The war in Iraq, officially called Operation Desert Storm, began under President George H. W. Bush. First-class postage increased from 25 cents to 29 cents. Silence of the Lambs was released in movie theatres. The Dow Jones Industrial Average closed at 3000 for the first time in its history. Mikael Gorbachev resigned as president of the Union of Soviet Socialist Republics and member states declared their independence. Clinical trials of statin drugs for treating high-cholesterol were being studied with mixed results. Looking back, research professionals undoubtedly would say that these major events occurred a long time ago.

It was 1991. In June, the U.S. Department of Health and Human Services (HHS) adopted the Common Rule, which pertains to human subject protections and is adhered to by 15 federal agencies that fund research. These regulations, which are referenced at 45CFR46 as Subpart A, delineate what the policy applies to and define terms such as “human subject,” “identifiable private information,” and “minimal risk.” This regulation also covers compliance, institutional review board (IRB) membership, criteria for IRB approval, including expedited review, continuing review, and requirements for informed consent; and waiver of consent requirement. The Common Rule has three additional subparts:

• Subpart B — Additional Protections for Human Fetuses and Neonates Involved in Research, Pregnant Women, and Human In Vitro Fertilization;
• Subpart C — Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects;
• Subpart D — Additional Protections for Children Involved as Subjects in Research.

Research practitioners have been applying the Common Rule to their professional work for more than two decades. When viewed from the broad perspective of the other events that were happening in 1991, and where the world has evolved now (e.g., Internet, social media, the human genome), there is no doubt that changes to the regulations governing research are prime for revision. The cliché that “change is inevitable” certainly applies in 2016 to human subject protections.

On September 2, 2015, HHS and the 15 other federal departments and agencies that have agreed to abide by the Common Rule published a Notice of Proposed Rulemaking (NPRM),1 a major step in developing rules for 21st century research. Publication of an NPRM follows an Advanced Notice of Proposed Rulemaking (ANPRM). The ANPRM was published July 26, 2011.2 More than 2000 comments were sent to HHS on the ANPRM. There has been limited activity by the federal government on the ANPRM following the close of the comment period. Generally, under federal rules, the comment period for an ANPRM is 90 days. Likewise, comments can be submitted on an NPRM during a 90-day review period.

“The [NPRM/2015] proposed changes to the regulations have profound implications for researchers, research institutions, IRBs, and the sponsors of clinical research,” says David Borasky, vice president of quality management at Copernicus IRB, a WIRB-Copernicus Group Company. “The most important and substantial proposals involve informed consent.” These include content changes to the consent document and a mandate to publish consent documents publicly. A second new requirement pertaining to informed consent would make it mandatory for the study investigator to obtain broad consent for future research use of biospecimens. Another substantial proposal is that most multi-site trials will be required to use a single IRB chosen by the government agency that is funding the research. The NPRM also makes extensive efforts to limit administrative burden in the current system for minimal risk research. Borasky adds, “Current exemptions have been expanded, and several categories of research are being excluded from the Common Rule altogether.” These include oral histories, journalism, and public health surveillance. Continuing review requirements for certain classes of minimal risk research that require IRB review will be eliminated. Additional security requirements will be added to allow research in which the only risk is breach of confidentiality to proceed with less oversight, he says.

While change in the rules governing human subjects research is inevitable, it is proving also to be difficult. After 5 years and thousands of comments from research professionals and the public to HHS, there are many comments in favor of some changes. But there is also serious concern about the proposed changes and whether publication of a final rulemaking without major revisions would pose a grave harm to human subjects and the research enterprise itself. The concerns raised in the comments submitted to the Office for Human Research Protections (OHRP) come from people from many different backgrounds. Some are patients or family members who have a serious disease and may hope to help others by participating in research trials. Some are from several highly respected professionals who have played a key role in the development of the ANPRM and NPRM.

One of these highly respected research professionals is Jeffrey Botkin, the current chair of the Secretary’s Advisory Committee for Human Research Protections (SACHRP). Botkin commented on the ANPRM in 2011, acting in his capacity as the associate vice president for research integrity at the University of Utah. In December 2015, in his capacity as SACHRP chair, he said the following in a 50-page document sent as a comment on the NPRM from SACHRP:

“SACHRP and its subcommittee members have taken this opportunity seriously and have spent hundreds of hours in efforts to understand the proposals, assess their ethical foundation, anticipate the consequences and potential adverse consequences of the proposals for a range of stakeholders, and to craft responses and recommendations. … Despite extensive study of the NPRM in collaboration with numerous colleagues, the universal assessment is that the proposals are virtually impenetrable due to opaque language, unclear concepts, the overlapping nature of various elements, and the intricate relationships of elements to one another. A common refrain is, ‘If we can’t understand this, where will that leave the average IRB, administrator, and investigator?’”

So, here we are on a precipice. It is unlikely that OHRP will abandon its effort to change the Common Rule. As the final year of the Obama Administration draws to a close, an HHS spokesperson says the Obama Administration has been “very supportive of the effort to update the nation’s research regulations.” Institutions, investigators, and IRBs may be faced with implementing some of these provisions later this year, although the NPRM grants a three-year implementation for most changes. This and subsequent articles in Research Practitioner in 2016 will focus on explaining the proposed changes and how research professionals can respond to the new requirements. Research practitioners may need to begin implementation of some areas of the NPRM as early as late fall 2016 or early 2017.

Behind the movement for change

The first hint that the Federal Policy for the Protection of Human Subjects (the Common Rule) might need some revision began to surface in the early 2000s. Between 1991 when the Common Rule was promulgated until the turn of the 20th century, the federal oversight of human research was done by the Office of Protection from Research Risks (OPRR). In the decade that followed, the number of clinical research trials exploded. There also were an increasing number of situations that prompted concern not only about human subject protection but also about the burden of government regulations on investigators, institutions, sponsors, and IRBs. These concerns gradually became the core reason behind the ANPRM published in 2011. To understand why and how the first change in human subject protection regulations in 25 years came to be, it is instructive to review its past roots.

The number of research trials increased in the 1990s and in 1996, the Health Insurance Portability and Accountability Act (HIPAA) was adopted. The Privacy Rule set standards to address the use and disclosure of “protected health information.” Under the Privacy Rule, individually identifiable health information could be “de-identified by removal of certain identifiers such as DNA.”

Also during this time period, the federal government required that research institutions (mainly academic medical centers) obtain from OPRR an assurance document stating that they would conduct research in compliance with the federal regulations on human subject protection. In essence, the Multiple Product Assurance was a license to practice or conduct research with human subjects. OPRR could completely revoke the assurance if it found non-compliance or suspend it (and enrollment in clinical trials) until requirements were met.

The late 1990s and early 2000s also saw a sharp rise in the number of research institutions that OPRR determined were non-compliant with federal regulations on human subject protection. West LA Medical Center, Duke University, University of Illinois at Chicago, Johns Hopkins University, University of Rochester, University of Chicago, Virginia Commonwealth University (Medical College of Virginia at Richmond), Fred Hutchison Cancer Research Center, University of Oklahoma, and others, were told to suspend or shutdown their research programs until they could correct problems found by OPRR during a “for-cause” site visit.3 Research inefficiencies were similar, if not the same, at these sites. They included:
failure to adequately educate research staff regarding human subject protection regulations;

• failure to document informed consent;
• failure to conduct continuing review;
• failure to keep adequate records;
• failure to develop standard operating procedures;
• failure to obtain informed consent.

In September 1999, Jesse Gelsinger, a young man who had just turned 18 years of age, volunteered for research that might help other teens and children who suffer from ornithine trans carbamlase (OTC) deficiency, a genetic liver disorder that denied the person the ability to metabolize ammonia. Jesse suffered from OTC deficiency as a child, but his mild case was manageable. Jesse’s unexpected death sent shockwaves through the clinical research community and the public when The New York Times broke the story.4 His father, Paul Gelsinger, told the in-depth story of how Jesse Gelsinger decided to volunteer in the study and the medical consequences in “Jesse’s Intent.”5

HHS officially dissolved OPRR in 2000 and created OHRP, moving the agency from the National Institutes of Health and elevating it to an HHS level office due to concerns about OPRR’s dependence with the NIH structure. This is why there are current concerns about the NIH’s influence on OHRP around the NPRM. The new OHRP director and staff reported directly to the Secretary of HHS. Greg Koski, a physician researcher at Harvard Medical School and Massachusetts General Hospital, Boston, was named the first OHRP director. Koski promoted two significant policy changes at OHRP: the single assurance program and a quality improvement program.6

The goal of the federal-wide assurance is to allow research sites to increase human subject protection efforts and decrease the paperwork burden, says Koski. This was intended to address the issue of regulatory burden, “The program is what allows [us] to move from reactive enforcement to proactive support,” he says.

HHS Secretary Tommy Thompson created SACHRP in 2002 after the dissolution of the National Human Research Protection Advisory Committee. The group’s charge is to provide expert advice and recommendations to the Secretary. (There have been several heads of HHS after Thompson. The current Secretary is Sylvia Burwell.)

SACHRP appointed the Subpart A Subcommittee (SAS) in 2005, to review and assess all provisions of Subpart A of 45CFR46 and relevant OHRP guidance documents.7 Based on this review and assessment, SACHRP aimed to develop recommendations for consideration by the full SACHRP in three categories:

• interpretation of specific Subpart A provisions;
• development of new or modification of existing OHRP guidance;
• possible revisions of Subpart A.

The chair of the SACHRP at that time was Ernie Prentice, vice chancellor, College of Medicine, University of Nebraska Medical Center. Prentice wrote a memo to the Secretary Jan. 15, 2005, which listed the following three goals of the SAS:

• enhance protection of human subjects;
• reduce regulatory burdens that do not contribute to the protection of human subjects;
• promote scientifically and ethically valid research.

The subcommittee had its first meeting via teleconference on January 18, 2005, and met four to five times a year. Chairs Elizabeth Bankert, assistant provost and director of the IRB at Dartmouth College and Dartmouth Hospital Medical Center, and Daniel Nelson, Office of Human Research Protections, University of North Carolina, presented the SAS findings and recommendations to SACHRP from October 27-28, 2008. Throughout the findings, SAS proposed two questions: “What is the issue? What are we trying to fix?”

In 2007, SAS formed three working groups in the areas of institutional responsibilities, informed consent, and exemptions. The first issue SAS tackled was that assurance requirements do not always “fit” with today’s environment. They presume a single-site model and a one-to-one relationship between the institution filing assurance and “their local IRB(s).” Bankert and Nelson say that the requirements do not fully anticipate multicenter collaborations and work against effective and efficient implementation of alternate models of IRB review, which SACHRP and others are attempting to encourage, such as cooperative review arrangements, consortia, and central IRBs. The second issue was regulatory review of informed consent (form and process). The task of review was given to the working group on institutional responsibilities led by Gary Chadwick, professor emeritus, School of Medicine and Dentistry, University of Rochester. Chadwick presented the group’s findings to SACHRP on Sept. 23, 2008.

“While the basic and additional elements of consent have remained unchanged in the human subject protection regulations, the level of detail provided in consent forms has skyrocketed in the past few years,” says Chadwick. This has led to erosion of IRB-investigator trust and respect for regulatory compliance, as well as diminished the consent process for subjects. “In clinical trials, clinical investigators report that consent forms are of such length and complexity that they only serve to overwhelm subjects … and that subjects just ask them, ‘Where do I sign?’” Investigators report that overly detailed consent forms impede the enrollment process without improving subject protection and that IRB review is unproductive and intrusive to the point of abuse. Furthermore, the working group explained that the regulations on informed consent place responsibility for consent on the investigator rather than the IRB. The regulation lists the elements of informed consent that are required in the process. “There is no reference to a form in this section of the regulations, just information.”

One step toward resolving this problem may be in regulatory interpretation, says Chadwick. “If the word ‘embodies’ in 45CFR46.117 (and 50.27, FDA) can be understood to mean ‘information in general’ versus ‘information in detail,’ then consent forms can be designed to aid to the subject’s informed consent decision that the Belmont Report envisioned,” says Chadwick. “The use of addenda and alternate formats can support the provision of information in the consent process. The only way to change the practice in the field is for OHRP and FDA to take the lead and actively endorse and support the use of shortened consent forms.” 

According to Chadwick, the primary responsibility for fulfilling the requirements of 45CFR46.117 would be placed back with investigators. “The amount of detail in the consent discussion would be more flexible and could better meet the needs of individual subjects rather than a form-dependent, ‘one size-XXL-fits all’ model,” he says. IRBs would still have to approve the process for informed consent and the written materials. “The focus on the process will probably mean more work for IRBs. Institutions will have to ensure that the consent process is ‘effective’ and this will probably require more resources (auditors, mentors, and oversight).”

Chadwick’s group said that subjects would still have access to the same information that they have now through an addendum, but that information would be presented in a more subject-appropriate and less burdensome way, and informed consent would be enhanced. The recommendations that emerged from the SAS working group on informed consent included the following:

• repackage the consent form;
• use an addendum;
• move institutional elements to an addendum;
• move HIPAA to an addendum;
• consider  use of executive summaries or information sheets;
• consider alternate formats (videos, CDs, web-based information);
• consider expanded use of short form (not just for foreign language or illiterate populations).

The ANPRM begins to take shape

The proposed changes in the NPRM likely come from these earlier SACHRP recommendations with some expansion. For instance, the NPRM requires that most multisite clinical studies use a single IRB chosen by the government agency funding the research. “The most important and substantial proposals involve informed consent,” says David Forster, chief compliance officer at WIRB-Copernicus Group. “The NPRM will make the consent form shorter and more directed to information important to the subject. Less important information will be placed in appendices. Consent forms must be posted publicly to enhance transparency.”

The working group suggested sample educational tools that might improve the informed consent process and investigator training directed at the consent process that includes not only the regulatory aspects of consent but also provides practice or mentoring in the process itself. It also recommended that OHRP address the confusion regarding guidance on HHS-funded research using coded specimens or information.

The NPRM makes additions to the basic elements of informed consent in 45CFR46.116, including a “statement about whether or not the subject’s data will be used for future research studies if the identifiers are removed.” It also lists the following three elements that are added to the list of additional elements:

• discussion of commercial profit and whether the subject will share in such profit;
• whether clinically relevant results will be returned to the subject;
• options for consenting or refusing to consent to be contacted for more information/biospecimens or another research study.

The major change in the Common Rule proposed in the ANPRM and NPRM is probably the most controversial, says Borasky. (The Subpart A subcommittee is now co-chaired by Borasky and Michele Russell-Einhorn, senior director of the Office of Human Research Studies, Dana-Farber Cancer Institute). “Consent will be required for all future biospecimen research, regardless of the setting in which it is collected,” he says.

According to HHS, “informed consent would generally be required for secondary research with a biospecimen (for example, part of a blood sample that is left over after being drawn for clinical purposes), even if the investigator is not being given information that would enable him or her to identify whose biospecimen it is. Such consent would not need to be obtained for each specific research use of the biospecimen, but rather could be obtained using a ‘broad’ consent form in which a person would give consent to future unspecified research uses.” This proposed change has received overwhelming opposition from various stakeholders, engaged in different disciplines.

The change in biospecimen research consent would also have to meet additional requirements for storage of data. IRBs will be tasked with the added responsibility of reviewing these safety measures. One of the groups of professionals who are most concerned about the ramifications of going ahead with this requirement is public health professionals. “The Minnesota Department of Health Public Health Laboratory (MDH-PHL) believes that requiring written consent for secondary use of biospecimens previously collected for non-research purposes will be detrimental to the work performed by public health laboratories and to the practice of public health in general,” says Joanne Bartkus, MDH-PDL director. “The need for consent for use of existing specimens should be related to the nature of the study and the risk of compromising the privacy of the subject.”

“It is the opinion of the MDH-PHL that it is critical to protect and respect the privacy of individuals. However, requiring informed consent for the use of biospecimens collected outside a research study would be an almost insurmountable barrier to conducting public health studies. A physician has no way of knowing in advance whether a specimen will be of public health importance; therefore, informed consent would need to be obtained essentially for every specimen collected,” says Bartkus.

Boston Children’s Hospital (BCH) is one of several pediatric facilities with concerns about requiring written consent for all biospecimen research. “We disagree with the premise that all biospecimens are inherently identifiable by virtue of containing DNA that could be extracted and analyzed for research. DNA only becomes identifiable when someone has access to a named reference sample, and analyzes it against unknown samples. Treating all specimens as inherently identifiable, regardless of the type of research actually conducted on these samples, misleads the public, and will impact the ability to conduct valuable non-genetic research,” according to a BCH comment.

Many comments to HHS on the proposed changes in consent for biospecimen research are also against the change on philosophical/ethical grounds. Russell-Einhorn does “not support the different treatment in the NPRM for biospecimens and data. The NPRM creates very rigid requirements surrounding the use of biospecimens and yet opens the flood gates to research on identifiable data. And, it eliminates any incentive to de-identify biospecimens,” she wrote in a comment Nov. 20, 2015. Russell-Einhorn says that broad consent is not meaningful consent and raises ethical questions. She does not support the criteria regarding a waiver for use of biospecimens.

HHS explains it this way: Waiver or alteration of consent will not be required regardless of identifiability if it meets the other requirements of a broad consent and meets strict storage criteria. HHS says that the NPRM changes would mean that, “Some studies that are now considered exempt would specifically be declared as outside the scope of the regulations (‘excluded’), and thus would not require any administrative or IRB review.” OHRP will develop a web-based tool to be used by investigators and IRBs to determine when a study is exempt.

The new waiver criteria require that there are compelling scientific reasons for the research and that the research could not be conducted with other biospecimens for which informed consent was obtained or could be obtained. “These criteria limit the ability of the IRB to assess the proposed use of biospecimens in light of the specific protocol, the participant populations, institutional needs, and other legitimate competing considerations,” says Russell-Einhorn. She likewise does not support adding biospecimens to the definition of human subject. The proposed change would state, “Human subject means a living individual about whom and investigator…conducting research…obtains, uses, studies, or analyzes biospecimens.”

According to Jerry Menikoff, current OHRP director ,there are two main goals of the changes: To better protect human subjects and to reduce the regulatory burden on investigators and IRBs. “The rationale behind the new consent for use of de-identified biospecimens is autonomy. People want to know what is happening with their blood,” he says. In an OHRP NPRM webinar conducted in fall 2015, Menikoff further noted that, “If an investigator asks a potential subject for permission to use biospecimen and he/she declines, it cannot be used.”

Exclusions and exemptions

The ANPRM and NPRM propose a change in the definition of the term “exempt,” and also add a new “excluded” category to the regulations. This would exclude from coverage under the Common Rule certain categories of activities that should be deemed not to be research, are inherently low risk, or where protections similar to those usually provided by IRB review are separately mandated.

HHS says the addition of categories of exempt research are intended to accommodate changes in the scientific landscape and to better calibrate the level of review to the level of risk. A new process would allow studies to be deemed exempt without requiring any administrative or IRB review. Certain exempt and all non-exempt research would be required to provide privacy safeguards for biospecimens and identifiable private information. The new categories include:

• certain research involving benign interventions with adult subjects;
• research involving educational tests, surveys, interviews, or observations of public behavior when sensitive information may be collected, provided that data security and information privacy protections policies are followed;
• secondary research use of identifiable private information originally collected as part of a non-research activity, where notice of such possible use was given;
• storing or maintaining biospecimens and identifiable private information for future, unspecified secondary research studies, or conducting such studies, when a broad consent template to be promulgated by the Secretary of HHS is used;
• safeguards are followed and limited IRB review approval of the consent process used is obtained.

Menikoff says that the new rule on “exclusions” is not a new concept. Rather, he says, it clarifies the line between exempt and non-exempt research activities and terms like “low risk” and quality assurance activities. Menikoff adds that OHRP will develop a tool for making the distinctions between exempt and excluded research that follows a strict algorithm.

Comments from research professionals to HHS on “excluded” research are split. Russell-Einhorn does not support the new exclusions and recommends that they be moved into the exemption criteria. “These exclusions are difficult to interpret and involve research that should be subject at least to some cursory IRB review as required for exempt research,” she says. “I cannot support the changes to the exemptions without being able to review the exemption decision-making tool.”

Groups that would likely benefit from the new “excluded” category submitted comments on the ANPRM and NPRM. “Our organization strongly recommends that history as a discipline, and the practice of oral history, specifically, be excluded from oversight under the Common Rule,” says Alice Kessler-Harris, president of the Organization of American Historians, Columbia University, New York. She says that oral history interviews are not intended to be systematic in the sense that the Common Rule implies.

Children’s Hospital of Philadelphia (CHOP) sent these comments on the NPRM on Jan. 6, 2016. “The current NPRM proposal on ‘excluded’ research will create confusion and will not reduce the administrative burden or improve protections of human subject research participants. There is no reason to include activities that are neither research nor human subjects research, such as program improvement or quality improvement activities, in regulations regulating human subjects research. Moreover, the NPRM does not give clear guidance on what types of activities would be considered QI activities excluded from the jurisdiction of the Common Rule. The term ‘low risk’ is not clearly defined and may be confused with the term ‘minimal risk.’”

Concern is also raised about relying on the investigator(s) to make that determination. “If institutions delegate the exempt determination to individual investigators, institutions will need to develop programs for verifying the accuracy of investigators’ completion of and compliance with the tools that will be developed. This would shift the burden from before the research starts to after commencement of the research, but this does not reduce the burden on the institution,” say CHOP officials. The NPRM lists biospecimen activities that would be deemed as “not research”:

• internal operational monitoring and improvement when data and specimens are not collected for this specific purpose;
• criminal justice or criminal investigation;
• quality assurance or improved activities;
• public health surveillance;
• defense, national security, homeland security.

Many of the NPRM commenters expressed their surprise that OHRP is proposing the mandated informed consent for future biospecimen use, particularly the use of broad consent. However, this is not the first time that HHS has issued guidance on informed consent for use and storage of biospecimens.8 In 1997, OPRR published Issues to Consider in the Research Use of Stored Data or Tissues.9 In 2008, OHRP published an updated guidance, Guidance on Research Involving Coded Private Information or Biological Specimens.10 The SAS reviewed current thinking on the issue and presented a set of additional guidance to SACHRP in the format of Frequently Asked Questions (FAQs).11

But it is two events that were/are in the public’s eye that may have served as an even greater impetus for OHRP officials who wrote the NPRM recommendations. In 2010, an award-winning science writer told the story of Henrietta Lacks and her tissue samples that made history. The Immoral Life of Henrietta Lacks by Rebecca Skloot is the story of a poor, African American woman named Henrietta Lacks who went to Johns Hopkins Hospital in Baltimore, MD, in 1951 after suffering severe abdominal pain and abnormal bleeding.12 She was diagnosed with cervical cancer. During her subsequent surgery, the surgeon on duty at the public hospital ward treated her tumor and took two tissue samples, one from her tumor and another from healthy cervical tissue that was in the same area. Without her knowledge or consent (not unusual at the time, especially in a public hospital where the patient was given free care), the doctors did what they had done numerous times with tissue from other patients — they watched it die in a glass dish. But Henrietta‘s sample was different; her cancerous tissue grew and grew. As the cover of the book says, “They launched a medical revolution and a multimillion dollar industry.” The book made the NY Times best seller list and won many accolades. According to an HHS spokesperson, “The Henrietta Lacks story, indeed, highlighted the issue of consent for further specimen use.” The original closing date for comments to HHS on the NPRM was December 5, but it was extended one month to Jan. 6, 2016. On Dec. 30, 2015, Rebecca Skloot wrote an opinion piece for The New York Times titled “Your Cells. Their Research. Your Permission?”13 Skloot strongly encourages the public to submit comments on the NPRM before the lingering deadline just 7 days away. Many commented.

According to OHRP’s Menikoff, this might be why the NPRM changes were made — because people want to know what happens to their blood or tissue.

Many research professionals who commented on the proposed Common Rule changes said there was no factual evidence to prove that point. Skloot disagrees: “The proposed changes are open for public comment, but so far most comments are coming from scientists, research institutions, bioethicists, and industry groups who strongly oppose the new consent requirements. Many favor the status quo; others want changes, but disagree with the ones proposed. Some question whether people even care what happens to a vial of blood or bits of a tumor after they leave the doctor. But trust me, they care…. People have told me by the thousands…. They want to know if their biospecimens are used in research, and they want to be asked first. Most will probably say yes, because they understand it is important. They just don’t want to find out later. That damages their trust in science and doctors. It makes them wonder, what else are you hiding from me?”

A second situation regarding use of blood for research that has raised both ethical and legal concerns is the storage and use of residual newborn screening blood spots.14 “With the completion of the human genome project and the popularity of genome-wide association studies, the value of residual dry blood spots (DBS) has increased.”14 One lawsuit in particular demonstrates the nature of the lawsuits. Families of babies who claimed storage and use of DBS alleged that use violated their constitutional protection from unlawful search and seizure. The out of court settlement required the state of Texas to destroy more than five million residual DBS.

Multicenter trials and a single IRB

With the goal of decreasing administrative burden, the NPRM proposes a mandate that U.S. institutions engaged in cooperative research rely on a single IRB for that portion of the research that takes place in the U.S. “To encourage the use of IRBs that are otherwise not affiliated with or operated by an assurance-holding institution, the NPRM includes a proposal that would hold such IRBs directly responsible for compliance with the Common Rule.” NIH’s draft policy that would require single IRB use continues to move toward implementation sometime this year. NIH would simply expand that policy to all federal departments and agencies.

There are definitely mixed reviews on this idea. The Academy of Nutrition and Dietetics, which represents more than 90,000 registered dietitian nutritionists, dietetic technicians, and registered and advanced degree nutritionist researchers, wrote in a comment to HHS: “The Academy continues to support the proposed move towards approval of multi-site research by a single IRB. We have experienced multiple challenges in obtaining both central and local IRB approval…. The order in which to seek approval is complicated by the fact that while first seeking the central IRB often seems logical, approval may be conditioned upon prior approval of all local sites. Similarly local sites often condition approval upon prior central approval.”

Bonny Boice, executive vice president of the Research Foundation of State University of New York, says in a comment, “There are advantages to establishing an IRB of record for multi-site clinical trials. For principal investigators, coordination under a single IRB provides a common review for all sites including common informed consent process that will increase efficiencies. However, adopting this for a local IRB could raise specific, and in some cases significant cultural differences associated with the site that may affect operational aspects of implementing the study at that specific site. There is no advantage to mandating the use of one IRB of record.”

“The advantages can be accomplished through education, guidance, and an emphasis on changing the current culture of over-review that results in institutions operating out of fear of regulatory compliance or of legal liability,” says David Lavallee, executive vice chancellor for academic affairs and provost of State University of New York.

Many institutions that commented see both good and bad in the NPRM. Botkin writes for SACHRP, “The NPRM assumes the mandatory use of single IRBs will increase the efficiency of IRB review, prevent duplication of effort, and prevent disparities among protocols and informed consent forms in multi-site trials that often have reviews by multiple local IRBs… SACHRP recognizes that many sponsors, institutions, and investigators have had favorable experiences with single IRB review for some types of multi-site, human subjects research. Our concern is the possibility of requiring a single IRB review to a multi-site research protocol may well result in new procedures and policies being created by the relying institutions and the reviewing IRB that could undermine the goals of this policy change and create a host of new challenges for research institutions….”

The Consortium of Independent Review Boards (CIRB) submitted comments on the NPRM regarding single IRB and associated regulatory liability for unaffiliated external IRBs. Independent IRBs have been a stalwart of IRB oversight for more than 20 years and have a different perspective on how this model works than an academic research institution that has used the site model IRB. “As independent IRBs, all CIRB members have served as the central IRB of record for multi-site studies under their purview,” says Matt Baker, chair of CIRB. “There is no evidence that duplicative review, as is currently typical for multi-site research, compounds protections to participants in a proportional manner. Inconsistency among IRB delays, and de-centralized reporting lines are inherent obstacles in our current system that detract from comprehensive and thorough participant protections.” Baker acknowledges that “The most obvious concern with the proposed mandate is that it will undermine the role of institutions in providing human research protections in a way that devalues and weakens the home grown culture of compliance that many institutions have successfully cultivated, converting human research protections into an externally imposed top-down model. However, that concern fails to appreciate the relatively discrete set of responsibilities that would be centralized in a single IRB under this proposal.”

Summary

The NPRM comment period ended Jan. 6, 2016. When asked about the possibility of OHRP publishing a new NPRM with the least controversial issues(s) in a separate NPRM, an HHS spokesperson says, “HHS and other relevant agencies will review the comments received. The outcome of that review will inform the next phase of the rulemaking process.” In addition, “the Unified Agenda, which compiles information about regulatory and deregulatory activities involving federal entities, reports that the final rule is expected to be published in September 2016.” However, that date could be changed, says the spokesperson.

The NPRM says that each of the new rules will be developed within separate time frames. New “exclusions” may be published within 1 year; informed consent rules including the mandate for broad consent for future use of biospecimens will be implemented over a 3-year period. The NPRM provides that the regulations on biospecimens will not cover research using any prior collections of biospecimens that are currently in storage or being maintained in an individually identifiable form, as long as the identifiers are removed before they are given to an investigator.

Outliers must be addressed as well. For instance, tribal research will require additional informed consent for future biospecimen use. Larry Jacques speaking on behalf of the Sault Ste. Marie Tribe of Chippewa Indians, submitted one of the last comments on January 6. “Many Native Americans that volunteer are vulnerable members of our tribal communities. If the Common Rule is the ‘floor’ of protection it must focus to protect our most vulnerable research volunteers. There also needs to be community protections for our historically traumatized communities.”

Research professionals indicated to Research Practitioner that they would like to see the HHS/OHRP address other concerns that are not mentioned (and are “missed” opportunities) such as the unique needs of women’s health, including pregnant women.

In summary, Borasky outlines these NPRM proposed changes to the Common Rule, 2015:

• Make the consent form shorter and more directed to information important to the subject. Less important information will be placed in appendices.
• Consent will be required for all biospecimen research. Broad consent for the future use of all specimens will be mandated regardless of the setting in which they are collected. OHRP will develop a template to be used for this purpose. Due to the substantial changes required to implement this broad consent, it will not apply to tissue collected before the implementation of the rule, and will have an effective date 3 years after publication of the final rule.
• Current exemptions are expanded with several categories of research that will be excluded from the Common Rule altogether. Additional safety requirements will be added to allow research in which the only risk is confidentiality to proceed with less oversight.
• Extend coverage of the Common Rule to clinical trials that involve more than minimal risk conducted at institutions that receive federal funding.

References

1. U.S. Department of Health and Human Services. NPRM for Revisions to the Common Rule. Available at http://www.hhs.gov/reohrp/humansubjects/regulations/nprmhome.html. Accessed Mar. 1, 2016.
2. U.S. Department of Health and Human Services. ANPRM for Revision to Common Rule. Available at:http://www.hhs.gov/ohrp/humansubjects/anprm2011page.html. Accessed Mar. 1, 2016.
3. Clinical Trials Advisor. PharmSource Information Services, Inc. 1999;4:16. Sept. 19, 1999.
4. Wade N. Patient Dies During a Trial Using Genes. The New York Times, Sept. 29, 1999.
5. Jesse’s intent. Available at: www.jesse-gelsinger.com/jesses-intent2.html. Accessed Mar. 1, 2016.
6. Clinical Trials Advisor. PharmSource Information Services, Inc, 2002;7:20. Nov. 7, 2002.
7. U.S. Department of Health and Human Services. Secretary’s Advisory Committee on Human Research Protections (SACHRP). Available at: http://www.hhs.gov/ohrp/sachrp/mtgings/mtg10-08/present/subparta.html. Accessed Mar. 1, 2016.
8. Hartnett T. Ethical, Legal, and Social Implications of Genetic Research: Informed Consent for Use and Storage of Biospecimens. Research Practitioner Jan-Feb 2012.
9. U.S. Department of Health and Human Services. Office for Protection from Research Risks. Issues to Consider in the Research Use of Stored Data or Tissues Available at: www.hhs.gov/ohrp/policy/repost.html. Accessed Mar. 1, 2016
10. U.S. Department of Health and Human Services. OHRP-Guidance on research involving coded private information or biological specimens. Available at: www.hhs.gov/ohrp/policy/cdebiol.html. Accessed Mar. 1, 2016
11. U.S. Department of Health and Human Services. HHS Attachment A to January 24,2011, SACHRP Letter to the Secretary. Available at: www.hhs.gov/ohrp/sachrp/20110124attachmentatosecletter.html. Accessed Mar. 1, 2016.
12. Skloot R. The Immortal Life of Henrietta Lacks. New York: Broadway Paperbacks; 2010.
13. Skloot R. Your Cells. Their Research. Your Permission? The New York Times Available at:http://nytimes.com/2015/12/30/opinion/your-cells-their-research-your-permission.html?action. Accessed Mar. 1, 2016.
14. Tarini BA. Storage and use of residual newborn screening blood spots: A public policy emergency. Genet Med 2011;13:619-620.

By Terry Hartnett

This article was reprinted from Research Practitioner, Volume 17, Number 2, March-April2016.