Ms. Gearhart will present on “IRB Response to Key Changes in Clinical Research Practice,” focusing on current issues such as biorepositories, utilization of central IRBs, social media and emerging eConsent tools.  The presentation will take place Monday, May 20^th at 4:45 p.m.-5:10 p.m.

Ms. Gearhart originally joined Quorum Review as a member of the IRB, and was appointed CEO in 2006. She has led the Quorum business through two AAHRPP accreditations and a successful expansion into Canada. Prior to joining Quorum Review, Ms. Gearhart practiced law in both the private sector, specializing in health care regulatory law for hospitals, clinics and other institutions, and the public sector, working for the Office of Attorney General protecting vulnerable populations.  Ms. Gearhart also serves as Treasurer of the Consortium of Institutional Review Boards and Vice President for the Northwest Association for Biomedical Research’s Board of Directors.

The Forum on Optimizing Clinical Research Performance is being presented through a new strategic alliance between CenterWatch and iiBIG.  This year marks the inauguration of the one-of-a-kind, strategic leadership forum that brings together sponsors, CROs, sites and other organizations. The conference provides high-quality, relevant content to all clinical research professionals. More information about the conference is available on the iiBIG website.

For the latest on Quorum Review News and Events.

Our practice sees many elderly patients that occasionally require someone to consent on behalf of the patients for their regular medical treatment. How is consenting different for these patients in a research context?

Before a site can obtain a person’s consent for research, the investigator must ensure that an individual has the decisional capacity to consent to the research. The investigator may make this assessment by using a capacity assessment tool, such as the Mini Mental State Examination (MMSE) or other appropriate tests or evaluations. The FDA and Department of Health and Human Services (HHS) define a legally authorized representative (LAR) as, “…an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research.”^[1] 

Local law determines whether a person can serve as an LAR and what powers this person has. It is the investigator’s responsibility to ensure compliance with his or her local laws and to have a system in place to ensure that only properly qualified LARs consent to research on behalf of a participant who does not have capacity to provide consent for themselves. 

An IRB has the authority to restrict the use of LARs in a study if it determines that it would not be appropriate to enroll individuals who cannot consent for themselves. For trials that do not present a therapeutic value to subjects, ICH GCP advises that individuals who cannot consent for themselves should only be enrolled with the consent of a legal representative when the following conditions are fulfilled:

• The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally
• The foreseeable risks to the subjects are low
• The negative impact on the subject’s well-being is minimized and low
• The trial is not prohibited by law
• The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/favorable opinion covers this aspect^[2]

When an LAR is needed and allowed by the IRB, study staff must conduct the consent discussion with the LAR, and the consent form must be signed by the LAR to document their consent. While the FDA and HHS regulations and guidance only require a copy of the consent form be given to the LAR, ICH GCP requires a signed copy of the consent be provided to the LAR once consent has been obtained.^[3]

Assent from adult participants who lack the decisional capacity to consent to research should be obtained where possible. Individuals who can provide assent can sign and date the consent as well, though their signature is not the legally valid documentation of consent.^[4] Dissent should be respected, and individuals should not be enrolled against their wishes. Even if an LAR has authorized an individual’s participation, an investigator has an obligation to discontinue that individual’s participation should the individual express fear, discomfort or any disagreement with study procedures.

Quorum Review takes several steps to evaluate the enrollment of subjects requiring an LAR in research. First, Quorum requests information from the sponsor and the investigator as to whether they would allow the enrollment of subjects requiring an LAR in the research. Second, during review of the research, Quorum’s Board determines whether the enrollment of such subjects is appropriate for the research. If the Board allows the enrollment of subjects requiring an LAR, Quorum’s approval documents will indicate this determination. The investigator will also be provided with information summarizing local laws that address surrogate consent for research. In addition, the consent form provided to the investigator will include an attestation and signature line for the LAR to indicate their consent for the subject to enroll in the research.

Our research site has a patient who understands English, but is illiterate and not able to sign the consent form.   If the patient qualifies and agrees to be in a trial, how can they indicate their consent to be in the trial?

If a participant can understand and comprehend English, but is unable to sign a consent form, two steps must be taken to capture the person’s consent on the consent form: 

First, a participant must “make their mark” where a participant would normally sign in accordance with state law.  An individual making their mark should be able to make the mark for themselves without an individual assisting them. If the individual is physically unable to sign, the method with which they indicate consent needs to be documented on the consent form.

Second, an impartial witness must witness the consent process and attest that they have witnessed the consent process.^[5] This should be documented on the consent form with a witness signature line. An impartial witness is someone who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, and who attends the informed consent process if the subject or legal representative cannot read.^[6]

The rule updated several definitions, making them consistent with the parallel HHS Subpart D regulations.  The rule comments and changes to the regulations also clarified the application of the emergency research provisions to children. Though the regulatory changes are minimal, there is an updated interpretation in the rule comments that has an impact on the IRB evaluation of placebo-controlled studies in children.

In research involving children, IRBs must find that the research meets one of three categories under Subpart D before it can be approved. A fourth, seldom used category requires referral of the research to the FDA.^[1] The three categories are summarized below.  

1. 21 CFR 50.51: Clinical investigations that present no greater than minimal risk to children
2. 21 CFR 50.52: Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects (either due to intervention procedure or monitoring procedure likely to contribute to the subject’s well-being)
3. 21 CFR 50.53: Clinical investigations in which more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit, if the risk is only a minor increase over minimal risk; the intervention and procedures present experiences commensurate with those in their expected medical, dental, psychological, social, or educational situations; and the intervention or procedure is likely to provide generalizable knowledge about the subject’s disorder or condition

In the comments to this final rule FDA concludes, the placebo arm of a study does not meet the requirements under §50.52. This section allows research that poses risks that are more than minimal if the research offers the possibility of direct benefit to subjects.^[2] The FDA further explains that arms receiving investigational products, however, could be considered to have direct benefit. Describing the Subpart D analysis this way suggests IRBs should conduct a separate analysis of each arm of placebo-controlled studies, as opposed to a single evaluation of the possible benefits and risk for the entire trial. As the FDA notes, it has been recommended by various groups, and this approach may be taken by some IRBs prior to the rule change. However, the comments indicate this approach would be FDA’s expectation going forward. 

Required Parent Permission

In addition to the IRB analysis of the approvability of the research, this interpretation has implications for the IRB determination related to parent permission. When research poses only a minimal risk (§50.51) or offers possibility of benefit (§50.52), the IRB can decide whether one or both parents should provide permission.^[3] If the research does not offer a direct benefit and presents risks that are more than minimal, Subpart D (§50.53) requires both parents to provide permission (with some exceptions if the second parent is unavailable).^[4]

Under the FDA’s updated interpretation, IRBs are more likely to consider a study with a placebo-only arm to meet the requirements under §50.53. This will require permission of both parents and two signature lines on the consent forms. When both parent signatures are required, and the second parent is not “reasonably available”—the standard used in the regulation—the lack of availability should be documented as part of the consent process.

A recent controversy in the news raises difficult issues for IRBs. In 2004 and 2005, 22 institutions initiated a study (the SUPPORT trial) of the optimum care of premature infants. A template consent form was developed and similar versions approved by 23 IRBs. The study yielded clinical information hailed as critically important.

But earlier this year, the Office for Human Research Protection issued a determination letter critical of the study’s informed consent forms. OHRP concluded that for one arm of the study, the consent forms identified a possible benefit without identifying possible risks; for the other arm, OHRP concluded that the consent forms did not identify either risks or benefits.

The OHRP letter has sparked controversy and criticism. Aside from the specifics of the SUPPORT trial, the letter raises the perennial question: how much information is enough? Regulators, researchers, and IRBs are concerned that consent forms are too long and technical. But the OHRP letter reminds us of the importance of fully informing patients and their families of the possible risks and benefits of the proposed research.

In this increasingly complex world of research, we all struggle to make the right decisions. To help you with your human research protection program, enclosed are two articles regarding vulnerable populations. One article describes the use of legally authorized representatives and witnesses in the consenting process. The other summarizes recent FDA developments regarding pediatric research.

Quorum Review is honored to have the privilege of working with you and your research teams. Please let us know if we can be of further assistance.

Sincerely, 

Cami Gearhart, CEO
Quorum Review IRB

Join Quorum’s CEO, Cami Gearhart, JD, at the inaugural Forum on Optimizing Clinical Research Performance.

Ms. Gearhart will present on “IRB Response to Key Changes in Clinical Research Practice,” focusing on current issues such as biorepositories, utilization of central IRBs, social media and emerging eConsent tools.

The presentation will take place Monday, May 20^th at 4:45 p.m.-5:10 p.m.

The Forum on Optimizing Clinical Research Performance is being presented through a new strategic alliance between CenterWatch and iiBIG.  This year marks the inauguration of the one-of-a-kind, strategic leadership forum that brings together sponsors, CROs, sites and other organizations. The conference provides high-quality, relevant content to all clinical research professionals. 

About Cami Gearhart, JD

Cami Gearhart, JD, CEO of Quorum Review, originally joined Quorum as an IRB member and, in 2006, was appointed as CEO. Cami has led Quorum to receive full AAHRPP accreditation and expand its expertise into federally funded and international research. Prior to Quorum Review, Cami practiced law in both the private sector, specializing in health care regulatory law for hospitals, clinics and other institutions, and the public sector, working for the Office of Attorney General protecting vulnerable populations. Cami serves as Chairperson of the Consortium of Institutional Review Boards and Secretary for Northwest Association for Biomedical Research’s Board of Directors. | Read more about Cami Gearhart.

Ms. Coleman’s presentation, “Good Clinical Practice Essentials: What You Won’t Learn from the Regulations,” provides unique insights into timely GCP topics.  The presentation covers recent guidance from the FDA as well as inspection and audit findings. Using real-life studies packed with practical information, Ms. Coleman’s workshop lays the groundwork for many topics covered in the meeting. The presentation takes place Sunday, May 5th at 9:30 a.m.-12:00 p.m.

Ms. Coleman has over a decade of legal expertise in clinical trial research and regulatory oversight. She joined Quorum Review in 2007 as the Director of Regulatory Affairs and today continues to serve that role in addition to the role of General Counsel, which she assumed early in 2011. In April 2012, Ms. Coleman was honored by Puget Sound Business Journal as “Outstanding Corporate Counsel for a Small Business” (<1000 employees), recognizing her legal expertise in research matters and contribution to education.

MAGI’s 2013 Clinical Research Conference is one of the fastest growing events in the clinical research industry. The conference offers an exceptional networking environment with over 90 sessions and workshops that provide practical tips in a coherent program for operations, regulatory compliance, contracts and budgets. More information about the 2013 conference is available on the MAGI website.

For the latest on Quorum Review News and Events, visit www.quorumreview.com.

Although the regulatory changes were not significant, in the comments, FDA provides an updated interpretation of the Subpart D requirements in the context of placebo-controlled studies.  The FDA indicates that it does “not consider the administration of a placebo to offer a prospect of direct benefit.” Therefore, the FDA concludes, the placebo arm of a study does not meet the requirements under §50.52 of Subpart D, which allows research that offers the possibility of direct benefit to subjects even if it poses risks that are more than minimal.^[3] The comments further explain that arms receiving investigational products could be considered to have direct benefit.

Describing the Subpart D analysis this way suggests IRBs should conduct a component analysis of each arm of placebo-controlled studies, as opposed to a single evaluation of the possible benefits and risk for the entire study. Quorum plans to evaluate new studies in accordance with the FDA comments and does not expect this updated interpretation to have a significant impact on approvability of most pediatric research. However, there are some practical implications.

Required Parent Permission and Consent Signature Lines

• When reviewing research involving children, the IRB must determine that parent permission will be obtained.
• When research poses only a minimal risk or offers possibility of benefit, the IRB can decide whether one or both parents should provide permission.^[4]
• If the research does not offer a direct benefit and presents risks that are more than minimal, Subpart D requires both parents (with some exceptions) to provide permission.^[5]
• Under the FDA’s updated interpretation, IRBs are more likely to consider a placebo arm to meet the requirements under §50.53. This will require permission of both parents and two signature lines on the consent forms.

Varying Age of Majority and Subpart D Determinations

A second issue that may arise comes from FDA’s definition of “children” and the age of majority according to local law.^[6] The FDA defines “children” in relation to the local law.  Some jurisdictions have an age of majority above age 18—some even up to age 21.^[7]

 Often protocols for adult studies include a lower age limit of 18. Quorum’s policy is to make an evaluation under Subpart D whenever the protocol includes a lower age limit below 21. This ensures that if the research is conducted in any jurisdiction where the age of majority is below 21, the IRB has evaluated whether “children” can participate. This can lead to confusion if the IRB makes a determination that children can (or cannot) participate in a study planned for adults only. One way to prevent confusion is to include a statement in the protocol indicating that only individuals who have reached the age of majority will be allowed to participate. In that case, no Subpart D analysis will be required.

 As indicated above, Quorum does not expect that this change in interpretation will change the approvability of most research; however, clients that have a concern about the design of a particular study are encouraged to contact Quorum to discuss their questions or concerns.

Want to know more about Pediatric Research and working with the IRB?   Download Quorum’s recent webinar slides and the recording, “Navigating Research in Pediatric Populations.”

Ms. Carbary co-presents with Joseph Kim, Clinical Operations Director at Shire, on “eConsent and the iPad,” a case study involving deployment of eConsent technology delivered on the iPad. The presentation provides an overview of the process involved in eConsent activity using the iPad, including documentation, review and approval in the consent process from both the sponsor and the IRB perspective. Ms. Carbary draws upon her solid experience in ethics review and technology to outline electronic consent requirements relating to FDA Part 11 compliance and HHS regulations, as well as offering recommendations on how to prepare an electronic consent process for IRB review.

Ms. Carbary and Mr. Kim join with Linda Harper, Medical Director, and Shawna Martin, Administrative Director, from CNS Healthcare, Inc., also participants in the case study. The presentation takes place Sunday, April 14th at 9:00-11:00 a.m.

Ms. Carbary regularly delivers IRB-focused presentations covering such topics as: social media, HIPAA requirements, and safety reporting.  Ms. Carbary is a member of the Northwest Association for Biomedical Research and Public Responsibility in Medicine and Research. She received her Juris Doctor from Seattle University in 2007, and was admitted to the Washington State Bar Association (WSBA) in the fall of 2007.  Prior to joining Quorum Review in 2009, Ms. Carbary worked as a Regulatory analyst at Western IRB.

The ACRP supports the clinical research community, with a focus on fostering educational growth and professional interaction.  For more information about ACRP membership, visit the ACRP website.

Ms. Gearhart’s presentation, “IRB Review of Registries, Databases and Biobanking,” focuses on the regulatory considerations involved with the collection, storage, and distribution of human biological specimens used in clinical research.  Gearhart’s presentation covers an introduction to bio-repositories, the regulatory statutes and related guidance defining IRB review, as well as considerations when submitting such research for IRB review.

Ms. Gearhart originally joined Quorum Review as a member of the IRB, and was appointed CEO in 2006. She has led the Quorum business through two AAHRPP accreditations and a successful expansion into Canada. Prior to joining Quorum Review, Ms. Gearhart practiced law in both the private sector, specializing in health care regulatory law for hospitals, clinics and other institutions, and the public sector, working for the Office of Attorney General protecting vulnerable populations.  Ms. Gearhart also serves as Treasurer of the Consortium of Institutional Review Boards (CIRB) and Vice President for the Northwest Association for Biomedical Research’s Board of Directors (NWABR).

The 2013 AAHRPP Conference offers programs that support AAHRPP’s mission of promoting high-quality clinical research and human research protection through its accreditation programs.  

Boston Convention and Exhibition Center
Boston, MA
June 23-27, 2013

Join Quorum Review at the DIA 2013 49th Annual Meeting: Advancing Therapeutic Innovation and Regulatory Science. 

The DIA Annual Meeting is the largest multidisciplinary event that brings together a global network of professionals to foster innovation that will lead to the development of safe and effective medical products and therapies. Partners from a diverse range of global organizations (clinical research, regulatory affairs, diagnostics, medical devices, and more) come together to discuss enhancing the health and well-being of patients.

Quorum Review representatives will be on site during the conference to answer questions and discuss the latest in Quorum’s IRB services.