the subject has decided to participate, investigators are to obtain a signature and date of signature from the participant on an IRB approved informed consent document.  The IRB also require that the person obtaining consent sign and date the form.  At this time, a copy of the signed and dated consent form must be provided to the subject along with the Research Participant Feedback Form

The original signed consent form must be stored in accordance with the plans for storage described in the study application and protocol (e.g., consent form is to be filed in a research folder, or in separate secure location apart from research record, or in the medical record).

Notes in a research chart indicating on-going discussions with the subject at subsequent study visits may supplement documentation of the informed consent process.

 

Educational Resources for Investigators at UConn Health – Informed Consent Process and Documentation

Checklist and Weekly WebEx Sessions

 

Investigators may use this Self-Audit /Checklist tool along with the IRB Policies listed above to ensure the consent process and its documentation comply with UConn Health IRB Policies.

 

SELF -AUDIT TOOL/CHECKLIST
INFORMED CONSENT PROCESS & DOCUMENTATION	Consenter Initials
The consent process was conducted using the latest approved and stamped consent form
The consent process occurred in a private setting
The consent process was conducted in a language understandable to the  subject
The consent process started with a potential participant being given the opportunity to review the informed consent form and it was followed by a discussion about the research
The process was  free of coercion or undue influence
The process provided the subject, sufficient time to discuss, ask questions and consider whether or not to participate
Once the subject had all his/her questions answered and had ample time to consider the information s/he decided whether or not to participate.
If documentation of consent was not waived by the IRB (e.g., informed consent form contains signature lines) informed consent process was documented in an IRB approved informed consent form.
The consent form was signed and dated by the subject (or legally authorized representative) in the section assigned to the participant
The consent form was signed and dated by the investigator in the section assigned to the investigator
All names, signatures and dates were entered in the document on the same date and at the same time
After the signatures were entered in the consent form the participant was  provided with a copy of the complete signed informed consent document
At the conclusion of the consent process, the investigator provided a Research Participant Feedback form to the subjects.
The signed consent form has been stored in accordance with the plans for storage described in the study application and protocol (e.g., consent form was filed in research folder, or in separate secure location apart from research record, or in the medical record).

 

The HSPP is offering a one-hour WebEx “Informed Consent Process and Documentation” education session every Thursday and Friday at noon time for study coordinators, investigators, first time principal investigator, and students who plan to conduct Human Subjects Research at UConn Health.  To register for these sessions please email Mayra Cagganello at cagganello@uchc.edu

 

Educational Resources for Investigators –OHRP –Simplifying Informed Consent Video

 The Office of Human Research Protection (OHRP) has posted a video titled: “Simplifying Informed Consent.”  In this video OHRP representatives discuss what goes into a meaningful informed consent. Practical examples are used to illustrate how to discern meaningful information for potential participants, and how to present information simply in consent documents and materials to ensure consent processes fulfill their goal of enabling potential participants to make informed decisions about whether to participate in the research.

To access this Simplifying Informed Consent video please click here

 

 

Informed Consent – Process & Documentation – Frequently Asked Questions

  

Why do I need to use the Main Consent Form Checklist to create my Consent Form?

UConn Health IRB created and posted the Main Consent Form Checklist .doc to assist investigators and research staff when creating consent documents. This checklist outlines the basic and additional elements of a consent form.

Although, not all elements of the informed consent form template will be required for every study, as applicable to a study, the IRB recommends inclusion of all relevant elements noted on this form and reserves the right to require additional elements.

In addition, as applicable to the study design, investigators must use additional consent checklists along with the above one when creating their Consent forms.    For example, if the study involves genetic research the investigator must also complete the Consent Checklist – Genetic Research Addendum If the research involves the use of stem cells  the Consent Checklist – Stem Cell Research Addendum.doc must also be used.  When funding for a study comes from the National Institute of Justice, the Consent Checklist – National Institute of Justice Requirements Addendum.doc. must be used along with the main consent checklist.

 

Do I need to use the Consent Form Template?

UConn Health IRB created and posted the Main Consent Form Template .doc  to assist investigators and research staff when creating consent documents.  The IRB strongly recommends investigators to use the standard UConn Health Main Consent Form Template .doc  because this template contains all the basic elements, and is tailored to multiple study designs (e.g., consent for federal funded research, consent for genetic research, consent for research subject to FDA oversight). However, this template may not cover all nuances for various studies.  You may need to add, delete and/or edit sections to make them applicable to your study.

  

What should I do if I realized I have not documented the consent process correctly (e.g., the subject did not incorporate the date when signing the Informed Consent Form)?

In the event that an informed consent (IC) form is found to be undated, if the error is not discovered while the subject is present, the research staff should prepare a note to file attesting to the fact that they witnessed the signing of the form, and the date that it was witnessed.

Since this incident was under the control of the study team, this event should be reported to the IRB within 5 days of becoming aware of the non-compliance.  The investigator should complete and submit a problem report form via iRIS system.

To avoid this type of issues, investigators obtaining consent should review the IC forms once they are signed/completed, and before the subject leaves that day to ensure that all signatures and dates are properly entered on the forms.

 

Who may provide consent when a subject is unable to provide consent?

When a potential subject is unable to provide consent because of impaired competency, consent must be obtained from a legally authorized representative (LAR) of the subject. Documentation of this status must be obtained except when the LAR is the parent of a participant who has not yet reached the age of majority, or attests to being the next of kin. One exception to the next of kin provision is that adults with intellectual disabilities who have been declared incompetent must have an appointed legal guardian provide consent to participate in research. The natural parents of the adult are not authorized to give permission unless they have been appointed legal guardian(s).

The investigator obtaining consent from a LAR must be knowledgeable of the IRB Policy 2011-008.5.pdf – “Informed Consent – Providing and Obtaining Informed Consent” which describe in detail who in Connecticut meet the definition of a legally authorized representative.

 

How far in advance of research participation, can informed consent be obtained?

The U.S. Department of Health & Human Services (HHS) do not identify how far in advance of study entry a subject can provide consent. They explain that the amount of time required by a subject to make a decision would presumably depend on the nature of the study, taking into account, among other factors, the degree of risk, potential benefits, alternatives, and desire to consult with family members or others. HHS recommends reviewing the information contained in the consent form with the subject again if a prolonged period elapses from the date of consent to the date of entry into the study.

 

 FDA Regulated Studies -Compliance with 21 CFR Part 11

 Title 21 CFR Part 11 is the portion of the Code of Federal Regulations that provides standards determined by the Food and Drug Administration (FDA) on electronic records and electronic signatures.   During the COVID-19 pandemic, an FDA enforcement discretion of Part 11 was implemented, which is still in effect.  However, this enforcement discretion will eventually end.

If any FDA regulated studies at UConn Health are using work-around solutions from the FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency these systems will need to be discontinued when the Public Health Emergency is declared over.

 

FDA Sends Warning Letter to Individual Investigator for  Clinicaltrials.gov Non-Compliance

 For the first time, the FDA sent a warning letter to a principal investigator for a ClinicalTrials.gov record that was not updated in accordance with the law. Civil money penalties currently stand at $12,316 per day until the violation is corrected. Previous warning letters were sent to industry sponsors, but this is the first time the FDA has sent a letter to an individual investigator for non-compliance.

For any questions related to ClinicalTrials.gov, please contact UConn Health’s ClinicalTrials.gov Administrator, Ellen Ciesielski (eciesielski@uchc.edu) for assistance.

 

HSPP- April-May-June, 2021- Newsletter

  

What is Exempt Human Subjects Research?

 

Exempt human subject research is a project that does constitute human subjects research but is exempt/excused from satisfying the requirements of the Department of Health and Human Services (HHS) policy for the protection of human research.  Research activities that involves no more than minimal risk are exempt from the human research protection regulations when the only involvement of human subjects falls within one or more of the exempt categories described in the Request for Exemption Form .doc. While the research may be exempt from certain regulatory requirements, human subject protections, such as plans for protection of privacy and confidentiality of data, are still applied per accreditation standards and internal policies.

As per UConn Health’s Human Subjects Protection Program Policy 2011-009.2.pdf – Institutional Review Board – Exemptions, investigators cannot make the determination as to whether a human research project meets the criteria of exempt research.  This determination is to be made by the Institutional Review Board (IRB).

To aid those who need to decide if an activity is research involving human subjects that must be reviewed by the IRB for Exempt determination, the Office of Human Research Protection (OHRP) published graphic charts titled Is the Research Involving Human Subjects Eligible for Exemption Under 45 CFR 46.104(d)? .

 

 

What is Non-Exempt Human Subjects Research?

 

If the project does not fall within one or more of the defined categories of exemption, then it is not exempt and must satisfy the regulatory criteria for approval.   Non-Exempt human subject research may be a project for which research activities involve no more than minimal risk to subjects and all of the procedures in the research are described in the categories of research that may be reviewed by the expedited procedure.  The expedited review procedure means that only one member of the IRB needs to conduct the review. This type of research is reviewed on a daily basis and there are no submission deadlines.

Non-Exempt human subject research may also be a research project involving greater than minimal risk and/or involving procedures not described in the categories for exempt status or expedited review.  This type of research would have to be reviewed by the convened IRB committee and submission deadlines will apply.

In order to obtain IRB review investigators must complete and submit an on-line Application in the iRIS submission system and attach to that application the relevant submission checklist and corresponding documents.

 

 

IRB Frequently Asked Questions

 

 Q: Who is consider “Key Study Personnel” in a Human Subjects Research Study?

A: The key study personnel (KSP) are those people designated by the Principal investigator as back–up principal investigator, co-investigators, study coordinators, data managers, or consenters on an application submitted to the IRB for review and approval.   The KSP often include individuals involved in the study through an interaction or intervention with research subjects for research purposes or those reviewing or accessing identifiable data for the research.  Individuals who will be interacting with research subjects during the course of a study, but only in their regular non-research employment capacity (e.g. a nurse or phlebotomist) should not be listed as KSP if they are not associated with the study as researchers.

 

Q: Do key study personnel added to a study need to complete Human Subjects Training? 

A: Yes. All key study personnel listed on an IRB application must complete training in the protection of human subjects.  Training completed through the Collaborative IRB Training Initiative (CITI) is the most used method of training to fulfill this requirement. Training must have been completed within the past three years to be considered current.

 

Q: I have little experience in IRB submissions.  Where can I find information about the IRB process for a new proposed study?

A: The Human Subjects Protection Program offers a one-hour general educational session for study coordinators and investigators who plan to conduct Human Subjects Research at UConn Health. This training provides an overview of the research proposal submission and maintenance process. Registration is required. Interested staff should e-mail Mayra Cagganello at cagganello@uchc.edu.  Individuals who need study specific guidance on preparing IRB submissions are encouraged to request assistance from the Education Specialist as noted above. WebEx orientation sessions are available on a daily basis.

 

Recent Articles Published by a  Central IRB

 

ADVARRA IRB:  

FDA Inspections of Clinical Investigators: Understanding the Process and What to Expect: This article provides answers to a series of questions regarding FDA inspections process.

Among the questions answered in this article are:

• What is the likelihood an investigator-initiated Investigational New Drug application (IND) and non-IND study would undergo an FDA inspection at an academic center?
• For multisite studies, does FDA inspect all sites, or might one specific site be selected to be monitored?
• How do you suggest research staff/coordinators educate clinical investigators (CIs) that they need to pay attention to study oversight and the FDA will not hold coordinators responsible by FDA if things go awry in the study conduct?
• Do you anticipate inspections to pick back up as more people become vaccinated and COVID-19 cases decrease? Will the FDA catch up on missed investigations?

 

Cell and Gene Therapy vs Small Molecule Research: Understanding the Difference Cell and gene therapy’s popularity has grown exponentially in the past year. This article provides an overview of how cell and gene therapy research is different from traditional drug development. Among the issues discussed in this article is that sites need to build the required infrastructure for conducting cell and gene therapy research safely and successfully.

 

 Educational Resources for Investigators

OHRP Luminaries Lecture Series

 

The Office of Human Research Protection (OHRP) has posted a series of lectures on human subjects research protections titled: “Luminaries Lecture Series.”  Many of these lectures are recordings of keynote addresses at OHRP-sponsored Research Community Forum (RCF) events.  Among the topics presented in these lectures are “Use of eConsent in Human Subjects Research,”  “Making Mobile Clinical Trials a Reality” and “Big Data, Privacy, and the Public Good.” To access these Luminaries Lecture Series please click here.

 

 

HSPP-Newsletter January-February-March 2021

 

NIH Releases New Policy for Data Management and Sharing

On October 29, 2020, the National Institute of Health (NIH) published the final policy for data management and sharing (DMS).  This policy applies to all research funded or conducted by NIH that results in generation of scientific data.  As stated in this policy  “data sharing enables researchers to rigorously test the validity of research findings, strengthen analyses through combined datasets, re-use hard-to-generate data, and explore new frontiers of discovery.”  The NIH DMS Policy requires researchers to submit a plan to preserve, to share the data and to show compliance with said plan.

To learn more about the scope of this policy and the details of data management and sharing plans, please review the Final NIH Policy for Data Management and Sharing.

 

Limited Data Sets and Data Use Agreements

A limited data set (LDS) contains protected health information that is associated with indirect identifiers as defined in the HIPAA privacy rule.  The indirect identifiers that may be included in an LDS are: town, city, state and five digit or more zip code, dates directly related to an individual such as date of birth, admission date, discharge date and date of death.

Before an LDS can be received by a UConn Health employee or disclosed to another institution, a data use agreement (DUA) must be in place between the sender and receiver of the LDS.   This DUA is required under the HIPAA Privacy Rule. This agreement establishes the ways in which the information in the limited data set may be used, the purpose for which it was disclosed, and identifies who is permitted to use or receive the information.

Moreover, the DUA stipulates that the recipient will use appropriate safeguards to maintain the confidentiality and protect the data from further disclosures.

Since the data use agreements establish institutional obligations and bind the institution to the terms of the agreement, investigators are not authorized to execute research DUAs.  UConn Health DUAs for research related activities are processed through the Office of Sponsored Programs Sponsored Program Services (SPS) or the Office of Clinical and Translational Research (OCTR).  The specific contacts in these offices are listed below:

• If the DUA is  related to a Clinical Trial contact: Cherron Payne chpayne@uchc.edu
• If the DUA is  unrelated to a Clinical Trial contact: Jennifer Pomales pomales@uchc.edu

 

 IRB Forms – Update

The   Main Consent Form Template .doc  has been revised to include instructional text about the option to decline payment for participation. The Main Consent Form Checklist .doc has also been revised to reflect this option.

 

Which Initial Application Form is the Correct One for Your Study?

 Once an investigator has determined that his/her project is a human subject’s research project, the next step for the investigator is to submit the project for review and approval to the IRB. This task will require that the investigator complete the “Initial Study Application Form” within the Integrated Research Information System (iRIS).

The investigator creating a new study application in iRIS will need to select one of the three available Initial Study Application Forms listed below:

• Application for a General Study
• Application for a Humanitarian Use Device
• Application for a Registry and /or a Repository

 

The following section provides a description of the three Initial Application Forms available in iRIS along with examples of when each one should be selected.

Application for a Humanitarian Use Device (HUD):

According to the U.S. Drug and Food Administration (FDA) a Humanitarian Use Device (HUD) is defined as a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in not more than 8,000 individuals in the United States per year. An HUD is an FDA approved device.  Because the HUD device is approved for use in such a small population, the FDA regulations requires that an IRB approve the use of the HUD in accordance with its approved label even though the use of the HUD is not research.

If you are requesting approval for use of an HUD, select the application specific for HUDs.

 

Application for a Registry and /or a Repository:

A registry/repository is used for the collection and maintenance of information/biospecimens on individuals who have a similar condition and who will consent to being contacted for future studies.  The investigator must develop a protocol that describes how the data/biospecimens will be collected, how they will be maintained, and how release of information from the registry or biospecimens from the repository will occur.

If you are requesting approval for a Registry and /or a Repository, select the application specific for Registry/Repository.

 

Application for a General Study:

The Application for a General Study form is the most commonly used application type. The investigators should select it when their research is categorized as either biomedical research, social & behavioral research or community based participatory research.  These projects may qualify for Exempt Status or Expedited review in accordance with regulatory criteria, or otherwise they will be review by the convened board.

Examples of human subject research projects that should be submitted with this General Application Form are:

• Minimal risk studies (e.g. studies limited to a survey, studies limited to a retrospective or prospective data review, clinical studies of drugs and medical devices when the conditions for expedited review are met, studies 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).
• Studies submitted for full board review (e.g., investigational new drug (IND) studies, investigator new device (IND) studies, social & behavioral studies including more than minimal risk to subjects).

 

Research with Children

When children are to be involved in non-exempt research, the investigator must address the additional protections for the inclusion of children in research.  The investigator does this by completing IRB Form D – Additional Protections for Children Involved as Subjects in Research.   The additional requirements set forth on this form are derived from DHHS and FDA regulations.

On Form D the investigator makes the initial assessment of risk level and sets forth plans for obtaining parental permission and assent.  The IRB reviews this form and makes the final determination as to whether the requirements for additional protections have been satisfied.  Depending on the level of risk of the study, UConn Health IRB will determine whether one or both parents (or legally authorized representatives) must give their permission.  The IRB will also make the final determination as to whether assent of the child is required and if so how that assent will be obtained.  In making this determination the IRB will take into consideration the age and maturity of the children, and the psychological state of the children involved.

Per UConn Health policy, 2011-006.3.pdf – Additional Protections – Children the additional protections for children apply to all non-exempt research (e.g., Expedited and Full Board Submissions) that is federally funded or supported, and/or that involves an intervention or interaction with a child regardless of funding source. Therefore, the additional protections do not apply to non-federally funded or supported chart review studies that qualify for exempt status.

 

OHRP New Video

Research with Children:  What Parents Need to Know

The Office of Human Research Protection (OHRP) has posted a new video on its public outreach website. This short video titled “Research with Children: What Parents Need to Know” is for parents/legal authorized representatives who may be or have been approach about permitting their children to participate in research.  It provides an explanation as to why research-involving children is necessary, its importance and what parents should expect if considering enrolling their child in a study. This video is found under the category of Videos on Protecting Human Research Volunteer

 

HSPP- October, November, December, 2020- Newsletter

 Accessing and Signing-off Submissions in iRIS

In order for a member of the study team to be notified that there is an IRB submission that requires the study team member’s sign-off, there must be a valid e-mail address associated with the study member’s account in iRIS.  Therefore, it is important to verify the validity of email addresses when selecting the members of a study team.  For UConn Health faculty, staff, students and residents, iRIS is linked to the LDAP active directory at UConn Health; so if a user does not have an e-mail in that directory there will likely be problems notifying them of the required sign-off task in iRIS.  In addition to verifying addresses by using the active directory; at the time of adding study team members to the form in iRIS there should be an email address listed next to the team member’s name in iRIS.  Lack of a valid e-mail address prevents the submission from being routed to the study team member for sign-off and from being submitted to the IRB for review and approval.

To avoid these problems, the person creating the study form in iRIS should follow the steps described in pages 7 and 8 of the iRIS user manual entitled “Basics for Creating a New Study Submission- Manual 1.”  The manual is available in the help section within iRIS.

 

FAQ about Facilitated Review – Reliance on External IRB

Q: What changes do I have to report to the UConn Health IRB when my study has been approved by an external IRB?

 A: When the UConn Health IRB has elected to rely on an external IRB, the external IRB is referred to as the IRB of Record.  Per the IRB Reliance Agreement in place, with one exception, only the IRB of Record for your study is responsible for all reviews of your study, inclusive of continuing reviews, requests for study modifications or amendments, and for reviews of non-compliance and unanticipated problems.

The one exception is that changes to UConn Health study personnel must still be processed through the UConn Health IRB by submitting a request for modification form through the iRIS system.

 

OHRP Determination of Exception to the Single IRB Review Requirements for Certain HHS-Conducted or – Supported Cooperative Research Activities Subject to the 2018 Requirements During the Coronavirus Disease 2019 (COVID-19) Public Health Emergency

 To ensure that institutions conducting cooperative research are able to take advantage of the most appropriate IRB review structure, the Office for Human Research Protections (OHRP) in the Office of the Assistant Secretary for Health of the Department of Health and Human Services has determined that, for studies that are conducted or supported by HHS and subject to the 2018 Requirements, and for purposes of 45 CFR 46.114(b) (2)(ii), an exception to the requirement to use a single IRB is appropriate for the following category:

Cooperative research:

1. that is ongoing or initially reviewed by the IRB during the Coronavirus Disease 2019 (COVID-19) public health emergency, as declared by the Secretary of Health and Human Services here.
2. where reliance on a single IRB would not be practical; and
3. for which the HHS division supporting or conducting the research approves of the use of this exception.

This exception applies for the duration of the HHS-conducted or supported research.

OHRP has made this exception determination due to concerns regarding the application of the single IRB requirement to cooperative research subject to the 2018 Requirements when this research is initially reviewed or ongoing during the COVID-19 public health emergency. The COVID-19 public health emergency has created unprecedented burdens and disruption to the research enterprise, while at the same time requiring urgent research responses that necessitate flexible approaches to oversight in order to provide vital information and to allow other research to continue where possible. This exception represents an effort to prioritize the health and safety of both research subjects and investigators, and provides flexibility to institutions in seeking IRB review due to the unique challenges created by the COVID-19 outbreak.

The exception includes some scenarios for which OHRP anticipates it may not be practical to rely on use of a single IRB for multi-site, cooperative research trials during the ongoing COVID-19 pandemic. This exception determination can be accessed here.

OHRP’s November 2019 Determination of Exception and related background information can be accessed here.

   

NIH Policy on Registration/Results Posting Of Basic Experimental Studies with Humans (BESH)

NIH’s clinical trial definition includes prospective basic science studies involving human participants. Basic Experimental Studies with Humans (BESH) use an intervention to understand fundamental aspects of a phenomenon without specific application towards processes or products in mind. NIH published case studies with examples of BESH (cases 9, 14, 40 & 41).

NIH funded clinical trials, including BESH, are required to register and post results in ClinicalTrials.gov.

On December 7, 2020, the Acting Director of ClinicalTrials.gov, presented the results of the National Library of Medicine analysis of challenges and considerations for registration and results information reporting of BESH in ClinicalTrials.gov. The recording of this webinar is available at https://videocast.nih.gov/watch=40141

For more information about ClinicalTrials.gov, including assistance with registration, please contact Research Compliance Monitor, Ellen Ciesielski at eciesielski@uchc.edu.

  

Recent Articles Published by Central IRBs

ADVARRA IRB:  

Beginner’s Guide to Investigator-Initiated Trials  This article describes the basic concepts an investigator must understand about “investigator initiated clinical trials” and how they fit into the clinical research landscape.

Western IRB (WCG):

Virtual Clinical Trials: Best Practices in moving Toward a Patient-Centric Research Model

This article defines virtual clinical trials, describes the potential benefits/risks of this new paradigm, and best practices for maintaining regulatory and Institutional Review Board (IRB) compliance.