May a subject with worsening cognitive decline continue participation in a clinical trial when study drug administration is complete but follow up visits are ongoing?

– Principal Investigator, Research Institute

Response:

If a participant is no longer able to provide legally effective consent for themselves, the principal investigator needs to notify the IRB and the sponsor to determine if the subject may remain in the study. 

If the IRB determines that ongoing participation is permissible, the IRB will require consent by a LAR and may require assent by the participant (when feasible) to continue enrollment in the study.  The IRB will also determine how assent will be documented.

Brief Question:

Why does WCG IRB require assent from adults who lack decisional capacity when consent was already provided by a legally authorized representative (LAR)?

– Contract Regulatory Document Reviewer for a Pharmaceutical Company

Response:

Although the FDA regulations do not explicitly mandate the IRB to consider requiring assent from adults who lack the capacity to provide legally effective consent, there is support for this requirement in multiple regulatory frameworks. These frameworks include the guiding principles of the Belmont Report and FDA guidance on informed consent.

The Belmont Report states three basic ethical principles to guide IRB review of human subjects research. These principles are Respect for Persons, Beneficence, and Justice. The first principle of Respect for Persons advocates for two ethical convictions, “first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection.” The second conviction is addressed by requiring consent be obtained from a legally authorized representative whenever an adult subject lacks capacity to consent. The IRB acknowledges that decisional capacity is not a binary attribute. Subjects may fall along a spectrum of capacity and awareness. In order to ensure a subject’s autonomy is respected, the IRB requires investigators to obtain assent whenever a subject is capable of being reasonably consulted. 

The FDA states the following in a guidance document on informed consent:

IRBs and investigators should carefully consider whether the inclusion in research of individuals who lack consent capacity is ethically appropriate and scientifically necessary. Whenever individuals with impaired consent capacity (partial, fluctuating, or complete) are or may be enrolled in clinical studies, ethical and procedural challenges arise. Considerations that may help address these challenges, and provide additional safeguards, include:

Assessing whether individuals who cannot provide legally effective consent on their own behalf may nonetheless be able to provide some form of oral agreement (e.g., assent) at the outset of the study and, as appropriate, throughout the course of the research (e.g., for subjects with progressive disorders), and how such oral agreement would be documented. In such a circumstance, a legally authorized representative would need to provide documented written consent.

In conclusion, although the requirement for obtaining assent from adult subjects who lack the capacity to provide legally effective consent is not formally established in the federal regulations, WCG IRB has determined that this process is necessary to ensure respect for their autonomy.

The post Adults with Limited Capacity to Consent to Research appeared first on WCG.

We are submitting an amendment and revised informed consent document to our currently approved study. Do all subjects need to be reconsented with the revised consent form?

Response:

The federal regulations do not specifically address “reconsent”. Both the Common Rule and the FDA regulations require that researchers provide subjects with significant new findings developed during the course of the research when those findings may relate to subject’s willingness to continue participation in the research.

Many researchers, IRBs, and sponsors struggle with just how that notification should take place. In March 2020, the Secretary’s Advisory Committee on Human Research Protections (SACHRP) published a set of recommendations on this topic. The SACHRP recommended that IRBs should encourage use of the least burdensome approach for the subject. “…the provision of new information should not automatically result in a process whereby subjects are expected to review and initial every page of the revised consent form every time there is a minor change.”

Examples provided by SACHRP of instances where changes to the study may affect a research participant’s willingness to continue and therefore should be disclosed to participants include:

• New research-related risks or increased frequency or magnitude of risks or a decrease in expected benefits
• Change to the research that add burden / discomfort to the subject
• Availability of new alternative therapies

SACHRP also devised a list of scenarios and suggested options for communicating new findings depending urgency of the communication and on the status of the subject. That table can be found at: https://www.hhs.gov/ohrp/sachrp-committee/recommendations/april-7-2020-attachment-a2-reconsent-appendix-2/index.html

Building on the SACHRP’s recommendations, Currien MacDonald and Bert Wilkins, WCG IRB Chairs, proposed the following hierarchy for communicating new information to subjects:

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Is it possible that a post-market patient registry that collects patient experience with the use of a medical device would not need informed consent? The study does not involve collection of specimens. Does the Food and Drug Administration (FDA) require informed consent for this kind of registry study? If an informed consent is needed, can it be administered online?
– VP, Medical Device Company

Answer:

If you are contacting the subjects and asking them questions about their experience, you could do online consent with a waiver of the signature requirement. On the other hand, if you are obtaining the information without actual subject contact, e.g., doing a medical chart review, a waiver of consent may be granted by the IRB. 

Under current FDA regulations, a waiver of the requirement for informed consent is narrowly limited to emergency research or certain life-threatening situations. The authority of the IRB to waive informed consent for certain kinds of FDA regulated minimal risk research is based on a 2017 guidance from the agency. 

In this 2017 guidance document, FDA noted that allowing a waiver of informed consent for certain FDA-regulated minimal risk research would facilitate investigators’ ability to conduct studies “that are important to addressing significant public health needs without compromising the rights, safety, or welfare of human subjects.”  The FDA subsequently published a proposed rule to align its requirements on informed consent waivers with those of the Common Rule. Under the Common Rule, informed consent may be waived for minimal risk research that meets certain criteria.

The guidance goes on to say that until FDA promulgates these regulations, they do not intend to object to an IRB waiving the requirements to obtain informed consent when the IRB finds and documents that the following (Common Rule) criteria are met:

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

This is the FDA’s way of allowing “enforcement discretion” until the regulations are changed and catch up with their decision to allow waivers of consent.  So, it is possible that an IRB would allow a waiver if your research meets these criteria.

The post Is informed consent needed for post-market patient registry? appeared first on WCG.

Does the IRB need to approve doctor-to-doctor letters?
– Site Activation Lead, CRO

Response:

We address this question in our WCG IRB Guide for Researchers. The guidebook can be downloaded here, under “Most Popular IRB Downloads” on page 43.

Essentially, in our Guide for Researchers, we advise that doctor-to-doctor materials follow the FDA Information Sheet. This states that: “Direct advertising includes, but is not necessarily limited to: newspaper, radio, TV, bulletin boards, posters, and flyers that are intended for prospective subjects. Not included are: (1) communications intended to be seen or heard by health professionals, such as “dear doctor” letters and doctor-to-doctor letters (even when soliciting for study subjects), (2) news stories and (3) publicity intended for other audiences, such as financial page advertisements directed toward prospective investors.”

Based on this guidance, WCG IRB does not require prior IRB review of doctor-to-doctor letters, press releases, or interviews with the media and there is no need to provide WCG IRB with copies of these materials. However, if you like to have IRB review for such materials we will provide a review upon submission. Please note WCG IRB Policy on submitted press releases: WCG IRB reviews submitted press releases as advertising. Learn more about WCG IRB reviews and approvals.

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When do I report a protocol deviation to the IRB? Do I need to report a summary of deviations at the time of continuing review?
—Independent Research Center

Response:

For protocol deviations, reporting to WCG IRB is required only for deviations that harmed a subject or placed a subject at risk of harm and a deviation made without prior IRB approval to eliminate an immediate hazard to a subject.

Our Promptly Reportable Information Form (HRP-204) includes a listing of events that you are required to report to WCG IRB. You can use this list to guide your decisions about what kind of events require reporting.

Once you have reviewed the criteria for reporting and you still have questions about the reporting requirements, you should reach out to your point of contact at WCG IRB for the specific study or contact WCG client services. They would be in the best position to offer advice for a protocol specific question. You can call WCG IRB Client Services at 855-818-2289 or email at clientcare@wcgclinical.com.

Regarding continuing reviews (CR), our CR form asks the following question: “Is there any information that required reporting per IRB ‘POLICY: Prompt Reporting Requirements’ that has NOT yet been reported to this IRB?” So, at the time of continuing review you would report only those deviations that meet the threshold for reporting (defined above) and that had not been previously reported to the IRB.

Note that IRB’s reporting policies may vary so be sure to check in with your IRB if WCG is not the IRB of record for your study.

The post Ask the Experts: When Do I Report a Protocol Deviation to the IRB? Do I Need To Report a Summary of Deviations at the Time of Continuing Review? appeared first on WCG.

For a pediatric trial, at what age would you recommend the use of an assent form?
– Project Manager, Device Company

Response:

The federal regulations require child assent unless it can be appropriately waived, or if capability of some or all the children is so limited that they cannot reasonably be consulted.

The regulations do not provide a set age threshold for assent and leaves it up to the IRB to decide whether to require an assent form; so, the requirement for assent forms and documentation of assent may vary across IRBs.

Assent requires that participants have at least a basic understanding of what might be asked of them, and what might happen. For that reason, WCG IRB recommends providing a simple assent information sheet that explains the research to older children and adolescents and a simple oral script for younger children.

Whether you use an assent discussion, information sheet, or assent form, you should still include the basic elements of consent; and, the information should be appropriate to the child’s maturity and cognitive level. You may also consider different assent processes for different age groups of children.

If you decide to use a form, the FDA and OHRP offer the following guidance on the question of signature documentation of assent:

The Office for Human Research Protections notes that:

The post When should a child assent form be used in a pediatric clinical trial? appeared first on WCG.

When the signature of a parent or legal guardian is required for pediatric research, what is expected in terms of the documentation collected by the investigator to prove that the person accompanying the child and signing consent is the parent or a parent with sole custody or is a legal guardian. Are legal documents required in all cases where two parents are not accompanying the child? And even then, is legal proof required?
– Quality Manager, Clinical Trials Management Group

Response:

The requirements for permission of parents or guardians and for documentation of consent are intended by the IRB and the federal regulations (Source 1 | Source 2) as an additional safeguard and protection for children and not as an obstruction for researchers. As there is no federal regulatory requirement to provide proof of a parent or guardians’ legal authority to consent, IRBs are unlikely to set a requirement. This is consistent with respect to confirming the identity of individuals presenting themselves for inclusion in research.  Sponsors or sites may impose their own requirements.

The WCG informed consent template does include the following statements below the signature lines indicating parental permission.  Some sponsors choose to include this as a check box “attestation” in the parental permission/consent form. 

1st signature line: Signature of adult subject capable of consent, child subject’s parent, or individual authorized under state or local law to consent to the child subject’s general medical care. 

2nd signature line: When the IRB requires permission of both parents, the signature line for the second parent includes the statement that the signature is required unless this subject is an adult, the second parent is deceased, unknown, incompetent, or not reasonably available, or the parent providing consent has sole legal responsibility for the care and custody of the child.

The approach to documentation of legal authority to consent for may depend on both the research setting and on state law. State laws may vary widely. Investigators should be familiar with state or local law requirements that may be more stringent. When the research is done in a clinical care setting, the practice may already have policies in place that guide the practice of pediatric medicine.  At a minimum, the clinician would have established some knowledge of the relationship between the parent and the child, and when in doubt, would have asked for additional information or documentation.

Note that the federal regulations require that when research poses greater than minimal risks with no potential benefit to subjects, both parents must give their permission “unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care of the child.”  While there is no regulatory definition for “not reasonably available,” and no federal guidance on how to make the determination, the Secretary’s Advisory Committee on Human Research Protections concludes that “ultimately the responsibility of the investigator to adequately assess, document and decide whether a parent is not reasonably available given the specific facts and circumstances of each situation, including the level of that second parent’s participation in the life of the child.”  In this case, the investigator could include a note to the study file documenting the assessment and decision to allow one parent’s permission to enroll in a study.  Here is a link to the SACHRP recommendations for a discussion on how the term “reasonably available” should be applied and interpreted.

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What are the regulatory requirements for training of home health individuals who are working remotely to collect study data? If personnel have limited roles in the study (i.e. document management, study recruiter) should their CV be on file in addition to training?
– Manager, Clinical Development, Pharma

Response:

FDA regulations allow flexibility in how a principal investigator fulfills the training requirements for staff involved in the conduct of a clinical trial.

FDA regulations allow flexibility in how a principal investigator fulfills the training requirements for staff involved in the conduct of a clinical trial. FDA guidance, “Investigator Responsibilities – Protecting the Rights, Safety and Welfare of Study Subjects” affirms that the FDA takes a flexible and risk-based approach to training. Based on this guidance, staff – and by extension – those working remotely (such as home health care workers) should have adequate training in their assigned tasks and an awareness of regulatory requirements and standards for protection of human subjects.

WCG IRBs require human research subject protection training of all staff members involved in the procedures specific to the research including the consent process, interaction or intervention with participants, recording data, and submission of reports of unanticipated problems. Principal Investigators, through the initial submission process, are required to confirm that they will ensure that research staff are qualified to perform procedures and duties assigned to them during the research, including completion of human subject protection training.  Consistent with FDA guidance, training may be tailored to the fundamental role of the staff member. 

Training and documentation of training requirements may vary across IRBs and sponsors; so, it is important to ensure that local practices align with the IRB’s and sponsor’s requirements.

Regarding the question of CV’s for remote staff, the site should maintain documentation of each staff member’s qualifications and training to perform their assigned tasks. Consistent with good clinical practices, if maintaining a CV is described in the site’s standard operating procedures on documentation of training, then the site should collect the CVs, revise their SOP with a description of alternative and acceptable documentation of training and experience, or maintain a record of the exceptions as a deviation from the SOP.

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A study has an observation component in a Twelve Step Program. For the purposes of this case study, you can presume that the activity meets the definitions of “research” and “human subjects.” What kind of safeguards should the investigator put into place to ensure the ethical conduct of this kind of observation?
– Director of research integrity at a university

Response:

One approach would be to do “community consultation” with members of the 12 Step group in advance of the actual observation and to share with them the research plan and to get their input about what kinds of safeguards they would want to put into place to feel comfortable participating in the research.  The researcher could speak to the safeguards that will be put into place to maintain the privacy of the subjects and the confidentiality of the data collected.  Safeguards could include recording the information about the participants in such a way that they cannot be linked to the data collected. An IRB could also waive of the requirement for subjects to sign the consent form that would link subjects to participation the study.

In the spirit of getting buy-in ahead of time, the researcher could reach out to the 12 Step group and ask the group for ideas about what to do if some attendees do not choose to participate.  For example, would group members be willing to attend a different meeting or could the attendees break out into groups for that particular session.  From my experience working, the community consultation allows the prospective subjects to weigh in on what is important to them, informed the IRB review process and may have helped with recruitment process.  A process that engages the group of perspective participants before the research begins may in the end save time and is consistent with the ethical principle of respect for persons.

The post What ethical safeguards are needed for research involving observation of group behavior? appeared first on WCG.

We have a generic flyer for a specific condition that we would like to send out.  The flyer is IRB approved at the sponsor level and we would like to know if it is acceptable for our site to use.
– Regulatory Coordinator, University Medical Center

Response:

For this question, I am assuming that a “generic” recruitment flyer is one that includes protocol specific information and may include information about the sponsor but does not include site-specific information.

Generic flyers approved by the IRB may be used by the site.  Changes to approved generic materials must be reviewed and approved before use. For example, including site-specific information such as an address or phone number, changing font type or format, or including site-specific dollar amounts that will be paid to subject participation in the research would trigger the requirement for IRB approval of the flyer.

As is often the case, if there is any question, you should contact your IRB for assistance in determining if the material needs to be submitted for review, being mindful that different IRBs may have different policies regarding review and approval of recruitment materials.

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