Higgins will present on Quality Management and Quality Improvement in Research – one of the featured tracks of the March 7-9 conference at the Grand Copthorne Waterfront Hotel. Other speakers in Higgins’ track include HRP Consulting Group Consulting Services Director Nicholas C. Slack and Johnson & Johnson Quality and Compliance Lead Regional Director Angie Sim.

APREC is a premier Asia Pacific platform focusing on human subject protection. APREC is committed to bringing together the region’s institutional review boards, ethics committees, research and academic institutions and health authorities, as well as representatives from the pharmaceutical industry.

The Food and Drug Administration this year published revised regulations pertaining to safety reporting for drug and biologic products under an Investigational New Drug (IND) application. The FDA also made bioavailability (BA) and bioequivalence (BE) studies conducted to support the approval of a generic drug subject to IND safety reporting requirements.

Let’s look at how these changes in 21 CFR 312 will impact IND safety reporting.

Why revise?

The FDA appears intent on reducing the number of IND safety reports that are uninterpretable or do not contribute to a better understanding of the developing safety profile of the drug or biologic. In the guidance that accompanies the new regulations, the FDA seems to acknowledge there are too many reports for adverse events in which there is little evidence of a causal relationship between the drug and the adverse event. In fact, the default position for both sponsors and investigators has been “over-reporting” safety events.

The FDA also appears intent on clearing up confusion over the term “adverse drug experience.” Under prior IND regulations (21 CFR § 312.32), there was little guidance about which “adverse drug experiences” during clinical trials required reporting, resulting in sponsors often reporting all serious adverse events, even when there was little reason to believe they were associated with the investigational drug.

As a result, the new regulations eliminate the term “adverse drug experience” and replace it with two terms: “adverse event” and “adverse reaction.” An “adverse event” is, simply, any adverse event observed during a clinical trial. An “adverse reaction” is an adverse event in which there is reason to conclude the drug caused the event.

What gets reported?

The FDA now requires sponsors to file IND safety reports for suspected adverse reactions that are both serious and unexpected. There must now be a “reasonable possibility” the drug caused the adverse event – that is, there must be evidence to suggest a causal relationship.

The FDA provides three examples of when such a “reasonable possibility” of causality may be drawn, requiring an IND safety report:

• When the event is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome)
• When the event is not commonly associated with drug exposure, but is uncommon in the population exposed to the investigational drug (e.g., tendon rupture)
• When an aggregate analysis of specific events indicates the events occur more frequently in the drug treatment group than in controls

In addition, the guidance document makes it clear the FDA expects such information be based on unblinded analysis of the events, as information on what treatment the patient received could “provide critical safety information about the drug that could have implications for the ongoing conduct of the trial.”

What else must sponsors report?

In addition to serious and unexpected suspected adverse reactions, the new regulations require the sponsor to submit IND safety reports to the FDA and all investigators about:

• Findings from other studies
• Findings from animal or in-vitro testing
• An increased rate of occurrence of serious suspected adverse reactions

Findings from other studies

IND safety reports must be submitted when findings “suggest a significant risk in humans exposed to the drug” in other studies. These may include epidemiological studies, analyses of multiple studies and clinical studies other than those conducted under the present IND. They can also include studies not conducted under an IND or by the sponsor of the present IND.

Information that requires reporting would typically be that which would lead to safety-related changes in the protocol, informed consent document, investigator brochure or other aspects of the clinical investigation.

Findings from animal and in-vitro testing

The new FDA rule requires sponsors to submit an IND safety report if animal or in-vitro testing suggests a significant risk to humans exposed to the drug. This would include reports of mutagenicity, teratogenicity, carcinogenicity or organ toxicity.

Findings requiring reporting would typically be those which lead to safety-related changes in the protocol, informed consent, investigator brochure or other aspects of the clinical investigation.

Increased rates of occurrence of serious suspected adverse reactions

Sponsors are also required to file an IND safety report when they discover “any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.” This requirement was added for consistency with ICH guidance and the FDA’s expectation that the sponsor track and identify changes in rates of adverse events during the conduct of a clinical trial.

In addition, there is a requirement to report serious suspected adverse reactions that are anticipated within the drug class but not specifically mentioned as occurring with the particular drug under investigation. Under this rule, a serious adverse reaction known to occur in the class of drugs, but not yet observed in the drug under study, would be considered “unexpected” – and therefore reportable the first time it occurs in the study drug.

The final rule also adds the requirement that sponsors report serious and unexpected suspected adverse reactions even if the event may be considered a component of a study endpoint. For example, death from anaphylaxis must be reported, even if a study endpoint is all-cause mortality, when death from anaphylaxis is unexpected and if there is a reasonable possibility that the drug caused the anaphylaxis. Serious and expected suspected adverse reactions that are study endpoints need not be reported as IND safety reports, and should only be reported as described in the study protocol.

What must investigators report?

Under the FDA’s revised reporting requirements in 21 CFR § 312.64 (b), investigators must immediately report to the sponsor any serious adverse event, whether it is considered related to the drug or not – including events listed as “known to occur” in the protocol or the investigator’s brochure.

The investigator must include an assessment as to whether there is a “reasonable possibility” that the drug caused the event. Study endpoints that are also serious adverse events should be reported in accordance with the study protocol unless there is evidence suggesting the event was caused by the study drug. These requirements are in addition to other protocol-specific requirements for safety reporting.

The takeaway

The new regulations are a good start on addressing the problem of over-reporting of IND safety reports under the previous regulatory scheme. But whether the new regulations will result in decreasing the number of individual IND safety reports remains to be seen.

In addition, sponsors and investigators will be dealing with new expectations pertaining to analysis of adverse events and will need to develop new processes to determine the significance of adverse events in clinical trials. We may see the role of Data Monitoring Committees (DMC) expanded for the purpose of analyzing and evaluating un-blinded data to determine whether the events must be reported.

As with any overhaul of regulations, the true effect of the changes is yet to be shown.

CGIRB Chairperson Glenn Veit, JD, CIP, spoke on “Sponsor Responsibilities in Unanticipated Problems and Adverse Event Reporting.” His presentation reviewed new FDA regulations on adverse event reporting in Investigational New Drug (IND) trials, which went into effect in March.

CGIRB Quality Management Director Yvonne Higgins, CIP, spoke on IRB operations and management, as well as research team oversight and education. She also participated in an open discussion with other HRPP and IRB experts, and served as co-chairperson for the conference’s workshop and didactic subcommittee.

The conference was presented by Public Responsibility in Medicine and Research (PRIM&R), an organization dedicated to advancing the highest ethical standards in the conduct of research.

Dec. 6, 2011, Research Triangle Park, N.C. – Copernicus Group IRB (CGIRB), a leading independent institutional review board, has been named a finalist in Training Magazine’s annual Top 125, which ranks companies’ excellence in employer-sponsored training and development programs.

The final rankings will be announced during Training’s 2012 Conference and Expo, scheduled for Feb. 13-15 in Atlanta.

Training determines its Top 125 rankings using benchmark statistics and by evaluating corporate commitment, formal training programs, program efficacy and innovation. In addition to Copernicus Group IRB, the 2012 finalists include such powerhouse brands as ADP, Intel Corp., UPS and Verizon.

“CGIRB is honored to be the only IRB named as a finalist for the Training Top 125,” Copernicus Group IRB president and CEO Bruce Tomason said. “Our ongoing commitment to the protection of human research subjects demands we maintain the highest training standards. Better staff education leads to increased employee competence, overall experience levels and, ultimately, improved service and impeccable quality for our clients.”

Copernicus Group IRB ’s corporate trainer, Sydney Douglas, manages a training program which includes new employee orientation, skill development, interdepartmental trainings, accreditation/certification programs and coordination of corporate training initiatives.

The resulting training-focused environment enables new employees to quickly acclimate and contribute to the corporate culture, while ensuring seasoned staffers remain at the forefront of the industry.

“This award validates our approach to training at CGIRB,” Douglas said. “By making ongoing training and certification efforts a top priority, we keep ourselves and our work on the cutting edge. At CGIRB, we fully realize the impact of training – that the quality of service we provide to our clients is directly related to the quality of employee training we provide for our staff. Training has always been a part of our culture, and we are thrilled to receive this honor.”

About Copernicus Group IRB
Experience and innovation in ethical review ®
Copernicus Group IRB, established in July 1996, is a leading U.S. independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. The IRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004, reaccreditation in 2007 and 2011, and ISO 9001:2008 certification in 2010.

About Training magazine
Based in Minnesota, Training magazine is a 48-year-old professional development magazine that advocates training and workforce development as a business tool. Training is published by The Lakewood Media Group.

Corporate Contact: Rebecca Sipes, CGIRB rsipes@cgirb.com

Media Contact: Gwen Hoover, Altitude Marketing gwen@altitudemarketing.com

Sawyer’s lecture  included a general overview of the IRB process, with a focus on Human Subject Protection history and the IRB role in the research process. As an example of the IRB review process, Sawyer provided students with information on IRB ad requirements. The talk also included an activity in which students practiced creating an ad for IRB approval.

In the session, entitled “Building Quality IRBs,” Higgins discussed methods of improving human research protection programs by outlining attributes of a quality HRPP, strategies for gaining institutional support, providing guidance and support to the research community, optimizing resources, streamlining reporting requirements and developing a quality improvement program. Additionally, she shared a case study on how one institution brought about improvement of its human research protections program.

November 1, 2011, Research Triangle Park, NC — Copernicus Group IRB (CGIRB), a leading independent institutional review board, today announced it has been named a finalist in the 2011 North Carolina Technology Association (NCTA) 21 Awards. CGIRB was selected in the “Leading Environmental Steward Company Award” category.

The NCTA 21 Awards are recognized as North Carolina’s most prestigious technology awards, celebrating innovation and excellence in the state. This annual showcase honors companies and individuals in 21 categories who represent the best and brightest in technology and business.

The Leading Environmental Steward Company Award honors the company that best implements a sustainable plan to be more environmentally conscious and socially responsible.

“As an organization focused on quality and innovation, CGIRB is honored to be named as a finalist in the Environmental Steward Company category,” said Bruce Tomason, president and CEO of Copernicus Group IRB. “We are proud to have our paperless e-document management system, CGIRB Connexus®, recognized for its environmental benefits. The system’s advanced functionality makes a truly paperless work environment possible.”

Connexus has altered the landscape and expectations for everyone involved in the IRB review process. Before Connexus, the clinical trial review process was paper-intensive. CGIRB was generating approximately 2,860,000 new pages a year, many of which had to be stored for 10 years or more and accessed repeatedly.

The transformation to a paperless organization allows CGIRB to perform more thorough, efficient reviews by providing secure access to all electronic documentation for current, pending and past studies. In addition, CGIRB dramatically reduced internal and client expenses and created a greener work environment by eliminating paper, printing, storage, shipping and document handling. By combining the inherent advantages Connexus technology with CGIRB’s traditional commitment to personal attention, the result was a new level of excellence in the client experience.

Winners will be recognized at the NCTA 21 Awards Gala on Thursday, November 10, 2011 in Durham, North Carolina.

About NCTA
The North Carolina Technology Association’s mission is “Making North Carolina #1 in Technology and Technology #1 in North Carolina.” The organization does this through three main focus areas: executive engagement, public affairs and enabling member transition to a technology-enabled workforce. For more information, visit http://www.nctechnology.org.

About Copernicus Group IRB
Experience and innovation in ethical review ®

Copernicus Group IRB, established in July 1996, is a leading US independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. The IRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004, reaccreditation in 2007 and 2011, and ISO 9001:2008 certification in 2010.

About CGIRB Connexus®
CGIRB Connexus® is the most advanced integrated paperless document management web portal technology serving the institutional review board (IRB) services industry. Connexus streamlines and enhances the way sponsors, CROs and investigative sites conduct the IRB submission and review process. For more information, visit http://www.cgirb.com/cgirb-connexus/.

Corporate Contact: Rebecca Sipes, CGIRB rsipes@cgirb.com
Media Contact: Gwen Hoover, Altitude Marketing gwen@altitudemarketing.com

October 12, 2011, Research Triangle Park, NC – Copernicus Group IRB will be leading a webinar on Tuesday October 18, 2011. This is a free educational webinar entitled, “Reducing the Barriers to the Conduct and Oversight of Clinical Trials: A Case Study.”

The webinar will discuss the recent announcement of the proposed revisions to existing federal regulations governing human research subjects by the US Department of Health and Human Services (HHS).

The speakers for this presentation will be Barry Mangum, Pharm.D., FCP, Director Clinical Pharmacology, Duke Clinical Research Unit and Yvonne Higgins, A.B., CIP, Director Quality Management at Copernicus Group IRB.

The webinar will provide methods for reducing the barriers to the conduct and oversight of clinical trials. A case study of the collaborative relationship between the Duke University and Copernicus Group IRB in the review and conduct of clinical trials will be presented.

Barry Mangum will present an academic institution’s perspectives of the IRB Process in. Dr. Mangum will describe key barriers and solutions for success in an academic model.

Yvonne Higgins will describe some of the perceived barriers and real solutions the use of independent IRBs as an alternative to the traditional institutional review board model.

The free webinar will be held Tuesday, October 18, 2011 at 11am EDT. Click here to learn more or to register.

About Copernicus Group IRB
Experience and innovation in ethical review ®

Copernicus Group IRB, established in July 1996, is a leading US independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. The IRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004, reaccreditation in 2007 and 2011, and ISO 9001:2008 certification in 2010.

About Duke Clinical Research Unit

The Duke Clinical Research Unit is a state-of-the-art research facility located within the Duke University Medical Center campus that provides infrastructure support to sponsors and investigators who are testing new drug candidates and other cutting-edge therapies and seeking to identify and validate novel biomarkers.

Building on the strength of Duke’s thought leadership, therapeutic expertise, patient base, and access to the latest technologies, the DCRU is a critical component of the Duke Translational Medicine Institute’s efforts to speedily translate new laboratory discoveries into treatments for patients. For more information, please click here.

Date: October 18, 2011    Time: 11 am EST

In a recent announcement of the proposed revisions to existing federal regulations governing human research subjects, the US Department of Health and Human Services (HHS) acknowledged, “There is very little evidence that having multiple IRBs review the same study is increasing protections to subjects,” according to an HHS publication on the recent proposed changes to the review and conduct of human. “By diffusing responsibility for that review, it might actually be leading to weakened protections.”

Click here for more information and to register.

Goals

The goals of this presentation are to provide clarity on the rationale for this proposed change to the federal regulations; to discuss the potential impact on sponsors, CROs, and academic institutions; to dispel some of the myths regarding the independent review board model and to provide a case study of the collaborative relationship between the Duke University and Copernicus Group IRB in the review and conduct of clinical trials.

Background
On July 22, 2011, the U.S. Department of Health and Human Services (HHS) announced a proposal that may result in significant changes to federal regulations on the protection of human research subjects. In the notice, published in the federal register, HHS acknowledged that “the landscape of research activities has changed dramatically” and that there are “many questions about whether the current regulatory framework is adequate and appropriate for the protection of human subjects in the 21st century.” A key purpose of the proposed change is to “…better focus oversight resources on higher-risk research studies.” ¹

The Rulemaking Process

The rulemaking process involves two phases: an advanced notice of proposed rulemaking (ANPRM) followed by a notice of proposed rulemaking. Each phase requires an extended public comment period and subsequent analysis by the government of the comments before publication of the final rule.

The rulemaking process is outlined as follows:

This process presents an invaluable opportunity for IRBs, academic institutions, CROs, pharmaceutical and medical device companies and other stakeholders to provide HHS with initial comments on the proposed changes. Commenters are invited to provide general feedback or to respond to any of the 74 specific questions raised by the authors of the advanced notice.

Key features of the proposed rule
Single IRB of Record for Multi-site US trials
One proposed requirement would be for a single IRB of record for all of the U.S. sites in a multi-site study. This would replace the current practice of multiple and redundant IRB reviews at participating sites.

This proposed streamlined approval process addresses a concern of sponsors and investigators – that a delay in IRB approvals mean delays in the impact of research findings. The ANRPM also suggests that duplicative IRB reviews of multi-site studies not only increases burden, but may also result in weakened protections. Thus, the ANRPM proposes the requirement for a single IRB of record for multi-site studies.

In the discussion of possible solutions, the ANPRM describes two current alternative models of IRB review: the use of central government run IRBs (specifically, the Veterans Affairs CIRB and the National Cancer Institute’s CIRB) and the use of academic consortia. The advanced notice does not acknowledge the existence or merit of other alternative models of IRB review such as review of industry sponsored research by independent IRBs.

Calibrating IRB review based on research risk
A series of changes to the review of research that poses no more than minimal risks to research participants including:

• Expanding the list of research categories eligible for expedited review
• Eliminating the requirement for continuing review of minimal risk studies
• Expanding the categories of research currently reviewed as exempt

Enhancing Informed Consent
The advanced notice calls for greater specificity about how consent forms are written and what information they contain. The document proposes that researchers, sponsors and IRBs adopt strategies to shorten and simplify informed consent documents. The notice invites comment on the value of standardized consent language and the use of oral consent for any research involving surveys, focus groups and interviews conducted with consenting adults, even if identifiers are kept.

The proposed changes would also require written informed consent for collection of biospecimens for research purposes even if no identifiers are kept – but would allow consent to be obtained by the use of a standardized form allowing for unspecified future research. The requirement for written informed consent would not apply to specimens collected prior to the effective date of the new rules.

Establishment of an electronic reporting system for adverse events and unanticipated problems
The advance notice suggests the establishment of a single government-owned website for reporting, storage, and dissemination of adverse events. The notice seeks comment on the use of a set of harmonized definitions and reporting requirements that would fulfill multiple federal reporting requirements.

Data security standards
The advanced notice also proposes mandatory standards for data security and information. The proposed rule would replace the IRB’s authority to evaluate risks to privacy and confidentiality with mandatory data security standards and requirements for all human research. This suggested approach mirrors the current HIPAA Privacy Rule data security requirements including encryption and audit trails.

To submit comments, visit http://www.regulations.gov and search for docket number HHS OPHS-2011-0005. The comment period closes October 26, 2011.

¹ Reforming the Regulations Governing Research with Human Subjects, Ezekiel J. Emanuel, MD, PhD & Jerry Menikoff, MD, JD; New England Journal of Medicine, July 25, 2011

AAHRPP is an independent, non-profit accrediting body that sets rigorous standards for quality and protection of research study participants. To earn AAHRPP accreditation, organizations must provide tangible evidence—through policies, procedures, and practices—of their commitment to scientifically and ethically sound research and to continuous improvement.

“At CGIRB, we are committed to the continuous improvement of our Human Research Protection Program,” said Yvonne Higgins, CGIRB’s Director of Quality Management. “Reaccreditation is evidence of our commitment to the highest level of quality and to upholding our mission–protecting the rights and welfare of human research subjects.”

As an organization driven by quality and innovation, CGIRB became one of the first independent institutional review boards awarded full AAHRPP accreditation in 2004. CGIRB was awarded full reaccreditation in 2007 and 2011. The most recent reaccreditation will extend through fall 2015.

About Copernicus Group IRB

Experience and innovation in ethical review ®

Copernicus Group IRB, established in July 1996, is a leading independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. The IRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004, reaccreditation in 2007 and 2011, and ISO 9001:2008 certification in 2010. For more information, visit http://www.cgirb.com.

About the Association for the Accreditation of Human Research Protection Programs

The Association for the Accreditation of Human Research Protection Programs, Inc. (AAHRPP) promotes high quality research through an accreditation process that helps organizations worldwide strengthen their human research protection programs. For more information, visit http://www.aahrpp.org.

To safeguard the rights, safety and welfare of human subjects, clinical research is a shared responsibility among sponsors, investigators, contract research organizations (CROs) and institutional review boards (IRBs). Central to this shared obligation is the meaningful review and communication of new safety information developed during the clinical trial.

Many federal guidance documents pertaining to reporting have been issued in the past few years. Their intent is to assist the research community in interpreting reporting regulations, and to respond to concerns that the overwhelming volume of reports were inhibiting rather than enhancing the protection of human subjects.

A Change in the Reporting Process

But until the reporting process itself changes—among sponsors, CROs and investigative sites—these federal guidance documents will remain largely academic. For reporting to be both effective and sustainable, the reporting burden on all parties must be reduced. Only then will the bar be raised on providing substantive protections for the subjects participating in clinical trials.

Safety reporting is inherently a complicated process. The stakeholders in the research industry all share responsibility for protection of human subjects, but each performs a different function, with different reporting responsibilities and different methods of handling reports. Loose federal regulatory jargon compounds the issue. For example, the investigational new drug (IND) regulations alone use terms such as adverse effect, adverse experience, adverse event and unanticipated problem seemingly interchangeably.

The Role of the Institutional Review Board

Helpful at this point is insight into the role of the IRB—and the negative effect that non-essential reporting has on the review process.

Upon receiving safety-related information, regardless of source, the IRB is obligated to report the following information to its own board members, the institutional official and the Food and Drug Administration (FDA):

• Any unanticipated problems involving risks to human subjects or others
• Any instance of serious or continuing non-compliance with these regulations or the requirements of the IRB
• Any suspension or termination of the IRB approval

An Institutional Review Board must consider action when the potential arises for new or increased risks to humans subjects. Specifically, we look for:

• Modifications to the informed consent document
• Changes to the conduct of the study
• Stopping the study or suspending enrollment until safeguards have been put in place
• Serious or continuing non-compliance, generally at an investigative site

Corrective action plans can include retraining of staff, re-consenting of subjects, or even suspension of enrollment or approval.

When Is an Event Truly Reportable?

Safety reporting to an Institutional Review Board carries an implicit understanding: That the information is important enough that every party is required to be aware of it, and potentially, to take action on it. This understanding is the crux of the entire issue, because it dictates—or rather, should dictate—what is reported to the IRB and when.

At the very least, information delivered to the IRB should warrant the possibility that some action has to be considered. Action may be in response to any of the three types of information required to be reported by the IRB:

• Risks to subjects
• Serious or continuing non-compliance
• Suspensions or terminations of approval

Keep in mind that taming the reporting burden—reducing the amount of non-critical or non-essential information being reviewed—is central to everyone’s ultimate goal of safeguarding and improving the rights and welfare of trials’ subjects. And so the fundamental question becomes clear: When is an event reportable?

An event is reportable when it meets all of the following criteria:

• Is related or possibly related to the research
• Is unexpected in terms of its nature, severity or frequency
• Suggests that the research places subjects or others at a new or increased risk of harm

Generally, to be reportable, an event should be previously unknown to the IRB and require at least consideration of action to minimize the risk to subjects or others (e.g., a safety-related change to the protocol, or disclosure of risk information in the consent document or investigator’s brochure).

By this definition, most adverse events will not meet reporting requirements. The FDA itself has acknowledged that submission of reports that fail to meet the definition of an “unanticipated problem” do not yield useful information about adverse events—and thus add unnecessarily to the reporting burden, hindering the IRB’s ongoing ability to ensure the protection of human subjects.

This is especially true of most IND safety reports, all of which have already been reported to the same regulatory authority to which the IRB must report—the FDA. In a multisite trial, for example, IND safety reports should be fully assessed and submitted to the IRB by the sponsor or delegated CRO, not by individual investigators—if they are reported at all. As the FDA has noted, the sponsor is in the best position to analyze the significance of the information. Put simply, unless an individual safety report contains information previously unknown to the IRB, and it requires IRB action, then it should not be reported.

Of course, nothing is black-and-white—particularly regulated processes that involve so many different parties. Many of our own clients, for example, have SOPs that require reporting of any event. In such cases, the best practice should become to submit these reports to the IRB in batches, with a narrative explaining the sponsor’s analysis—and the clear indication that no change to the conduct of the study is required.

What Must Be Reported?

In our experience, routine safety events are over-reported to the IRB. This results in many wasted hours receiving, analyzing and responding to meaningless information. If the event doesn’t require the IRB to even consider taking an action, there is no reason to report it.

So what must be reported to the IRB? The answer is straightforward—any risk that was previously unknown or unexpected in type, severity or frequency of occurrence. The IRB should be provided with sufficient information to assess what action is needed to address mitigation of the new risk.

When your safety reporting policy meets these guidelines, the downstream effect will be a dramatically reduced burden of reporting on sponsors, CROs and investigators. The end result will be increased time and attention—for everyone in the process—to attend to the truly important task of assuring the safety of the people who participate in clinical trials.

Tita Simmons’ presentation, entitled, “Quality Assurance and the Protection of Human Research Subjects: The Sponsor, CRO and IRB Partnership,” will discuss how partnerships between the three groups enhance the protection of the safety, rights and welfare of human subjects. Simmons will illustrate her talk with case studies demonstrating how effective communication between all parties can make a difference. Simmons’ presentation will be on Tuesday 6/21 from 10‐11:30am.

CGIRB’s second presenter, Sydney Douglas, will speak on “Training within an IRB – The Importance of Quality Training Programs for IRB Board Members and IRB Staff.” Douglas’ presentation will focus on the often overlooked area of training, and how a company’s commitment to a formalized training program can increase quality and efficiency. Recognizing the need for integrated training to better support IRB functions, Douglas will discuss corporate training programs and their direct benefits when implemented. Douglas’ presentation will be on Thursday 6/23 from 9‐10:30am.

“We are happy to be providing these educational presentations to the research community,” said Bruce Tomason, CEO of CGIRB. “Tita and Sydney are experts in their respective fields. Both of their presentations will demonstrate innovative ways we can work together as an industry to enhance the protection of human research subjects.”

For more information about DIA, please click here.

About Copernicus Group IRB
Experience and innovation in ethical review™
Copernicus Group IRB, established in July 1996, is a leading independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. CGIRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004 and ISO 9001:2008 certification in 2010.

Tita Simmons is Manager, Quality Assurance and Regulatory Compliance at CGIRB with over 15 years of industry experience. Her current focus is the protection of the safety, rights and welfare of human research subjects, regulatory compliance and continuous process improvement. She is a member of the Society of Quality Assurance’s RQAP‐GCP Exam Committee and a Certified Six Sigma Black Belt. Simmons recently presented at the 27th Society of Quality Assurance (SQA) Annual Meeting. She can be reached at TSimmons@cgirb.com.
Sydney Douglas is Corporate Trainer for CGIRB. Ms. Douglas currently provides instructional design and resource and development for Board members and support staff. In addition to managing internal training events, Ms. Douglas also coordinates training for new CGIRB Connexus® users. She can be reached at SDouglas@cgirb.com.

According to federal regulations regarding human research, the principal investigator holds the ultimate responsibility for protecting the safety, rights and welfare of research subjects. Of particular importance is obtaining informed consent according to strict regulatory and ethical requirements.

Complicating the issue, certain “vulnerable” populations or classes of individuals — such as children — may have limited capacity to make voluntary and informed decisions. To this end, both the Food and Drug Administration (FDA) and the Department of Health and Human Services (HHS) have adopted additional safeguards for research involving children.

Regulations define “children” as persons “who have not attained the legal age for treatments or procedures involved in the research under the applicable law of the jurisdiction in which the research is being conducted.” (Thus, the age of consent is determined by state or other local laws.)

Specifically, regulations charge the investigator with responsibilities for:

• Seeking parental permission for the child to participate in the research.
• Securing the child’s assent to participate in the research.

Parental Permission
When research involves children, “parental permission” replaces “informed consent.” For clinical trials and other research that poses greater than minimal risk, the Institutional Review Board (IRB) is required to determine whether the parental permission form has to be signed by both parents, or if the signature of one parent is sufficient.

Assent

“Assent” is a child’s affirmative agreement to participate in the research. The capacity to make voluntary, informed decisions evolves throughout childhood and adolescence and varies among individuals of the same age. The goal of the assent process is to involve children in discussions and decisions about research participation.

Regulations require the assent of the child for certain kinds of research, but they do not elaborate on the specific elements that are required to prove the assent. In his essay on the ethical dimensions of research involving children (written in 1996 but still applicable today), William Bartholome identified the following elements of assent to guide the assent process.

According to Bartholome the investigator should:

1. Help the child “achieve a developmentally appropriate understanding of the nature of her condition.”
2. Disclose to the child “the nature of the proposed intervention and what she is likely to experience.”
3. Assess the child’s understanding of the information provided.
4. Secure “the child’s willingness to accept the proposed intervention.”

Study-by-Study Determinations

The IRB is required on a study-by-study basis to make a determination whether assent will be required. The IRB must consider a number of factors, including the characteristics of target population and the potential for direct benefit. The IRB may waive the requirement for assent in situations where the intervention is important to the health or well being of the subject, or in situations where the child is not capable of assent given his cognitive and emotional maturity and psychological state.

An Ongoing Dialogue

While IRBs and regulatory oversight agencies focus much attention on the documentation of consent, research suggests that gaining informed consent from parents and children is most effective when it occurs as an ongoing/iterative process — as opposed to the one-time act of signing the written document. When possible, parents and children should be given time to think about whether they want to enroll in the study. They should also be afforded the opportunity to speak with others before making a decision. Discussions should allow sufficient time for questions and further explanations. These discussions may take place over several visits — and should happen before presenting a parental permission or assent form.

For younger children, the investigator should focus on providing basic information about what will happen, responding to questions and concerns. For older children and teenagers, the assent process may be similar to the consent process for adults. In some cases, it may be easier for the prospective subject to ask questions of the research team without the parent present.

Signed Documentation

Regulations require a signed form from parents when the research is greater than minimal risk, as is the case with clinical trials.

In deciding whether documentation of assent will be required for studies involving children, the IRB may consider the intellectual and emotional ability of the children to comprehend the concepts involved. In most cases, IRBs require a signed form with a fully detailed explanation for older children and a shorter, simpler documentation of verbal assent for younger children. (For example, this could involve a signature by a parent assenting that the child agreed to participate and appeared to understand what they were being asked to do.)

Therapeutic Misconception

When parents are asked for permission for a child to participate in clinical research, it is often a time of great stress and time pressure. A key ethical tension of clinical research is that some research participants — and parents who enroll their child in a study — will think that the research intervention is designed to provide a therapeutic benefit, when in actuality the intention is to gather data for the purpose of contributing to medical knowledge.

A recent publication in the journal IRB, Ethics & Human Research underscores the problem of therapeutic misconception during the consent process. The study assessed the ability of parents of critically ill neonates to recall core information provided to them before agreeing to enroll their children in a Phase II double-blind placebo-controlled trial. The clinical trial was designed to evaluate the effectiveness of azithromicin in the prevention of bronchopulmonary dysplasia in neonates who weighed less than 1,250 grams at birth and required mechanical ventilation during the first 72 hours of life. Twenty-three percent of parents interviewed for the consent process study stated that the primary purpose of the phase II clinical trial was to help their newborn’s lungs. Fewer than 10% of parents surveyed at the time of discharge could recall any of the potential risks from participation in the clinical trial.

This study underscores the importance of an investigator’s need to be sensitive to the influence of therapeutic misconception when talking with parents of ill or injured children who may misunderstand the purpose of the research.

From Minor to Adult

When the clinical investigation includes subjects who will reach the legal age of consent during the course of the study, both legal and ethical issues come into play. In this case, the subject — who is now considered an adult — must be again given the opportunity to provide informed consent before continuing in the clinical investigation. As a result, the IRB may require a statement in the parental permission and assent form to remind the subjects of their right to continue or to withdraw from the study once they become an adult.

Conclusion

Parental permission and a child’s assent remain critically important protections both during initial discussions with potential subjects and throughout the child’s participation in clinical research. As such, it is the responsibility of the investigator to ensure that all regulations and documentation is handled in a compliant and timely manner.

Additional Resources

Both the FDA and the NIH provide important information and tools online to inform parents and children who are considering participation in clinical research. These tools are often used by clinical investigators to guide parents through the decision-making process.

NIH Website — Children and Clinical Studies: http://www.nhlbi.nih.gov/childrenandclinicalstudies/index.php

FDA Website — Should your child be in a clinical trial? http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm048699.htm

References

William Bartholome. “Ethical Issues in Pediatric Research,” in The Ethics of Research Involving Human Subjects. Frederick, MD: University Publishing Group, 1996; pages 360-361

Marilyn J. Field and Richard E. Berman, Editors. The Ethical Conduct of Clinical Research Involving Children. National Academies Press, 2004

David Ungar, Steven Joffee and Eric Kodish, “Children are Not Small Adults,” in The Journal of Pediatrics. July 2006; 149:S31-S3

Hubert Ballard, et al., “Parents Understanding and Recall of Informed Consent Information for Neonatal Research,” in IRB Ethics and Human Research. May – June 2011; 33:3, 12-17

Sodrel’s article describes the goals, challenges and benefits of CGIRB’s transition to a fully paperless company.

Ms. Higgins comes to CGIRB from the University of Pennsylvania where she served as Executive Director of the Human Research Protections Office since 2004. Prior to that, Ms. Higgins held positions at the Office of Human Research Protections (OHRP) within the Department of Health and Human Services as well within the offices of the US Army and the US Air Force Surgeons General. Ms. Higgins has been an AAHRPP site auditor since 2007 and a member of AAHRPP’s Council since 2009.

The recipient of many awards, Ms. Higgins’ most recent achievement was the Distinguished Service Award bestowed by Public Responsibility in Medicine and Research (PRIM&R), which is awarded to a member of the organization who has made valuable and unique contributions to the field of research ethics, and who has attained distinction in promoting PRIM&R’s purpose and ideas through writing, teaching or research.

“The knowledge and deep commitment to human subject protection that Ms. Higgins brings with her will be a tremendous asset not only to our organization, but also to our clients and ultimately, the human research subjects we protect,” said Bruce Tomason, CEO of CGIRB. “With Ms. Higgins’ experience and guidance, CGIRB will continue to innovate and to constantly improve its human research protection program and quality management system.”

Ms. Higgins earned her A.B. in Biology from Hood College and a Certificate in Human Research Ethics from the University of Washington School of Medicine. In 2001, Ms. Higgins became among the first to earn a certificate as an Institutional Review Board Professional (CIP), from the Council for Certification of IRB Professionals. Additionally, she earned a Level II Certification in Quality Assurance from the Defense Acquisition University.

Copernicus Group IRB, established in July 1996, is a leading independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. The IRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004 and ISO 9001:2008 certification in 2010.

About Copernicus Group IRB
Experience and innovation in ethical review™
Copernicus Group IRB, established in July 1996, is a leading independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. The IRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004 and ISO 9001:2008 certification in 2010.

CGIRB’s chairperson, Glenn Veit, JD, CIP, described an effective approach to safety reporting for sponsors, CROs and investigative sites. The goal of the webinar was to bring clarity to the recent guidance and to help reduce the burden on sites, sponsors, CROs and review boards while raising the bar on providing meaningful protection of the subjects participating in clinical trials.

“The truly important task is protecting the safety of the people who participate in clinical trials,” said Veit. “Central to this is the meaningful review of new safety information. By providing this presentation on understanding FDA’s guidelines and IRB reporting requirements, we hope to provide clarity regarding the responsibilities of the stakeholders involved to reduce duplicative reporting and to re‐emphasize the priorities of patient care and subject protection. I look forward to addressing several common reporting errors and to hopefully demystifying FDA guidance and IRB reporting requirements during the webinar.”

Download recording of this Webinar

About Glenn Veit
Glenn Veit is a graduate of Duke University Trinity College of Arts and Sciences and North Carolina Central University School of Law. He was trained and practiced as a trial lawyer since 1987, concentrating on issues of medical and hospital negligence, criminal defense and civil litigation, including juvenile law and children’s issues.

Glenn has served as Chair of the Copernicus Group IRB since its inception in 1996. He is a Certified IRB Professional by Public Responsibility in Medicine and Research, the national organization for the protection of human subjects in research.

About Copernicus Group IRB
Experience and innovation in ethical review™
Copernicus Group IRB, established in July 1996, is a leading independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. CGIRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004 and ISO 9001:2008 certification in 2010

CGIRB’s chairperson, Glenn Veit, JD, CIP, will describe an effective approach to safety reporting for sponsors, CROs and investigative sites. The goal of the webinar is to bring clarity to the recent guidance and to help reduce the burden on sites, sponsors, CROs and review boards while raising the bar on providing meaningful protection of the subjects participating in clinical trials.

“The truly important task is protecting the safety of the people who participate in clinical trials,” said Veit. “Central to this is the meaningful review of new safety information. By providing this presentation on understanding FDA’s guidelines and IRB reporting requirements, we hope to provide clarity regarding the responsibilities of the stakeholders involved to reduce duplicative reporting and to re‐emphasize the priorities of patient care and subject protection. I look forward to addressing several common reporting errors and to hopefully demystifying FDA guidance and IRB reporting requirements during the webinar.”

The webinar is open to all interested parties and will be held Wednesday, May 4 from 11am‐12pm EDT. For more information on the webinar and to sign up for free, please click here.

About Glenn Veit
Glenn Veit is a graduate of Duke University Trinity College of Arts and Sciences and North Carolina Central University School of Law. He was trained and practiced as a trial lawyer since 1987, concentrating on issues of medical and hospital negligence, criminal defense and civil litigation, including juvenile law and children’s issues.
Glenn has served as Chair of the Copernicus Group IRB since its inception in 1996. He is a Certified IRB Professional by Public Responsibility in Medicine and Research, the national organization for the protection of human subjects in research.

About Copernicus Group IRB
Experience and innovation in ethical review™
Copernicus Group IRB, established in July 1996, is a leading independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. CGIRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004 and ISO 9001:2008 certification in 2010.

Simmons delved into Institutional Review Board ethics, quality assurance, regulatory compliance and protection of research subjects. She discussed how partnerships between Sponsors, CROs and IRB Quality Assurance professionals enhance the protection of the safety, rights and welfare of research subjects. Her talk included an analysis of CGIRB case studies illustrating effective sponsor, CRO and IRB QA professional partnerships in the prevention, detection, and handling of investigator noncompliance.

“I appreciated the opportunity to raise awareness on improving partnerships to enhance the protection of human safety,” said Simmons. “At CGIRB, we are always looking for innovative new ways to apply and share our experiences in ethical review.”

CGIRB’s dedication to providing educational resources will continue with a webinar on May 4. The webinar will focus on safety reporting to the IRB and cover effective approaches to safety reporting for sponsors, CROs and investigative sites. Ultimately, the goal is to reduce the reporting burden while raising the bar on providing meaningful protection of the subjects participating in clinical trials.

For more information on the upcoming webinar, please click here
For more information on the SQA, please click here.

About Copernicus Group IRB
Experience and innovation in ethical review™
Copernicus Group IRB, established in July 1996, is a leading independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. CGIRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004 and ISO 9001:2008 certificatio

February 10, 2011-Research Triangle Park, NC ‐ Copernicus Group IRB (CGIRB) announced today that it has been named a finalist for the 2011 Carl E. Nelson Best Practices Award. This prestigious award was established by AIIM (Association for Information and Image Management) to recognize excellence in information management.

Copernicus Group IRB is a finalist in the Small Company category for its transformation into a paperless company, in partnership with Sitrof Technologies and Xerox Corporation’s DocuShare® enterprise content management (ECM) software. CGIRB now operates in a paperless environment as it approaches the two year anniversary of its implementation. The paperless endeavor involved a massive legacy document scanning operation, including 1.5 million documents totaling 5 million pages. It also included the transitioning of all inbound paper and internal documents while maintaining FDA 21 CFR Part 11 compliance.

“We are pleased to be a finalist in the AIIM Best Practices Awards,” said Bruce Tomason, CEO of CGIRB. “This was a large undertaking but we view it as part of our ongoing commitment to innovation in ethical review. Going paperless has made us a more efficient, green company but most of all, it allows us to better serve our clients.”

“The quality of the submissions for the Carl E. Nelson Best Practice Award continues to improve raising the bar on best practices while emphasizing innovation, benefits and lessons learned,” said John Mancini, President, AIIM. “Our AIIM Emerging Technology Advisory Group (EmTAG) selected the finalists in each category for the Best Practices Award. Our professional members are determining the winner in each category. Each of the finalists share many valuable lessons learned to help others with their implementations.”

AIIM professional members will choose the winner from the finalists. Award winners will be announced at the AIIM Annual Awards Celebration, March 22 at The W Washington, DC, where John Mancini, AIIM’s President, will announce the winner.

About Copernicus Group IRB
Experience and innovation in ethical review™
Copernicus Group IRB, established in July 1996, is a leading independent institutional review board (“IRB”) dedicated to ensuring the rights and welfare of research study participants. CGIRB provides ethical review of research protocols, investigators, and subject information and consent forms to ensure compliance with federal regulations set forth in 21 CFR, 45 CFR and ICH/GCP Guidelines. CGIRB achieved full AAHRPP accreditation in 2004 and ISO 9001:2008 certification in 2010.