New FDA Draft Guidance: Ethical Considerations for Clinical Investigations of Medical Products Involving Children
By Rachel Kinker, MPA
Have you recently joined the UI or taken on a new role? Will you be conducting research at the UI and want to learn more about the UI policies, procedures, and systems? The New Faculty/Staff Research Navigation Tool (formerly the New UI Faculty/Staff Researcher Survey) is sent to all new faculty and staff to begin the onboarding process with Research Administration and several other units on campus. Based on the responses that are received, representatives from the following units will contact the researcher to provide guidance and support for transferring or beginning to conduct research at the UI.
- Office of the Vice President for Research (OVPR)
- Research Development Office (RDO)
- Division of Sponsored Programs (DSP)
- Human Subjects Office (HSO) and Institutional Review Board (IRB)
- Offices of Animal Resources (OAR) and the Institutional Care and Use Committee (IACUC)
- Environmental Health & Safety (EHS)
- University of Iowa Research Foundation (UIRF)
- Institute for Clinical and Translational Science (ICTS)
- Information Technology Systems (ITS)
This Research Navigation Tool recently underwent a re-branding name change. It was formerly called the New UI Faculty/Staff Researcher Survey, but it was never intended to collect data from new faculty researchers. The new title more accurately reflects the purpose of this tool; to onboard new faculty and staff researchers and provide the guidance to transfer and conduct research at the UI.
In addition to the New Faculty/Staff Research Navigation Tool, there are other resources available to assist in the onboarding process.
- Researcher Handbook - This electronic guide for all researchers (new and existing) provides guidance for the entire lifecycle of a research project. The Handbook explains how to get started, learn about all applicable regulations, apply for funding, manage awards, conduct research responsibly, hire and supervise staff and close down a research study when it ends and prepare for a researcher to leave the UI.
- New Faculty/Staff Researcher Orientation to the IRB - For new faculty planning to conduct research with human subjects, the HSO offers one-on-one or small group IRB orientations to help new faculty and staff researchers find the resources and support they need to get started with research involving human subjects. This session provides an orientation to:
- The Human Research Protection Program (HRPP)
- The IRB review process and requirements for submission
- Other committees or entities that review and approve human subjects research applications
- Important features of the eResearch application system (HawkIRB), including the delegate permission system and Principal Investigator oversight responsibilities
- Educational resources available for all human subjects researchers
The new faculty/staff orientation is a supplement to existing educational opportunities offered by the HSO and other offices in the HRPP and across campus, such as HawkIRB Training Sessions, IRB presentations, and IRB Office Hours.
Contact the IRB Education & Outreach team to learn about other educational resources for new (and not-so-new) faculty and staff researchers.
Kelly O’Berry, BS, CIP
The decision to reconsent enrolled subjects may seem straightforward. If changes to the protocol have the potential to impact enrolled subjects, the research team must inform them via the Informed Consent Document. That requires a reconsent process. But as with many aspects of human subjects research, the decision about whether to reconsent depends on several factors.
What does it mean to reconsent subjects?Informed consent is not just a one-time signature on a document. It is an ongoing process throughout the study. It begins with the recruitment message, includes the discussion about the study with a member of the research team (if applicable), subject agreement to participate and subject signature on the document (also if applicable). The research team may revisit the study purpose and procedures at various timepoints throughout the study to assess the subject’s continued willingness to participate.
The Code of Federal Regulations for the Protection of Human Subjects (45 CFR 46) does not indicate all circumstances when researchers might need to repeat or review the informed consent process. But to ensure that informed consent remains legally effective in light of protocol changes or new risks, the research team might need to confirm that subjects are still willing to participate.
What protocol changes or other events require reconsent?
The protocol changes that must be shared with enrolled subjects and require documentation of subject agreement, via signed Informed Consent Document, to continue in the study, are:
- Additional study visits or procedures
- Change in the timing of study visits or overall length of the study
- New or additional study procedures
- New risks, or risks that are more frequent or severe
- New plans for data storage or sharing
- New information (positive or negative) that might affect subject willingness to continue participation
- When a minor subject ‘ages up’ to the age of majority
There are also categories of changes that do not necessarily require a signed Informed Consent Document to reconsent:
- Change in the Principal Investigator (PI)
- Change in study coordinator
- Change in research team member
- Change in Faculty Advisor for a Student PI
- Change in eligibility criteria
- Change in methods of data analysis
For a change in PI or contact person, the research team could send a notice by mail or email without conducting a full reconsent process. But the letter/email and the description of the process would need IRB approval.
What subject status requires reconsent?
Typically, protocol changes only require reconsent when they affect currently enrolled subjects. For example, enrolled subjects will have additional study visit or additional study procedures that were not described in the original Informed Consent Document. However, if additional visits/procedures will only be done with newly enrolled subjects, then reconsent is not required for currently enrolled subjects.
If new risks are identified, there may need to be an IRB-approved notification to enrolled subjects who already completed all study activities. But this is not considered ‘reconsent.’
Who decides whether to reconsent?
Typically, the PI is in the best position to decide whether reconsent is required. Describe the proposed reconsent process in a HawkIRB Modification form and IRB approval of that form documents agreement with the proposal. If reconsent is required due to a reportable event submitted on a Reportable Event Form (REF), it is best to submit a Modification form to describe the reconsent process.
Include the following components of a reconsent process in Section VII.D.29 (for adult subjects) and/or Section VII.D.30 (for minor subjects):
- Mode of contact with enrolled subjects (by mail, at next study visit, etc.)
- Consent process (verbal discussion, follow up phone call, sign in person or by mail, etc.)
- Describe all possible variations in the consent process
- Timeframe when reconsent will occur (immediately, within 30 days, at next study visit, etc.)
If a protocol change or reportable event is reviewed by the full convened board, there may be a required action to reconsent subjects. The PI can proactively describe the reconsent process in Section VII.D.29 and/or Section VII.D.30 rather than waiting for the IRB to request this modification.
If the project is overseen by an external, commercial, or central IRB, the PI should follow the policies and guidance from that IRB.
The PI and the research team create reconsent plans based on their knowledge of the study design and the subject population. If subjects return for study visits on a regular basis, the team could conduct the consent process in person. If subjects do not have regular study visits, the reconsent process could take place by mail or email.
There are as many variations possible for the reconsent process as there are for the initial consent process. Depending on the study design, there may or may not need to be a verbal discussion of the changes. The research team could mail the revised Informed Consent Document to enrolled subjects with an IRB-approved letter of explanation outlining a plan to discuss the changes and obtain signatures at the next study visit.
If there are variations in the way the reconsent process may be conducted with enrolled subjects, the PI should describe all possible variations in Section VII.D.29 and/or Section VII.D.30. The revised Informed Consent Document and cover letter outlining the reason for reconsent should also be attached to the HawkIRB Modification form.
When the protocol changes, the PI should determine whether reconsent is required, which subjects need to be reconsented and the process for reconsenting enrolled subjects. Describe this in a HawkIRB Modification form to obtain IRB approval for the reconsent process.
By Kelly O’Berry, BS, CIPFrom May through August 2022, the Human Subjects Office (HSO) / Institutional Review Board (IRB) and the Institute for Clinical and Translational Science (ICTS) collaborated on a series of lectures to provide IRB (regulatory) and researcher (practical) perspectives on a variety of topics. This article contains a summary of each lecture. Recordings are now available in the IRB ICON Course for Researchers. These lectures were just the start of an ongoing HSO/IRB and ICTS collaboration. Please send topic suggestions to email@example.com.
Use a Sample Protocol to Create a HawkIRB Application
Attendees/viewers are invited to use a sample protocol (Snapeacillium for Quidmort Sample Protocol.April 2022.pdf) to draft an application in the HawkIRB Training platform. [Just remember not to submit real research projects in the Training platform!]
This lecture covered the following topics:
- How to collect everything you need to prepare a draft HawkIRB application
- Study Start Up Meetings
- Where to put elements in the protocol or grant application into the HawkIRB application
- Study-specific aspects of the HawkIRB application (not specified in a protocol)
- When and how to request additional information from the Principal Investigator (PI), sponsor, coordinating center, or Other UI Committees involved in the review process.
The Recruitment Process: Plan, Describe, Implement
This lecture shared best practices for this often overlooked, yet essential, aspect of a research study. A study is doomed to fail without effective recruitment and retention of subjects. This lecture addressed regulatory and ethical requirements and reviewed a variety of recruitment strategies. Successful study recruitment helps to meet study recruitment goals and greatly affects subject retention.
We had so much information to share that we ran out of time. A second lecture is scheduled for December 1, 2022 (12-1 pm), “Recruitment Process (Part 2): How to design an Effective Plan.”
The Informed Consent Process: An Effective and Ethical Description of the Study
In this lecture, we started after a potential subject agreed to learn more about the study and discussed how to use the Informed Consent Document to conduct the consent process with a “real” subject.
- Best practices for the consent process: before, during and after
- The Gold Standard consent process
- Documenting the consent process
- Evaluating capacity to consent: consent process with a Parent/Legal Guardian or Legally Authorized Representative (LAR)
- Training staff to conduct the consent process
- Remote or virtual consent process
Reportable Event Panel Discussion: Being Clear About What, When and How to Report
Representatives from the Human Subjects Office, Institutional Review Board and the UI research community shared best practices for managing reportable events:
- Recognize the five types of events
- Identify events during a study
- Reportable Event Forms (REFs) in HawkIRB
- IRB review process for REFs
Additional Educational Resources: The Reportable Event Forms (REFs) portion of the Part 3 HawkIRB Training: Forms Submitted After IRB Approval (Modifications, Continuing Reviews, Reportable Events Forms and Project Close Forms). Recording available in the IRB ICON Course for Researchers (in the module called “HawkIRB Trainings Part 3, Part 4 and Part 5”).
Create an Informed Consent Document and Consent Summary
Attendees/viewers are invited to use sample protocol (Phase II/III, Randomized, Double-Blind, Placebo-Controlled Trial of Snapeacillium for Quidmort) and the UI IRB templates in the HawkIRB Training platform to create an Informed Consent Document and Consent Summary. Presenters discussed:
- The process of translating the protocol into lay language
- Where to include elements of the protocol in the Informed Consent Document and Consent Summary
- Best practices for creating a clear, concise Informed Consent Document and Consent Summary
Upcoming Lectures in this Series
- December 1, 2022 – Recruitment Process (Part 2): How to Design an Effective Plan (Details will be posted by August 22, 2022)
Rachel Kinker, MPA
It is common for a clinical trial protocol to describe the collection of data from enrolled subjects or partners of enrolled subjects who become pregnant. The protocol may also include the collection of data about the child from the pregnancy. Each of these would be considered an additional subject population and would require additional informed consent document(s). However, the IRB does not review pregnancy consent documents attached to the HawkIRB New Project form as it is often a rare occurrence that an enrolled subject or their partner becomes pregnant. This article will address why there is a watermark on those pregnancy consent documents and what the Principal Investigator or research team should do if an enrolled subject or their partner becomes pregnant during the study.
When a researcher submits a pregnancy consent with the New Project form, the UI IRB watermarks the document before the IRB meeting. At that time, they are not reviewed by the board. The consent document(s) cannot be used until the watermark is removed by the IRB.
If the protocol mentions enrolling pregnant women, pregnant partner(s), or child(ren) of the pregnancy, the IRB does not require a pregnancy consent until it is needed. The PI should follow the sponsor’s guidance about whether to attach the pregnancy consent document up front or just describe plans to collect data from pregnant subjects/partners and submit a HawkIRB Modification form to attach the pregnancy consent when it is needed.
Either way, when the consent document is needed during the study, the PI should submit a Modification form to describe the following for this subject population:
- Eligibility criteria
- Recruitment methods
- Consent process
- Study procedures
This modification usually qualifies for Expedited review. The IRB meeting minutes typically include a directive to submit this Modification form if an enrolled subject or their partner becomes pregnant.
What to change in the HawkIRB application?
When submitting the modification make the following changes to obtain IRB approval to enroll the individual(s):
Section VI.13 - Update to describe the pregnant partner subject population
Section VI.26 - Update to Yes (you would now be enrolling people based on their pregnancy status)
Section VII.D.29 - Update to describe the recruitment and consent process for this subject population
Section VII.E.6 - Update to describe the study procedures for this subject population
Section VIII.1 – Update to describe risks to this population
Section VIII.2-Update to describe minimizing any new risks for this population
Section X.4 - Update to describe data security plan for obtaining medical records and anything else related to this population
Section XIII (other mod and/or comments) - Ask for the watermark be removed (if pregnancy consents were attached to the New Project form)
New FDA Draft Guidance: Ethical Considerations for Clinical Investigations of Medical Products Involving Children
By Kelly O’Berry, BS, CIPIn late September, 2022, the U.S. Food and Drug Administration (FDA) released draft guidance related to the participation of children in clinical investigations of drugs, biological products and medical devices. Past practices of excluding children from clinical trials to ‘protect’ them led to FDA approval for drugs, biological products and medical devices that did not include labeling information for a pediatric population. As a result, doctors prescribe products that have “not been reviewed by the FDA for safety and effectiveness in children. It became clear that children can be better protected by including them in clinical research.”
According to the FDA news release:
Children need access to safe and effective medical products and health care professionals need data to make evidence-based decisions when treating children. However, children are a vulnerable population who can’t provide consent for themselves and are afforded additional safeguards when participating in a clinical investigation,” said Dionna Green, M.D., director of the FDA’s Office of Pediatric Therapeutics. “The best way to provide children with safe and effective treatment options is by including them in clinical research and providing these additional safeguards to protect them during clinical trials.
The draft guidance includes the following fundamental concepts and ethical framework for IRBs, sponsors, and industry to consider when reviewing or conducting clinical trials with a pediatric population:
- Scientific necessity of conducting a clinical investigation in children
- Risk categories for interventions or procedures that do not offer a prospect of direct benefit to the child
- How to evaluate whether an intervention or procedure offers a prospect of direct benefit to the child
- Assessment of risk for interventions or procedures with a prospect of direct benefit
- Component analysis of the risks of interventions or procedures
- Potential for review, under a regulatory provision, of research that is not otherwise approvable by an IRB
- Parental or guardian permission and child assent
The FDA invites public comment on this draft guidance. Submit comments within 90 days to be considered for the final guidance document.
By Rachel Kinker, MPAMedical Ethics Advisor (a publication of Relias, LLC) is a monthly newsletter with articles about human subjects research and medical ethics. Current and past issues of Medical Ethics Advisor and IRB Advisor are posted in the “IRB ICON Course for Researchers.” The portal to this ICON Course is on the Education and Training page of the Human Subjects Office website. This month we are spotlighting some articles about human subjects research from the September 2022 Medical Ethics Advisor Newsletter.
The Trouble with Electronically Tracking Study Medication
Digital pills (a pill that contains an ingestible sensor) allow data to be recorded automatically regarding a patients’ medication adherence, however ethical concerns and challenges arise.
- Ethical concerns related to access, equity, and generalizability of results
- Inequality gaps could grow for those already underrepresented in research
- Considerations for how compliance is documented, records indicating pills were not ingested could be indicated as noncompliance in a patients’ medical record, which in turn could impact future participation in research, insurance coverage and decision making
- Confidentiality and privacy issues with the data generated
- Technological limitations of devices
How Should Researchers Proceed if They Suspect Neglect or Abuse?
What is the appropriate next step if it is suspected that a participant has experienced abuse or neglect? A plan should be in place for disclosure of suspected abuse to the appropriate authorities, prior to conducting research. This should be outlined in the consent and parental permission forms (if they are used in the study). The investigator and/or research team member may be a mandatory reporter. This varies by state. If there is uncertainty around mandatory reporting requirements, contact the institutions’ leadership, risk management or general counsel.
Researchers can be torn between reporting and not violating the confidentiality of the subject. If the research goals are related to past or present abuse or neglect, participants would be aware that researchers would have this information and they have consented to share. Even if the research is not related to abuse or neglect, it is possible investigators may learn of instances of abuse or neglect during their interactions with a subject. Researchers should prepare for such cases and alert the research team and participants that if discovered, abuse or neglect will be reported.
New Tools to Facilitate Single IRB Process
The revised Common rule brought about the requirement for institutions to rely on a single IRB (sIRB) for review of multi-site research. This change has simplified the process and prevented redundancies but has also brought about new challenges.
- Existing processes in place at institutions that had already been utilizing single IRB models, these may differ across institutions
- Inconsistent processes can cause delays when determining the appropriate sIRB, contacts, how to document local reviews, coordination of submission of site information, site documentation of approval documents
- External researchers will need to comply with protocols, consent forms, and submission and review processes of IRBs they are not familiar with
- Local and state laws and institutional policies that vary across institutions
Resources to assist with the single IRB process:
- Contact the Human Research Protection Program or IRB Office to seek guidance
- IRB Reliance Exchange (IREx) is a web-based platform to facilitate communication and documentation. Information can be updated with automated communication, notifying all involved of important developments and approvals. This platform is used by more than 35 single IRBs and 414 participating sites
- SMART IRB is a platform that provides a contractual reliance agreement to distinguish each party’s responsibility. (Currently, more than 850 Participating Institutions have joined the SMART IRB Agreement).
IRBs Must Review Study Protocols Rapidly and Ethically During Public Health Emergency
During a public health emergency, the IRB review process can exceed the window of time for conducting meaningful research on an emerging infectious disease. A creation of a single IRB tasked with the goal of IRB review of multisite research in 72 hours was the goal of the University of Nebraska. The success of a 72-hour review and approval process hinged on several elements.
- Excellent communication between research coordinators, IRB administration and researchers
- Preventing delays in communication by having the researcher on standby to submit any modifications to the protocol
Articles in the September 2022 Issue:
- Electronic Orders, Education Boost Requests for Ethics Consults
- Financial conflicts Reported Inconsistently
- Be Careful About Informed Consent if Pelvic Exams Happen While Patients Are Under Anesthesia
- Ethical Considerations for Trauma-Informed Care
- Updated Tactics for Parkinson’s Disease Study Recruitment
- For Individualized Therapy Trials, Remain Mindful of Transparency, Reporting Bias
- Using Social Media During a Research Study: How to Connect with Others Safely and Successfully, Ampersand, the PRIM&R blog
- The Ever-Increasing Importance of Financial Conflict of Interest, Ampersand, the PRIM&R blog
- Common gene variant linked to COVID mortality, Science Daily
- NIH-supported clinical trial of phage therapy for cystic fibrosis begins, National Institutes of Health
- NIH to award over $200 million to support potentially transformative biomedical research projects, National Institutes of Health
- How diet may disrupt gut microbes to promote weight gain, National Institutes of Health
- What is déjà vu? Psychologists are exploring this creepy feeling of having already lived though an experience before, The Conversation
- Long COVID Has Forced a Reckoning for One of Medicine’s Most Neglected Diseases, the Atlantic