SACHRP Minutes, March 12-13, 2014

Wednesday, March 12, 2014 – Thursday, March 13, 2014
Minutes

Voting SACHRP Members Present:  Jeffrey R. Botkin (Chair), Albert J. Allen, James R. Anderson, Gary L. Chadwick, Thomas Eissenberg, Owen Garrick, Susan Krivacic, Pilar Nicole Ossorio, Suzanne M. Rivera, Stephen Rosenfeld

Wednesday, March 12

Opening Remarks

Jeffrey R. Botkin, M.D., SACHRP Chair
Ivor Pritchard, Ph.D., Acting Director, OHRP

Members and ex officio member introduced themselves. The Chair noted that SACHRP was being webcast for the first time.

Dr. Menikoff was unable to be present for health reasons. Dr. Pritchard represented OHRP.

The minutes from July, 2013 were approved. (The usual October meeting was cancelled due to the shutdown of the Federal government.)

The Chair introduced Dr. Koh and expressed appreciation for his interest in and support for OHRP, SACHRP, and their shared mission of ensuring human subject protection.  

Welcome and Remarks

Howard Koh, M.D., M.P.H., Assistant Secretary of Health (ASH)

Dr. Koh thanked SACHRP members for their service and OHRP for its efforts, acknowledging in particular the contributions of Dr. Menikoff, Dr. Pritchard, and Ms. Gorey. He noted that 2014 is the year in which the Affordable Care Act (ACA) is being fully implemented, with the promise of better insurance, better care, and better public health. HHS is working to create systems of care and prevention that have not previously existed.

The ASH observed that the issues SACHRP and OHRP are addressing are complex. He appreciated the leadership Dr. Botkin is providing to the committee in guiding its efforts. He called the issues raised by cluster randomized trials and informed consent cutting edge. He also said that those related to understanding the meaning of engagement in research and the certificates of confidentiality are “critical.” He stressed the importance of the Office of the Inspector General’s report, Biospecimen Research, and of the report from the Presidential Commission for the Study of Bioethical Issues, Anticipate and Communicate, both of which SACHRP planned to review at the meeting.

He informed SACHRP that OHRP is actively working on an Advanced Notice of Proposed Rulemaking (ANPRM) to revise the Common Rule.

Dr. Koh noted that OHRP held a public hearing last August to get input related to its findings on the SUPPORT trial, which raised issues related to research that uses one or more interventions as standard of care treatment in the non-research context. HHS specifically sought input on how an IRB should assess the risks of research involving randomization to one or more standard of care interventions and what reasonably foreseeable risks of the research should be disclosed to research subjects in the informed consent. For more information, see: http://www.hhs.gov/ohrp/regulations-and-policy/requests-for-comments/public-meeting-08-28-2013/index.html

A Discussion of Cluster Randomization, Risk Assessment, and Consent Requirements

David M. Forster, J.D. and Mark Barnes, J.D., SOH Co-Chairs

Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART)

Note: PowerPoints for all presentations are provided upon request to Julia Gorey at julia.gorey@hhs.gov.  Please see these resources for more detailed information.

Mr. Barnes reviewed a large Cluster Randomized Trial (CRT) that is currently underway in South Africa and Zambia. The trial involves 21 different communities that each received one of three possible interventions. He reviewed the ethical and regulatory issues that arose as the study – the most expensive and extensive NIH has ever undertaken – was designed.  See http://www.hptn.org/research_studies/hptn071.asp

The underlying PopART hypothesis is as follows:

Universal voluntary HIV testing with additional appropriate combination prevention offered to all those testing HIV negative – in addition to immediate ART for all those testing HIV positive - will have a substantial impact on HIV incidence at population level.

The central research question is, “will a combination prevention approach including UTT confer a significant reduction in HIV incidence compared with standard care?” To answer this question, three arms of the CRT receive interventions as follows. Arm A will receive the full PopART Intervention Package, which includes universal voluntary HIV testing and counseling delivered annually through door-to-door, home-based testing for every single member of family. In this arm, everyone who tests positive, regardless of CD4 count, will receive antiretroviral treatment. Areas included in Arm B receive all the same elements, but people who are measured as not having the CD4 count of 50 or more are not offered antiretroviral treatment. Arm C receives the standard public health services the governments intend to have available (but which are often not available due to underfunding). All three arms, Mr. Barnes pointed out, are arguably within the “public health standard of care,” such that the study is poised between public health practice and public health research.

Among the design issues raised by the study are the following:

• If all three arms are within “public health standard of care,” is it ethical to assign communities randomly to the three levels of intervention?
• What interventions should a control group receive?  
• How should communities be selected?
• Who should be considered subjects?
• How should informed consent be handled?
• What information should community residents receive?
• How should issues related to the protection of pregnant women and children be addressed?

Mr. Barnes explained that neither informed or waived consent was considered necessary for any participants in Arm C.  However, informed consent is required for those in Arms A and B who experience more intense public health interventions, data collection, and follow up.  Data will be collected from these individuals, and full written informed consent will be obtained.  Household members under the age of 18 will not be considered eligible as cohort members, and there will be no follow-up to make sure these youth remain in care.  Pregnant women, however, may consent to be cohort members.

A subset of researchers is interested in conducting a phylogenetic study using deidentified blood samples from HIV testing in order to better understand the transmission pattern for the disease.  One specific research question is whether those who are recently infected have a higher transmission rate than others. Population Cohort members would give informed consent for this activity.  Findings by community/cluster would not be publicly reported, but unusual patterns of interest to the public health authorities might be reported as approved on a case-by-case basis.

Discussion

SACHRP members discussed issues raised by the major study.  In response to questions, Mr. Forster and Mr. Barnes clarified:

• A cohort of participants was identified as subjects for the purpose of data collection, and nothing was done to any of them prior to informed consent.
• It is not clear how the expensive interventions used in Arms A and B would be funded if they prove efficacious. No country has committed to providing the necessary funding.
• The only difference in study arm C is that efforts were made to ensure that the care the governments intend to have available in the districts is really available in sufficient quantity to meet residents’ needs.
• Zambia and South Africa were selected because both have high background prevalence, good infrastructure, and experience participating in previous studies.

Dr. Pritchard stated that OHRP understands Subpart B to allow consent and waiver of consent to apply to pregnant women.

Information provided to study participants.  A SACHRP member asked how participants would be informed and contacted in regard to the study. Mr. Foster explained that the study will be publicized through local media, churches, and a community advisory board.  The workers who contact households will arrive without an appointment.  The people who will deliver testing and training are well trained.  This includes training on how to handle issues related to confidentiality and privacy.

Choice to participate.  Dr. Eissenberg asked speakers to elaborate on ethical issues related to participants’ choice to participate in testing, receive counseling, and receive antiretroviral therapy.  Mr. Barnes noted that younger members of the household may defer to older ones and women may defer to husbands. NIH-funded studies have generally tolerated such cultural differences.  If discomfort with testing is apparent, workers will encourage private testing.

Participation of children.  Dr. Botkin pointed out that adolescents may be infected and may marry adults.  Mr. Barnes clarified that children can receive testing but will not actually enrolled in the study, so data on whether they were enrolled in care and continued to receive it will not be available.  The research team is seeking approval to enroll children in order to collect this information.

Selection of study cohort.  A random selection of households visited by workers will be approached to determine whether they would agree to be enrolled in the study.

NIH Collaboratory Trials: Regulatory and Ethical Issues

Ivor Pritchard, Ph.D., Acting Director, OHRP

Dr. Pritchard highlighted issues raised by several trials being conducted through NIH Health Care Systems (HCS) Research Collaboratory, noting that OHRP has been participating in discussions related to these large-scale trials.  He explained that the Collaboratory is intended to improve the way clinical trials are conducted by creating a new infrastructure for collaborative research.  It also supports the design and rapid execution of several high-impact Pragmatic Clinical Trial Demonstration Projects that will address “questions of major public health importance that engage health care delivery systems in research partnership.”  See: https://www.nihcollaboratory.org/Pages/default.aspx

Dr. Pritchard reviewed three studies that offer an opportunity to review the regulatory issues raised.  He noted that all the studies are designed to see how specific interventions work in the “real world” without attempting to eliminate “noise.”  The three studies highlighted included:

• Nighttime Dosing of Anti-Hypertensive Medications, designed to determine whether it is better to take these meditations at night or in the morning.  Six thousand subjects agree to follow one or the other protocol prior to assignment to a group.  Informed consent is obtained using a paper form or an online process with documentation.  People who already take their medicine at night were excluded from the study.

• Time to Reduce Mortality in End-Stage Renal Mortality (TiME) involves 320 dialysis centers in two provider organizations.  Selected centers will recommend that people starting dialysis get at least 4.25 hours.  Assignments are randomized at the cluster level.  Consent was waived, but people coming to centers are informed that a research study is being carried out and they do not have to participate.  If they say no, their information is not collected.

• Addressing Bioburden while Admitted to Eliminate Infection (ABATE) involves 50 hospitals and 400,000 subjects in non-critical hospital settings.  The intervention consists of daily chlorhexidine bathing and nasal decolonization with mupiricin, which is integrated into the regular operating procedure throughout the hospitals that are randomized to use this approach.  Informed consent was waived.  In either the intervention or the control arm, patients can refuse a bath.

Dr. Pritchard highlighted issues raised by these trials:

• IRB review.  Despite the large number of institutions participating, those involved seem to have worked out a satisfactory facilitated review process.  In two studies there is an IRB of record (lead).

• Risk assessment.  This aspect of the studies has generated considerable discussion in regard to informed consent.  Researchers believe that there is no added risk for participants, but a reasonable chance exists that the intervention could have positive effects.

• Control group status and information.  Control group participants are already taking the risks associated with the standard of care.  There is debate, however, about what information they should receive about the intervention others are receiving.  Some might want to opt to participate in this group, since there is some possible benefit.

• Clustering.  While the dialysis intervention could have been delivered individually without randomizing centers, it was considered more practical to use a single approach at each center.

• Informed consent.  One argument is that if it is offered, some may decline, resulting in a more limited population.  Conceivably, it could also bias the outcome.  For example, a person who knows he or she is participating in a study regarding the timing of hypertension medication might be more diligent about taking medication at that time than would occur in “real life.”

• Staff as subjects.  While it might be interesting to pursue, the kidney dialysis time study is not studying the effects of study participation on staff and their feelings about the recommendations they are asked to make.

Discussion

Several people involved in the studies raised additional points.  Laura Denver, who is on the research team for the dialysis trial, stressed that there is no trial-driven approach for the facilities providing “usual care.”  Wendy Weber, who is the Project Officer for the NIH Coordinating Center, noted in regard to the discussion of risks, that a major question is the distinction between “absolute” and “incremental” risk.  She observed that there is a good deal of variability in the care delivered to patients, and the trials are seeking to use a pragmatic approach to improve the standard of care.  Robert Califf, of the Duke Clinical Research Institute, thanked OHRP for its willingness to provide input during the design of the project and opined that the project has the potential to save thousands of lives.

Dr. Ossorio noted, in regard to the informed consent issue, that the argument that consenting individuals could bias results could be applied to nearly every research study.  She asked what it was about the type of studies described that lends this argument more weight.  Dr. Pritchard responded that such an argument becomes more compelling in studies that shade in the direction of effectiveness studies and are seeking to understand the effect of a specific intervention under normal circumstances (i.e., a public health intervention).  The greater the likelihood that results will be applied to a whole population, the more likely it is to be considered a public health intervention.  Autonomy and social responsibility both must be weighed.  He added that in studies where subjects are consented and randomly assigned to a specific intervention, subjects may respond that they want to choose what intervention they receive.

Dr. Goldkind (FDA ex officio representative) said the FDA was interested in how full informed consent might be obtained electronically.  She wondered if NIH would consider doing a substudy comparing the electronic vs. the traditional approach to informed consent.  An NIH representative responded that this was “a constant topic of discussion” and FDA’s interest might help get people involved.

Questions raised in regard to the Nighttime Dosing of Anti-Hypertensive Medications study included:

• Did the study include those who already take their medication at night?  No.

• Are participants informed that taking medication at night might be more effective?  Dr. Pritchard thought this statement might be included in forms reviewed by patients.

• How is informed consent being done?  The abstract and the PowerPoint presentation differ.  Everyone either sent in a paper survey form or clicked through the online informed consent form.  The telephone survey option is not being used.

• Was written consent waived?  Some elements of informed consent were waived, but the approach is still being discussed. Dr. Pritchard said that OHRP understood clicking on the box at the end of the online form to be an appropriate way to satisfy the requirement.  However, this type of study would not need to fulfill every element of informed consent.  The IRB viewed the study as approvable, noting that patients are getting sufficient information and know they can opt out.  Dr. Rivera noted that OHRP has issued a FAQ that indicates electronic approaches to “signing” an informed consent are acceptable.

• Are patients screened for glaucoma by eye exam or do they self-report?  Dr. Weber noted that researchers have more information about patients because the study is done within the health care system.  However, many details like this are still being worked out.

Questions raised in regard to the Time to Reduce Mortality in End-Stage Renal Mortality (TiME) study included:

• Are patients who receive the intervention receiving dialysis more frequently?  No, the number of sessions remains unchanged; only the duration is changing.

• Can patients opt out of data collection?  Yes, they can choose not to have their data transmitted to the research team.

• What information is given to participants?  Those receiving “usual care” know the purpose of trial and that it will not affect the duration of their dialysis sessions.  The duration of sessions in the intervention group is not given.  Those involved in the intervention group receive basic information about the trial and a list of FAQs with a toll-free number for further information.

Dr. Rosenfeld observed that the study description emphasizes that no matter where the patient is located, the patient can work out the issue of session length with the nephrologist.  Presumably, the patient could say he or she wants to receive a 4.5-hour session.  Laura Denver responded that patients engage in a conversation with their nephrologist about session length that goes on for a lifetime, and the length can change.  Most facilities have to have a narrow range of time that is the typical “default.” This study is changing this default recommendation at the cluster level.

No specific questions were raised in regard to the Addressing Bioburden while Admitted to Eliminate Infection (ABATE) study.

Cluster Randomized Trials and Informed Consent

David Forster, J.D., M.A., C.I.P., SOH Co-Chair

See Attachment A: SOH Recommendation: Regulatory Issues in Cluster Studies, as Approved

Mr. Forster presented recommendations regarding Cluster Randomized Trials (CRTs), which were designed to provide a focused review of the regulatory issues that arise in the review and oversight of CRTs under the Common Rule and FDA Regulations.  The recommendations focuses  on applying on the use of existing regulations to address the complex issues raised by CRTs. The focus is on applying existing regulations to address these issues.  Examples include:

• Which institutions are engaged in research?
• Can CRTs meet the definition of exempt research under 45 CFR 46.101(b)(1) through (b)(6)?
• What are the risks and benefits of research?
• Who is a subject?
• When is consent necessary for subjects?
• When can deception be used to help blinding?
• When if ever can “gatekeepers” give consent?
• How should the provisions of Subparts B, C, and D be addressed?

The most difficult issues, Mr. Forster suggested, were the determination of who is a subject and the identification of risks and benefits in this type of research. Issues related to consent are also challenging to address.

After reviewing criteria for determining who is a subject expressed in the Common Rule (see PowerPoints), Mr. Forster reviewed each section of the proposed recommendations, inviting discussion.

Discussion

Introduction and definition.  Definitions are adopted from the Ottawa group.  The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials” was published on May 9, 2013 in the British Medical Journal.  See: http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001346

In regard to the “professional cluster” definition, Dr. Rivera noted that when a waiver of informed consent is granted, the word “participating” is inappropriate. It was replaced by “included.”

Scientific rationale for use of CRT designs. Dr. Botkin was concerned that the CRT approach was a poor design for some types of studies.  He stressed that IRBs should make sure there is robust analysis and a good plan for statistical analysis. Dr. Allen observed that this concern was addressed in the discussion of reasons for use that follows.

Determining whether the activity is research involving human subjects.  Mr. Forster observed that this determination must be made for each institution involved and would be as straightforward as it is for any other projects.  The determination of who is a subject would be secondary, after determining whether the activity is research.

Overlap with Quality Improvement (QI) projects.  No concerns were expressed.

Public health projects.  No concerns were expressed.

Which institutions are engaged in research?  No concerns were expressed.

Can CRTs meet the definition of exempt research?  No concerns were expressed.

Who is a subject?  Mr. Forster commented that FDA would consider controls to be subjects, and the current document does not highlight this fact.  The following language was added: “It is important to note that under FDA regulations, persons in a control arm qualify as subjects.” In addition, the reference to FDA regulations was qualified to indicate that the intended  reference is to those that apply to “clinical investigations.”

Dr. Rivera objected to the use of the word “participants” in the first sentence, noting that some people will be included as subjects even though they have not been given the opportunity to decide whether or not to participate.  She suggested that volition is involved in being a participant.  Dr. Ossorio strongly agreed. The sentence was revised as follows:

An essential issue in the application of the regulations to CRTs is determining which participants meet who meets the definition of a subject under 45 CFR 46 and the FDA regulations.

A similar change was made in the fifth paragraph of the section, in which the term “subjects” was replaced by “individuals.”

SACHRP members had an extensive discussion of the fourth paragraph of this section, which introduces the concept of a “but for” test to determine whether or not the person’s environment has been manipulated.  Dr. Anderson gave the example of a study in which an institution’s standard therapy for advanced Hodgkin’s disease, MOPP, is compared to an ABVD chemotherapy regimen.  He said it seemed that the people on the MOPP regime would not be considered subjects because “but for” the experiment, they would have been on MOPP anyway.  Mr. Forster noted that the paragraph focuses on only one of the criteria for whether or not an individual can be considered a subject.  The intent is to isolate the concept of manipulating the environment.  Manipulation alone would not make a person a subject. However, an ex officio stressed the importance of considering at what point bystanders become subjects.

Mr. Forster gave two examples: seeding clouds and releasing an inert gas through the subway system to see how gas might spread in the event of a terrorist attack.  These instances introduce the concept of risk as well as the manipulation of environment.  In both cases, there is no expected risk to individuals.  In contrast, prior to World War II in Asia, experiments were conducted in which plague- contaminated containing ceramic pots were dropped on communities to determine whether or not local people got the plague as a result.  Dr. Rosenfeld noted that our environments are manipulated constantly, but all those changes do not have to be reviewed by an IRB.  Mr. Barnes said that obtaining a waiver of consent would be an unnecessary bureaucratic burden when the effect of an intervention is negligible, as in the instance of seeding clouds.  Mr. Forster suggested that in the case of the inert gas released into the subway system, one has to hope that the transit authority is involved and has considered the potential risks, and that this would provide appropriate protection.

Dr. Botkin gave the example of an experiment in which fluoride is added to the water in an entire community, but its impact on cavities is measured only in two dental practices.  Mr. Forster said that in terms of the current definition of subjects, only those from whom data is collected would be considered subjects.  A SACHRP member suggested that a waiver might be considered for others who would be affected but from whom data will not be collected. Dr. Botkin said he would be more comfortable if the IRB considered all affected individuals to be human subjects with the possibility of a waiver in such cases.  Dr. Rosenfeld agreed, noting that this is an example of a professional cluster design.  To clarify the intended application of the principle, the opening of the paragraph was amended to read, “In certain cases, such as professional cluster designs, a difficult issue is determining which individuals are subjects.”

Dr. Ossorio commented that her institution had recently determined that even though some individuals who would be affected by certain research would not be considered subjects under the regulations, the institution still had ethical obligations to them.  She noted that the Common Rule does not address every ethical issue that may arise.  In some instances treating a large group of people as subjects may affect the practicability of research.

Dr. Chadwick suggested a change to avoid locking people into using the “but for” test routinely, when in fact it is only one model.  Instead of saying that SACHRP recommends that the test be applied, the new wording adopted by SACHRP suggests instead that the test “may be helpful.”

Identifying the risks and benefits of research.  No concerns were expressed.

Informed consent and waiver or alteration of consent in CRTs.  In regard to obtaining consent following randomization, Dr. Rivera said this should not be considered to be obtaining consent but rather permission to use data already collected. Dr. Rosenfeld said that operationally, in all such instances the IRB would have had to have reviewed the research proposal and waived consent.

Dr. Ossorio observed that it would be wrong to assume that standard of care is never risky. In some cases, it may turn out to cause unnecessary risks.  Dr. Botkin observed that this is a major issue, but not necessarily one that should be addressed in this context.  Members also agreed that the issue of situations in which people affected by an environmental manipulation do not have the opportunity to withdraw is a broader problem than CRTs and also should not be addressed in this context.

Subparts B, C, and D.  No concerns were expressed.

The role of gatekeepers.  No concerns were expressed.

Recommended modifications to the regulations.  SACHRP focused on the proposed definition of human subject contained in the recommended modifications to the regulations.  The proposed language was:

Human subject means a living individual who an investigator
(1) intervenes or interacts with, or
(2) obtains identifiable private information about the individual.

Dr. Eissenberg observed that the intent is to make it clear that an individual may be a subject even in instances in which data is not collected from the individual.  Dr. Rivera said that the term “interacts with” was much too broad and could even refer to a parent giving a drug to a child.  Dr. Chadwick objected to defining everyone the research touches as a subject.  Mr. Barnes said the issue was how to confer protection on people when the environment is manipulated.  An alternative might be to issue guidance that says that IRBs should consider collateral risks to those from whom consent is not being obtained.

Noting the variety of perspectives among members, the Chair asked each member to comment on whether or not people should be considered human subjects if they receive a research intervention but no data is collected about them personally.

Revised language accepted by SACHRP was:

Human subject means a living individual
(1) who receives a research intervention about which data are collected about humans, or
(2) about whom an investigator obtains identifiable private information.

Action

• Recommendations on Regulatory Issues in Cluster Studies were approved unanimously as amended at the meeting (see Attachment A).

Opportunities to Improve Informed Consent Forms and Process

Jeffrey R. Botkin, M.D., SACHRP Chair

Dr. Botkin highlighted the long-standing recognition that consent forms in research:

• Are not evidence-based,
• Tend to be written at an educational level that is too high for most participants,
• Commonly use technical terms that are not understood by most participants,
• Are too long with formatting that is too dense, and
• Are not written in readable prose.

Similarly, the informed consent process:

• Is not evidence-based;
• Does not ascertain whether participants understand key information elements before a decision is made;
• May be insensitive to the stressful circumstances in healthcare environments;
• May not be conducted by a person with appropriate skills, time, and expertise;
• May provide limited time for decision-making;
• May provide limited opportunities for asking questions; and
• May not be adequately reviewed by the IRB.

These challenges have persisted, Dr. Botkin suggested, because an alignment of incentives favors the current approach. SACHRP previously addressed the topic with a series of approved recommendations designed to give IRBs and investigators more leeway to design the form around the protocol.  These may be found at:  http://www.hhs.gov/ohrp/sachrp-committee/recommendations/2013-january-10-letter-attachment-d/index.html

The Chair proposed a SACHRP initiative to inform the development of OHRP guidance to leverage changes in IRB standards for informed consent.  The initiative would build on previous work by SAS and engage additional experts.  The initiative would address issues related to the form used for informed consent, including reading levels, scientific terminology, the use of images and graphics, the use of boilerplate legalese (e.g., statements related to HIPAA requirements, or to limit liability), the applicability of an executive summary approach, and the use of audiovisual media. It would also address a variety of issues related to the process used to obtain consent, including:

• Who should be responsible for obtaining consent?
• Training requirements for obtaining IC,
• Use of teach back/teach to goal (teach back – test of YOUR ability to communicate – need to give questions),
• Time for dialogue and questions,
• Use of audiovisual aids,
• Comprehension requirements for enrollment, and
• Staged consent processes.

Other issues the subcommittee might want to address include the assent process, reading levels, the role of parents in the assent process, and the use of teach back/teach to goal methods.  To address these issues, the subcommittee might wish to add members with targeted expertise in literacy, communication, informed consent research, and cultural and diversity issues, as well as members of the advocacy community.

Dr. Botkin observed that the timing of the new initiative would be good; some SAS projects are reaching maturity and it should be able to turn its attention to the issue.

Discussion

Incentives for change. Dr. Rosenfeld stressed the importance of incentives in changing the current situation.  He observed that many groups have tried to address the problem, but barriers persist.  He suggested that the subcommittee’s charge should include consideration of how best to create an environment in which new approaches can be tested. Dr. Ossorio said that people who try to use alternative approaches to consent are often met with resistance.  Without a change in the regulatory environment, Dr. Botkin agreed, the incentives will remain allied against real improvement.

Ms. Krivacic found the National Cancer Institute’s (NCI) template for informed consent to be excellent, with good lay language.  OHRP could assist by providing similar examples on its site. Dr. Pritchard noted, however, that the problem lies in how the templates are filled in.

Addressing complex studies. Ms. Krivacic observed that studies are becoming longer and more complex, resulting in huge consent forms that subjects cannot possibly understand.  This is especially true of the field of oncology, where highly technical language is an additional impediment to comprehension.  Sponsors need incentives to simplify these forms.  Dr. Eissenberg noted that even relatively simple sociobehavioral studies often use lengthy consent forms.

A “constellation of changes.” Dr. Botkin noted that recent research has explored the impact of a constellation of changes rather than a single variable, such as reducing the reading level.  A member stressed the importance of checking potential subjects’ comprehension of key points. Dr. Botkin suggested that a 2-page version containing core information might be a helpful requirement, with additional information available.  Dr. Rosenfeld, however, felt it would be a mistake to mandate any set length.  He added that, at present, many Principal Investigators (PIs) have no idea what is in the informed consent document being used for their trial.  Informed consent has become a term of art rather than an ethical concept.

Promoting good decisionmaking. Dr. Ossorio opined that while we know a good deal about what is not working and what is unhelpful, we know less about how to promote good decisionmaking.  We do not yet know what works.  She noted that the new initiative to explore the topic should focus on the process of informed consent, not simply the forms involved. Dr. Rosenfeld agreed, noting that the process has been devalued in the emphasis on forms.  Dr. Pritchard commented that an outcome-based standard based on subject comprehension is more subtle to evaluate than an approach that concentrates on ensuring all the relevant information is contained in a form. Evaluating the form is an easier and more tangible focus for the IRB.

Dr. Ossorio noted, however, that subjects do often find the information included in longer consent forms to be helpful as a source of information once they are engaged in a trial.  The challenge lies in separating out the information a subject needs to decide whether or not to participate from the information the subject may want during the trial.

AAHRPP and OHRP. Dr. Rivera stressed the importance of having the major accrediting body “at the table” to “bless” any experiments.  Dr. Botkin commented, however, that OHRP is the final common pathway to change; if OHRP makes its expectations clear, the Association for the Accreditation of Human Research Protection Programs (AAHRPP) and legal liability issues will follow.

Action

SACHRP agreed that the Chair would work with SAS and OHRP to implement the new initiative.

Dr. Botkin invited SACHRP members who have recommendations for people who would be assets to the initiative to let him know.

Public Comment

Wendy Weber, an NIH staff member involved in the Collaboratory Trials discussed at the meeting, suggested that SACHRP consider guidance for IRBs related to waiving individual steps within informed consent.  For example, in one trial, the first step was accessing records to see who was eligible; consent was waived for this step.  A waiver was granted for informed consent regarding the randomization because informing participants could bias outcomes and there was no risk.  In regard to monitoring outcomes, the IRB determined that informed consent was not required for usual care but was required for study arms.

Dan Nelson noted that SACHRP approved recommendations regarding component analysis, which were forwarded to the HHS Secretary in March, 2012. See: http://www.hhs.gov/ohrp/sachrp-committee/recommendations/2012-march-30-letter/index.html

Wendy Weber noted that the Center for Medicaid Services requires that research visits be flagged in order to prevent double billing.  This affected the dialysis project described earlier, in which Medicaid paid for the treatment of participants.

Cary Shneiderer, also an NIH staff member, stressed the importance of clearly separating the risks associated with care and the risks associated with research.

SACHRP also heard recommendations from Harini Gangur, a sophomore at Okemos high school, who is interested in human research.  His letter included the following observations:

• Sometimes cluster trials need to examine the vulnerable groups, especially children.  Here the consent may be given by the so-called leaders of the group and in teens and students due to lots of peer pressure; the others may be just following or nodding. So how do we make sure that the informed consent is obtained?

• Another vulnerable group may be like my grandparents here who do not know proper English and they just keep on nodding their head. How do we ensure they are consenting?

Mr. Gangur also highlighted the Michigan Keystone Study, in which he said one IRB approved the study and other participating hospitals did not see a need to consent patients at their sites.

Thursday, March 13

Subpart A Subcommittee (SAS): Re-Envisioning Engagement

• Daniel K. Nelson, M.S., CIP, SAS Co-chair
• David Borasky, M.P.H., CIP, SAS Co-chair

See Attachment B:  Recommendations on Assurances and Engagement, as Approved
See Attachment C:  Current Version of 45 CFR 46.103 with Changes Tracked, as Approved

Mr. Nelson reviewed the committee’s charge, prior meetings, and the 21 Secretarial Letters that have incorporated SACHRP recommendations suggested by SAS.  He delivered a final report and recommendations from SAS on the subject of institutional engagement and assurances, explaining that their primary purpose is to reduce regulatory burdens that do not contribute to the protection of human subjects. The subject is important because engagement determines whether, when, where and how the regulations apply.  OHRP asked SAS to consider the topic, given that:

• OHRP, institutions, IRBs and investigators all struggle with provisions;
• Institutions devote considerable resources to navigating complex scenarios, attempting to determine who is and who is not engaged in research; and
• OHRP receives many questions on the topic.

SAS found it problematic that the examples given in OHRP guidance on the subject are centered around the definition of human subjects research (HSR), which is a different determination and should follow the determination of whether the institution is engaged in research.

Issues SAS considered include:

• It is assumed that awardees are engaged in research, but in fact some of them are channels to provide funding to subawardees who are the ones actually engaged.
• FDA does not have an equivalent assurance process.  Instead, applicability and enforcement focuses on investigator.
• All sites are not “created equal.”  For example, a multisite clinical trial may have sites whose activities are limited to components that could be exempt or are not HSR.

SAS and SOH met together to discuss the topic. Highlights of the joint discussion included:

• As long as regulatory applicability hinges on engagement, there is no good way to abandon or ignore the issue.
• The current assumption that the prime awardee as “always engaged” is problematic and warrants revisiting.  Can there be allowance for differential handling of limited activities or components that occur at sub-awardee sites?
• The biggest issues and challenges arise with multisite studies, where engagement as currently interpreted results in redundant protocol reviews, institutional burdens, and confusion.
• Engagement is easily confused with the determination that a given activity is “research involving human subjects.”
• Guidance is needed, and concrete examples and cases would be helpful.

Subcommittees noted that the issue is raised by this regulatory requirement: “Each institution engaged in research… shall provide written assurance” (45 CFR 46[103[[a]).  They considered repositioning or revising the assurance mechanism to address the issues raised by engagement.  They noted that there are apparently no regulatory or statutory restrictions that dictate how assurances are made, and if we were designing a system for assurances today, it would probably look nothing like the current system.  With this in mind, they proposed a new approach in which:

• A Federal Assurance is required from the entity that receives a grant to support HSR.  
• That prime awardee then determines, at their discretion:
o what level of agreement (MOU, etc.) needed from collaborating sites,
o who serves as IRB of record, and
o how many other IRBs, if any, are required to review those sites.

Mr. Nelson noted that comfort with this approach may increase if the Common Rule addresses the  responsibilities of the Principle Investigator, as recommended by SACHRP.  See: http://www.hhs.gov/ohrp/sachrp-committee/recommendations/2013-january-10-letter-attachment-c/index.html

Proposed recommendations as presented by SAS included:

Recommendation #1

SACHRP recommends that 45 CFR 46.103 be revised, in its entirety, as follows:

45 CFR 46.103 (REVISED)
46.103(a) Departments and agencies will conduct or support research covered by this policy only if the institution has provided an assurance, and only if the institution has certified to the department or agency head that the research has been reviewed and approved by an IRB, and will be subject to continuing review by the IRB.
46.103(b) The assurance shall be provided by an individual authorized to act for the institution and to assume on behalf of the institution the obligations imposed by this policy and shall be filed in such form and manner as the department or agency head prescribes.
46.103(c) Certification of IRB approval is required when the research is supported by a federal department or agency and not otherwise exempted or waived under §46.101(b) or (i). Institutions shall certify within 30 days after receipt of a request for such a certification from the department or agency, that the application or proposal has been approved by the IRB.  If the certification is not submitted within these time limits, the application or proposal may be returned to the institution.

Recommendation #2

SACHRP recommends that the items currently specified to be included in assurances under 45 CFR 46.103(b)(1-5) be addressed in other sections apart from the assurance process, as they are under counterpart FDA regulations.

Recommendation #3

SACHRP recommends that the assurance of compliance required under 45 CFR 46.103 be provided through the grant-making process, as one of multiple “Representations and Certifications” already made by institutions when they apply for federal grants, contracts or cooperative agreements.  The intent of this recommendation is to replace the current Federalwide Assurance (FWA) as the model for providing assurance.

Recommendation #4

SACHRP recommends that sub-awardees not be required to provide separate assurances of compliance, but that collaborating research sites (including prime, subs and unfunded sites) have the discretion and responsibility to negotiate the terms of agreements amongst themselves, depending on the circumstances of the project and the nature of collaboration.  These agreements should address, among other obligations and oversight mechanisms, the number and location of IRBs needed to review the research.  Sub-awardees should identify the responsible Institutional Official who is legally authorized to commit the institution to the terms of these agreements.

The Co-Chair stated that OHRP representatives have assured the subcommittees that if something goes wrong at non-assured site, OHRP would still have necessary authority to exert compliance oversight.  IRB registration would continue unchanged, and the IRB would continue to serve as a conduit for information from and to OHRP.  The primary change would be that the assurance process becomes a relationship between the prime awardee and the funding agency, as shown on the table.
 

How would this look in practical terms, for research scenario involving multiple sites?

Institutional Roll

Current Model

Proposed Model
Receives HHS grant FWA & IRB (unless excused) Assurance via grant
Obtains consent FWA & IRB TBD by prime
Conducts Survey FWA & IRB TBD by prime
Performs intervention and measures responses FWA & IRB TBD by prime
Conducts statistical analysis FWA & IRB (if IDs) TBD by prime
Provide lab services Probably not if not collaborating TBD by prime
Release data on subjects Not necessarily (but many would anyway) TBD by prime
Serves as biorepository FWA & IRB TBD by prime
Provides one-time treatments Probably not TBD by prime


The Co-Chair presented the “pros” of this approach as follows.  It would:
• Remove confusion over “engagement” – no longer asking that question
• Simplify assurance mechanism
• “Call it what it is,” removing the confusion with determination of engagement in HSR.
• Retains the “Reps and Certs” with which institutions are already familiar.
• Is more similar to the approach used by FDA, promoting harmonization.
• Promotes an integrated approach to responsibility by forcing a discussion of the best approach to ensure oversight, and may lead to enhanced communication and coordination among participating sites

Possible “cons” include:
• The prime awardee is put in the driver’s seat, with greater responsibility.
• OHRP loses one institutional mechanism for promoting a culture of compliance.
• There is no real clout except where funding is received.
• Different agencies may handle this responsibility in different ways.
• OHRP would lose authority over unfunded research, though in reality it is not clear that it has legal authority in such cases.

Discussion

Registration.  Dr. Chadwick clarified that the IRB registration process would still be in place.

Grantee institution.  Language was added to clarify that the institution referred to in the proposed new language is the grantee institution:

(a) Departments and agencies will conduct or support research covered by this policy only if the institution receiving the grant, contract, or cooperative agreement has provided an assurance, and only if that  institution has certified to the department or agency head that the research has been reviewed and approved by an IRB and will be subject to continuing IRB review.

Other engagement problems.  Dr. Ossorio observed that many problems with engagement will not be addressed by the change, such as negotiations among institutions over funding and negotiations over Memoranda of Understanding (MOUs).  She also noted that IRB review might still occur at multiple sites.  Dr. Anderson stated that MOUs and contracts are the best way to clarify responsibilities, rather than focusing on whether or not each institution has an FWA.  Dr. Chadwick added that many secondary institutions that do not understand assurances do understand contracts.  Dr. Botkin did not believe that the proposed change would add complexity to these issues.

Dr. Allen commented that the proposed change does not broaden Federal protections for subjects to a greater range of research, as contemplated in the Advanced Notice of Proposed Rulemaking (ANPRM) published in the Federal Register on July 26, 2011.  This would require legislative change.

Dr. Botkin observed that the approach automatically “unchecks the box” on the FWA that indicates the institution intends to apply the terms of the FWA to all research involving human subjects.  Others noted that this trend has been going on for years. Dr. Rivera said the change does not mean that institutions would stop applying the ethical standards of the Common Rule to all the research they oversee.

Liability and responsibility. Dr. Botkin noted that under the current approach, the prime awardee is subject to investigation and sanction if a subawardee does not comply with regulations. Mr. Nelson said that the new approach would not change this dynamic. He also noted that OHRP would have no less authority to take corrective actions involving subawardees. He said Laura Odwazny (HHS/OGC) had confirmed that OHRP would still be able to “reach through” to institutions whose work flowed from Federal grants, whether or not they received funding.

Dr. Pritchard observed that in some cases the prime awardee would rightly be held responsible for a subawardee’s performance.  For example, if the grantee gave a subcontract to a lab that was not approved in accordance with the Clinical Laboratory Improvement Amendments of 1988 (CLIA) but the subcontractor was expected to do analyses that would be disclosed to individuals, then that would be an error on the part of the grantee.  The grantee’s responsibility would be no different under the proposed approach than it is at present.  Dr. Ossorio noted that while the proposed approach does not allow a grantee to transfer its responsibilities to comply with the Common Rule to a subcontractor, it does allow each partner’s responsibilities to be defined and does not make anything worse.

Dr. Rivera felt the new approach did offer some improvement.  When an institution must take a collaborator under its own FWA to complete work, this places the institution’s own FWA at risk.  If the work is done under the other site’s FWA, this relieves some of the grantee’s concern about consequences to its own projects from the subcontractor’s errors.  She said she understood that this approach means that she could be the prime awardee and not be engaged in research if the research were performed by others under contract.  Dr. Pritchard differed, saying he understood the change to mean that if an agency accepted a Federal contract that included human subjects research, it was automatically engaged in research. Mr. Nelson said the institution would indicate its ability to comply with elements of the assurance through the representations and certifications filed with a proposal.

Subpart A agencies.  Mr. Nelson noted that the proposed approach had previously been opposed by agencies that subscribe to Subpart A, which would assume new responsibilities for their grantees.  So far, he reported, ex officios have not expressed concerns as these proposed recommendations were developed.

Impact on bureaucratic workload.  Mr. Nelson said that currently, his institution is doing research that involves interventions done through 50 barbershops.  The proposed change would certainly facilitate the research, since under current regulations each of the barbershops would have to have its own assurance – a step that has no real meaning and adds nothing to human subject protection.  Dr. Pritchard said this was his understanding as well. In following these recommendations, OHRP’s guidance would indicate that each subawardee no longer needs to have its own assurance.

Dr. Rivera stated that the proposed change would dramatically reduce bureaucratic workload for institutions.  She noted that there is often so much geographical distance between the grantee institution and its subgrantees that it cannot be fully responsible for assuring that they are fulfilling their responsibilities.  Dr. Pritchard reminded SACHRP that an institution’s assurance is suspended only in rare instances in which it is shown that there is a problem with the way the institution as a whole is conducting human subjects research.

IRBs and assurances.  Dr. Chadwick observed that IRBs currently operate under assurances that in turn are tied to an agreement to use specific procedures. Dr. Pritchard said, however, that registered IRBs do not have to have assurances. In addressing SACHRP’s recommendations in this area, OHRP could make its approach more harmonious with the approach used by FDA (as proposed in Recommendation 2).

Dr. Pritchard noted that Recommendation 3 might require a regulatory change, while the other recommendations probably would not; he asked whether it would still be worthwhile to make the other changes.  Mr. Nelson said it would be better than nothing.  Dr. Ossorio agreed. Dr. Botkin said OHRP could come back to SACHRP with other questions that arise as implementation proceeds.

Model MOU paragraph.  Dr. Rivera suggested that it would be helpful to craft a model paragraph that could be added to MOUs that would adequately describe the responsibility of subawardees to comply with Federal regulations on human subject protection. Members responded that this could be addressed at a future meeting.

Action

• Recommendations on Assurances and Engagement were approved unanimously as amended at the meeting (see Attachment B).

Various members expressed their appreciation to SAS for its “bold” and helpful approach.

Issues Related to “Big Data”

Ivor Pritchard, Ph.D., Acting Director, OHRP

Dr. Pritchard invited SACHRP comments in an area in which OHRP is increasingly asked to provide guidance.  The activities in question involve the secondary use of data for research purposes on a very large scale where arguably this is not especially dangerous, though there may be issues related to security and confidentiality.  Those involved have expressed concern to OHRP about excessive administrative requirements and impediments that stand in the way of their ability to carry out these activities.

An example of a case in which these issues arise is the development of a nationwide registry of people with a disease or condition who will be treated with a particular kind of surgical procedure.  The entity wants to get all the providers who perform the procedure to contribute their data to the national database so that benchmarks can be created to determine the best approach to treatment, to give providers information about whether they are successful performers, and/or to inform consumers and help them make a decision about where to seek care. Such a registry could also be used to recruit participants to a randomized clinical trial.  Often, data cannot be deidentified because of the intention to follow up with people who got the procedure to see whether it was successful.   

Questions directed to OHRP include whether such activities should be considered research, which if any of those involved should be considered “engaged” in research,  and whether or not this is human subjects research.  Other issues include whether or not the activity is exempt, which entities need to do an IRB review, and whether informed consent or a waiver of informed consent is required.  Dr. Pritchard wondered whether it would be worthwhile to develop recommendations that would facilitate this type of research without allowing it to become a “wild west” of secondary data use.  He noted that complexities are added by the Health Insurance Portability and Accountability Act (HIPAA), and OHRP has been asked to make its own regulations not apply in cases where HIPAA does apply.

Discussion

Dr. Botkin asked whether OHRP is seeking assistance in answering this type of question for itself or assistance in framing them for the benefit of the regulatory community.  Dr. Pritchard said that both were applicable.

Dr. Botkin observed that the issues raised are connected with other widely debated areas, including access to personal information and big data outside of research activities.  Dr. Rosenfeld noted that crafting guidance is rendered more difficult by the fact that an effort that begins with a small disease-specific registry may grow as that registry is linked to other data bases.

Dr. Botkin stressed the importance of addressing issues related to social and behavioral research as well as clinically focused research.  He felt the focus should be on reducing the burden associated with this type of research.  He highlighted the need to address issues around identifiability, since the more data are cross-referenced, the greater the probability that individuals may be identified.  Dr. Ossorio agreed, noting that researchers have often underestimated how quickly and easily individuals can be reidentified from deidentified data sets.

Dr. Trachtenberg stressed that for Indians, group harms associated with unauthorized data analysis are an abiding concern.  Dr. Ossorio stressed that social risks must be addressed.  Data is often useful because of its association with diagnosis and behavior, and disclosure can have serious consequences.

Dr. Allen placed some of the challenges in the context of a major push for data transparency, which began with Pharma and is now affecting a wide variety of NIH-sponsored research.  Dr. Garrick suggested that the goal is to be as transparent as possible so that people can be informed.

Dr. Rosenfeld and Dr. Allen pointed out that the topic is very wide.  They suggested that follow-up include identifying specific questions and “bite-sized” subtopics that can be addressed as a starting point.

SACHRP members observed that the issue might be addressed either by SOH or SAS, or by both. Elements of the problem involve harmonization with FDA.

Action

• SACHRP agreed that the issues outlined were worth pursuing and that either of the two active subcommittees would be an appropriate means of following up.  Dr. Botkin will discuss the best way to proceed with OHRP and with SOH and SAS Chairs.

Office of Inspector General Report: Biospecimen Research

Presidential Commission for the Study of Bioethical Issues Report: Anticipate and Communicate

Jeffrey R. Botkin, M.D., SACHRP Chair

OIG Final Report: Biospecimen Research: Meeting Basic Human Subjects Protection Requirements and Communicating Informational Risks

The Office of the Inspector General (OIG) has made recommendations to OHRP in the above report, and OHRP is inviting SACHRP’s opinion on these recommendations.  See: http://oig.hhs.gov/oei/reports/oei-01-11-00520.asp  The response from the Assistant Secretary of Health is included in the report as Appendix A.

Objectives of the OIG study, which included a review of 71 studies at 32 institutions, were as follows:  

• For research that includes the collection of biospecimens, to determine the extent to which
o informed consent documents comply with human subjects protection regulations,
o Institutional Review Boards (IRBs) comply with regulations, and
o principal investigators (PIs) and IRBs take measures to address informational risks (i.e., risks related to human subjects’ personally identifying information (PII) or personal health information).

Findings included:

• Informed consent documents for biospecimen research contained required information on human subjects protections, but varied in their substance and form.
• IRBs met basic requirements for membership, initial review, and continuing review.
• “In addition, 25 of 32 IRB chairpersons who responded to our survey reported that their IRBs require members to attend training on informational risks.”
• All informed consent documents included some description of risk and discomfort.
• Almost all IRB chairpersons—32 of 33—stated that they had required modifications to a research protocol to address these informational risks.
• Informational risks to subjects were included in 58 of the 71 IRB-approved informed consent documents.
• PIs identified a challenge in determining the level of detail to provide to potential subjects about the various risks associated with participating in biospecimen research.
• Among the 32 IRB chairpersons, 8 cited a lack of clarity in Federal regulations as a challenge in overseeing research that includes collecting biospecimens.
• 55 of 60 PIs stated that regulations clearly articulate what is expected of them.

Recommendations to OHRP included:

• OHRP could help ensure that IRB members and investigators address informational risks in biospecimen research by providing them with a forum for discussing challenges and best practices related to communicating these risks.
• Possible approaches include an online forum, Webinars, an OHRP-sponsored conference, or presentations at other scientific meetings.

OHRP supports the findings of the report, as indicated within the report (p. 23):

OHRP concurred with our recommendation to provide IRB members and researchers with a forum for discussing informational risks to human subjects.  It highlighted past efforts as well as plans to provide a forum to discuss informational risks with relevant stakeholders at upcoming
regional and national conferences.  OHRP also emphasized the informational risks present in research for which IRBs have issued waivers from the requirement to collect informed consent.  Although permitted by human subjects regulations, such waivers prevent human subjects from
being fully advised of those informational risks.

In December 2014, OHRP will send a report on the activities it has conducted in response to the OIG’s recommendations.

Discussion

Dr. Ossorio noted that social scientists are doing more specimen research, and SACHRP may wish to engage IRBs that are not part of the biomedical community.

Dr. Botkin noted that the focus is on informational risks and that SACHRP has developed extensive FAQs related to biospecimen use. He added that the track record on the management of such risks is remarkably good in the area of biospecimen research, and other than instances of group harm, it is difficult to identify significant breaches of privacy or confidentiality.  Dr. Trachtenberg reminded SACHRP that issues related to group harm have been a significant problem for Native Americans.

Ms. Krivacic observed that the information on future use provided by sponsors is highly variable and suggested it would be helpful to move toward a standardized approach.

Dr. Ossorio stressed the importance of addressing issues related to future use.  Dr. Rivera suggested that the new Subpart A regulation specifically address risks related to disclosure of such information.

Action

SACHRP approved the following motion: SACHRP has reviewed and considered the OIG report.  We commend HHS on its response and have no further comment at this time.

President’s Commission for the Study of Bioethical Issues: Anticipate and Communicate: Ethical Management of Secondary and Incidental Findings in the Clinical, Research, and Direct-to-Consumer Contexts

In July of 2013, the American College of Medical Genetics and Genomics issued a policy statement containing the following recommendations regarding the Reporting of Incidental Findings in Clinical Exome and Genome Sequencing:

• Constitutional mutations found in the genes on the minimum list (see Table) should be reported by the laboratory, regardless of the indication for which the clinical sequencing was ordered.
 

An Incidental Finding is finding concerning an individual research participant that has potential health or reproductive importance and is discovered in the course of conducting research but is beyond the aims of the study.  This means that IFs may be on variables not directly under study and may not be anticipated in the research protocol.

Wolf et al. (2008)
Managing incidental findings in human subjects research.
J. Law Med Ethics, 36 (2)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2575242/

• The Working Group recommends that laboratories seek and report only the types of variants within these genes that we have delineated (see Table).
• It is the responsibility of the ordering clinician/team to provide comprehensive pre- and posttest counseling to the patient.
• These recommendations reflect limitations of current technology, and are therefore focused on disorders that are caused by point mutations and small insertions and deletions, not those primarily caused by structural variants, repeat expansions, or copy number variations.
• The Working Group recommends that the ACMG, together with content experts and other professional organizations, refine and update this list at least annually.

The complete statement may be found at: https://www.acmg.net/docs/IF_Statement_Final_7.24.13.pdf

The President’s Commission for the Study of Bioethical Issues issued its report in December 2013.  The following recommendations are relevant:

Recommendation 12

Researchers should develop a plan to manage anticipatable incidental findings, including but not limited to those findings known to be significant and clinically actionable (and, when relevant, analytically valid and clinically valid). The plan should be reviewed and approved by an institutional review board.

Recommendation 13

Researchers should develop a process for evaluating and managing unanticipatable findings.  The plan should be reviewed and approved by an institutional review board.  During the informed consent process, researchers should notify participants about the possibility of unanticipatable incidental findings, including lifesaving incidental findings, and the plan for their management.  Researchers who discover an unanticipatable incidental finding of concern should assess its significance, consulting with experts as appropriate.

Recommendation 14

Researchers should consider carefully the decision to actively look for secondary findings.  In certain circumstances, with approval from an institutional review board, researchers can justifiably adopt a plan that includes looking for selected clinically significant and actionable secondary findings.  Approved plans should be disclosed to prospective participants during the informed consent process.

The complete report may be found at: http://bioethics.gov/node/3183

In general the report is not supportive of searching for secondary or incidental findings that might be of interest.

Dr. Botkin noted that OHRP has not released guidance on the issue and there are no applicable regulations.  While some cases of incidental findings are straightforward – for example, the discovery of an obvious brain tumor on an MRI done for research purposes – less clear-cut cases are the focus of debate. IRBs do not have extensive experience with the return of research results.  In the Chair’s opinion, the issue of what to disclose is not ripe for IRB regulations or guidance.  However, there are specific issues related to the appropriate role of the IRB. Dr. Botkin suggested that IRBs should:

• Expect investigators to address the issue in the protocol, one way or the other, and clearly articulate how the process would work;
• Set a general institutional standard for disclosure criteria;
• Develop IC templates and approve the consent language regarding Incidental Findings (IFs);
• Approve and oversee the process for review and disclosure of incidental findings.

The Chair queried: “If you fail to benefit someone, have you harmed them?”

Discussion

Dr. Trachtenberg, an ex officio representing the Indian Health Service, noted that a genetic screening program that assessed alleles unique to Alaska natives resulted in an article about natives and the possible genetic risk of respiratory infections.  Many Alaska Native representatives and allied physicians were disturbed about the article’s methods, conclusions, and ethics.  No IRB was consulted in regard to the study, even though it resulted in a generalizable claim regarding the association between a genetic variant and a specific conditions found by linking to Medicaid payment data.  It was considered by the authors to be a public health study that did not require review.

Dr. Rivera said that existing regulations do not address the issue of what is included in the medical chart of a patient who becomes a research participant.  She noted a high degree of variation in this regard.  IRBs generally do not have guidelines to address this.  Some would argue that anything that could be clinically relevant should be included in the chart in the interest of maximizing beneficence, while others would stress the importance of not entering data that could be stigmatizing.  Dr. Rosenfeld commented that anything that is included on a medical chart is essentially disclosed.

Dr. Allen noted, in regard to school testing, that children who are found to have a condition such as dyslexia need prompt access to that result in order to access services.

Dr. Ossorio observed that while there is relatively little debate about returning aggregate results, there is some data to suggest that people often misinterpret data and assume it says something about their personal status.  Another SACHRP member, however, pointed to community-based participatory research as a kind of research in which people are participating in research in order to have results they can use as a basis for action.

Dr. Rosenfeld was supportive of the recommendation that the issue of incidental findings be addressed by the investigator in a plan.  Dr. Pritchard noted, however, that IRBs may see this as an instance of “mission creep” in which they are being asked to do more than they can reasonably take on.  

Dr. Rosenfeld suggested that researchers are not doing badly in handling anticipated IFs, but unexpected findings can be more problematic and blur the line between research and health care.  Dr. Botkin pointed to the cost of counseling subjects about such findings as an additional issue that must be taken into account.

Dr. Botkin suggested that by addressing the subject, SACHRP might be able to help OHRP reach IRBs with useful information and guidance.

Action

SACHRP agreed the issues raised should be explored further.  Dr. Botkin will work with subcommittee chairs and OHRP to see how best to focus the issues in a manageable set of questions that might lead to guidance.

Certificates of Confidentiality

David Forster, J.D., M.A., C.I.P., SOH Co-Chair

See Attachment D:  Recommendations on Certificates of Confidentiality, as Approved

Mr. Forster reviewed the proposed recommendations, pausing for discussion as each section was presented.  He noted that the committee had had several teleconferences on the topic, reviewed recent articles, and shared experiences using COCs to identify related challenges and issues.

Discussion

SACHRP members raised questions in a few specific areas.  These included:
Exceptions to COC provisions. Dr. Rivera questioned the following exception to COC provisions cited in the document.

Voluntary disclosure by the researcher of information on such things as child abuse, reportable communicable diseases (http://grants.nih.gov/grants/policy/coc/cd_policy.htm); possible threat to self or others, or other voluntary disclosures provided that such disclosures are spelled out in the informed consent form.

She asked how this could be considered voluntary.  Mr. Barnes noted the language was straight from the NIH website.  Such disclosure is voluntary under federal law, but may be mandatory under state law.  Following this clarification, no changes were proposed or made in the document.

Signing the COC.  SACHRP questioned the following language regarding the required signature on the COC:

5. Provide clarity as to who can serve as the IO for the purpose of signature, particularly in small institutional settings such as doctor’s offices, or clarify the acceptability of delegation to other individuals within the institution.  Alternatively, remove the requirement for the IO to sign.  This would allow greater administrative efficiency, and would not weaken the statutory authority, as the enabling statute does not require an IO to be involved in the process.

Mr. Forster noted that there is some debate about who should sign COCs.  One contingent wants to get rid of the need for the Institutional Official (IO) to sign, while others feel it is prudent to have the IO’s signature on the document in case problems arise.  An ex officio noted that COCs mean little if the institution is not prepared to defend them, and the IO’s signature commits them to that course of action.  Dr. Rivera suggested that other institutional personnel could sign and make that commitment.
Mr. Barnes agreed, noting that the IO has other responsibilities and is often far removed from the types of issues raised by COCs.

The passage was revised as follows:

5. Remove the requirement for the IO to sign, and allow the institution to designate a responsible official who can commit the institution.  This would allow greater administrative efficiency, and would not weaken the statutory authority, as the enabling statute does not require an IO to be involved in the process. Alternatively, provide clarity as to who can serve as the IO for the purpose of signature, particularly in small institutional settings such as doctor’s offices, or clarify the acceptability of delegation to other individuals within the institution.  

Action

• SACHRP unanimously approved the recommendations on Certificates of Confidentiality as finalized at the meeting.

See Attachment D: Recommendations on Certificates of Confidentiality, as Approved

Public Comment

No public comment was offered.

Attachment A. Recommendations on Regulatory Issues in Cluster Studies, as Approved

Note: Italic font in text indicates areas that were revised by SACHRP during the meeting.

Introduction

Cluster randomized trial (CRT) designs are frequently used in human subjects research.  These trials bring up unique issues of regulatory application.  The purpose of this recommendation is to address the application of US HHS and FDA regulations to cluster randomized trials.  

Definition of a Cluster Randomized Trial

The central defining feature of a cluster randomized trial (CRT) is that randomization occurs on a group level rather than an individual level.  In a traditional randomized clinical trial, subjects are randomized sequentially as each subject is identified and then enrolled in the study.  In contrast, in a CRT the randomization occurs as a function of being a member of a group.  In addition, there can be several layers of groupings as well, for instance by school district, school, and class, or by health care facility, medical provider, and each medical providers’ patients.  

Examples of Cluster Randomized Trials
It is useful to distinguish between different kinds of CRTs based on the level at which the intervention is delivered.  In a cluster-cluster trial, the intervention is delivered at the cluster-level.  Usually, the intervention is "not divisible at the individual level" and is therefore necessarily delivered on a cluster-wide basis.  In a professional-cluster trial, the intervention is delivered to health or other professionals working within clusters (providers, teachers, employers), while outcomes are then collected on the individual cluster members (patients, students, workers).  An individual-cluster trial most closely resembles a standard randomized controlled trial in that the intervention is delivered directly to the individuals themselves.  Usually, in an individual-cluster trial it would be possible to randomize by individual rather than cluster, but the cluster method is used for a methodological reason such as the prevention of exposure to trial aims among subjects.  Another factor of the individual cluster design is that subjects have the ability to decline participation.  Three examples follow to provide illustration.

Cluster-cluster
The COMMIT study (Community Intervention Trial for Smoking Cessation) was designed to test the effectiveness of a comprehensive, community-oriented approach to influence citizens’ smoking behaviors.  As the intervention is delivered at the community-level, this is an example of a cluster-cluster trial.  Twenty-two communities with populations between 50,000 and 250,000 in the USA and Canada were randomly assigned to intervention or control.  The intervention included activities focused on public education using mass media and organized community events, training of health care providers in cessation techniques, promotion of smoke-free policies in health care facilities and worksites, promotion of policies to restrict the sale of tobacco to youth, and development of smoking cessation resources and activities in each community.  Population-based surveys, using random digit telephone dialing, were used to measure outcomes.  Before randomization and at the end of the study, cross-sectional samples of approximately 2500 households per community were surveyed about their smoking behaviors.  In addition, cohorts of approximately 550 heavy and 550 light-to-moderate smokers, willing to be contacted annually about their smoking status, were identified in each community.  Main outcome measures were cross-sectional changes in the prevalence of smoking from pre- to post-intervention, and quit rates in the cohorts of smokers.  Although the intervention significantly improved quit rates among light-to-moderate smokers, there was no significant effect on quit rates among heavy smokers or on the community prevalence of smoking.

Professional Cluster
Linder et al. used a cluster randomized trial to test a set of novel enhancements to electronic health records, designed to improve tobacco treatment and counseling in primary care.  The enhancements included smoking status icons, tobacco treatment reminders, and facilitated ordering of medication and counseling referrals.  Twenty-six primary care practices (521 clinicians) using electronic health records in Massachusetts were randomized to intervention or control.  The enhancements were introduced to intervention practices with an introductory e-mail to clinicians, a practice visit by an investigator, and periodic e-mails to encourage use of the enhancements.  Clinicians in control practices received no intervention.  Because the intervention was targeted at health professionals, this is an example of a professional-cluster trial.  Practices instead of physicians were randomized to facilitate the introduction of the intervention, reduce contamination, and potentially increase the effectiveness of the intervention through peer effects.  The primary outcome was the proportion of documented smokers who made contact with a smoking cessation counselor.  Secondary outcomes included documentation of smoking status in the electronic records and prescription of cessation medications.  Over a 9 month period, data on 315,962 visits by 132,630 patients in the control and intervention practices were collected from the practice electronic records.  The institutional review board granted a waiver of informed consent for included clinicians and patients.  The intervention significantly increased contact with a cessation counselor as well as documentation of smoking status, but no difference was found in prescription of smoking cessation medications.

Individual Cluster
The ObaapaVitA trial was a double-blind, placebo-controlled trial to evaluate the effect of weekly, low-dose Vitamin A supplementation on pregnancy-related and all-cause female mortality in Ghana.  As interventions were delivered to individual women, this is an example of an individual-cluster trial.  A total of 1086 small clusters of compounds were randomized to either vitamin A or placebo capsules.  Fieldworkers visited all compounds over a 1-2 month period to recruit women for the trial.  All women of reproductive age who provided informed consent were enrolled in the trial (104,484 women in the treatment arm and 103,297 in placebo).  Capsules were distributed during home visits undertaken every 4 weeks.  Fieldworkers gathered data on pregnancies, births, and deaths.  The study found no significant effect of Vitamin A supplementation on pregnancy-related or all-cause maternal mortality.  Although individual randomization could in theory have been used, the use of cluster randomization considerably simplified the trial organization and fieldwork.  The trial area was divided into small geographical clusters of compounds, designed to contain a maximum of 120 women each.  Each fieldworker was responsible for an area of four contiguous clusters and expected to visit women in one cluster per week over a 4-week cycle.  Randomization of clusters also minimized the possibility of women receiving the wrong capsules as fieldworkers only had one type of capsule in their possession during any week.  Furthermore, cluster randomization allowed implementation of an extensive information, education, and communication campaign to promote adherence through radio messages, loudspeaker vans and drum beaters, messages delivered through churches and mosques, posters, and health workers.

Scientific Rationale for use of CRT Designs

Generally, the reasons for adopting a CRT almost always rest on practical (e.g., cluster-level intervention), logistical, or other considerations (see below).  The CRT offers few scientific advantages over an individually randomized trial.  The advantages that do exist need to be weighed against several disadvantages and limitations.

Advantages/Reasons for Use
The appropriate use of the CRT is driven by the nature of the intervention, the logistics of implementing the intervention, and the particular scientific question of interest.  When the trial is evaluating a cluster-level intervention (cluster-cluster trial), a CRT is the only design option. For example, a large-scale community health trial for the prevention of cardiovascular disease involving television, radio and billboards, cannot possibly be evaluated using individual randomization.  Other examples of cluster level interventions requiring a CRT include interventions that involve changing the environment, such as fluoridation of community water supplies, and innovative changes in health service delivery or administration, such as the provision of improved HIV testing services at designated centers.

Another common reason for choosing a CRT is to avoid contamination.  This is a common justification in both professional-cluster and individual-cluster trials. Contamination occurs when individuals in the control arm are partially exposed to the intervention through interaction with individuals receiving the study intervention, thus biasing the results towards smaller effect sizes.  Contamination may arise at both the health professional and individual levels. For example, in a trial of an educational intervention administered by a health provider, it would be difficult for a health provider to educate some patients and not others; further, at the individual level, patients attending the same clinic may discuss the educational intervention in the waiting room.  The only way to avoid these risks is to randomize health providers, rather than patients.  The risk of contamination is particularly great in the case of unblinded or behavioral interventions.  For example, in a CRT for prevention of coronary heart disease, worksites may be randomized to minimize the likelihood of workers in different intervention groups sharing information about the trial.  Increasing the sample size of an individually randomized trial to allow for contamination may sometimes be preferable to adopting cluster randomization, given the methodological challenges presented by this design.

Another reason for choosing a CRT occurs when indirect effects of a study intervention are of interest.  For instance, in vaccine studies the overall effectiveness of a vaccine is a combination of individual immunity conferred by the vaccine and the reduced chance of encountering an infectious person (so-called "herd immunity"; see below).

Other common reasons for adopting the design in individual-cluster trials relate to logistical or administrative convenience.  Cluster randomization may considerably simplify fieldwork (see example 3 above).  CRTs may offer cost savings in some circumstances.  For example, a trial that requires the use of expensive equipment or personnel (e.g., nurse specialists) would be less costly when implemented as a CRT, because the equipment or personnel need be provided to only half the centers as opposed to all centers if individuals within centers were randomized.  In some trials, the outcome measure may be a rate defined at the level of the cluster with the data easily obtainable from routine administrative databases available for each cluster; individual randomization would require data directly from individuals with accompanying increases in cost and administrative requirements.  Cluster randomization may help ensure that the intervention is fully or properly implemented.  For example, in example 3 above, cluster randomization may have helped to prevent sharing or swapping of medications among community members (in the hope of getting some benefit should they be randomized to placebo).  Cluster randomization may enhance compliance, promote publicity at the cluster level, or reinforce the effective use of a new technology within a cluster.   Cluster randomization may be required for political reasons.  For example, a design whereby only half of the members in a community receive an intervention may not be acceptable to decision makers or village elders, and may cause resentment among those being denied the intervention.  Similar reasons may apply in professional-cluster trials: for example, it may not be acceptable to physicians to have only some of their patients offered a screening intervention. In these trials, the only feasible way to secure cooperation and successfully recruit participants is to use cluster randomization.  Whereas individually randomized trials provide information only about the direct effect of an intervention on the people who receive it, CRTs allow one to also study whether people benefit from an intervention provided to other members of the community (i.e., indirect effects of an intervention).  Indirect effects are particularly important in studies of infectious diseases.  For example, the effects of vaccines that are designed to block the transmission of a parasite that spreads malaria cannot be evaluated in an individually randomized trial.  To examine the effect of such a vaccine on infection rates in the community, a CRT is required.  Similar considerations apply in studies of HIV transmission where an intervention may be designed to reduce the "infectiousness" of HIV-infected individuals to their sexual partners.  Such an effect could not be measured in an individually randomized trial.

Disadvantages
The CRT design is statistically less efficient than an individually randomized design.  For the same total number of subjects, CRTs with positive intracluster correlation always have less power than an individually randomized trial; the sample size calculation must take the intracluster correlation into account to ensure an adequately powered trial.  This means that a larger sample size is required to yield the same power as an individually randomized trial.  The loss of efficiency is a direct result of positive correlation among responses from individuals in the same cluster.  CRTs require special methods to be used in sample size calculation as well as in statistical analysis as standard methods are usually invalid.  CRTs are therefore more complex to design and analyze. Results from CRTs may also be more difficult to interpret.  First, selection biases are a more serious concern in CRTs than in individually randomized trials, particularly when randomization of clusters is necessary prior to participant recruitment and allocation concealment is not possible.  Second, imbalances between study arms are more likely in CRTs because the number of clusters randomized is often quite small.  Given these methodological challenges associated with cluster randomization, individual randomization is always the method of choice, unless there are cogent reasons for adopting a CRT design.

Determining Whether the Activity is Research Involving Human Subjects

A threshold process for the ethical review of research is determining whether the activity does in fact meet the definition of research under the HHS regulations, and if it does meet the definition of research, then determining whether or not there are human subjects involved.  The use of a CRT design does not determine in and of itself whether or not a give project meets the definition of research or meets the definition of research including human subjects.  Certain activities that use cluster randomized design will not meet the definition of research, and some activities using cluster randomized design will not meet the definition of research involving human subjects.

Overlap with Quality Improvement (QI) projects as defined in OHRP FAQs

Often CRTs will meet the definition of “research” in 45 CFR 46, and the various definitions of “clinical investigation” in the FDA regulations 21 CFR Parts 50, 56, 312, and 812.   However, CRTs may also meet the definition of a quality improvement project as defined in the OHRP FAQs on quality improvement projects.  Thus, one of the threshold regulatory issues to consider with a given CRT is whether or not it is research or a clinical investigation under the regulatory definitions.  If a CRT does not meet those definitions, then as a regulatory matter the project does not meet the requirements for IRB review and informed consent.

The OHRP FAQs provide two examples of QI activities that do not meet the definition of research.  First, the HHS regulations for the protection of human subjects in research (45 CFR part 46) do not apply to quality improvement activities conducted by one or more institutions whose purposes are limited to: “(a) implementing a practice to improve the quality of patient care, and (b) collecting patient or provider data regarding the implementation of the practice for clinical, practical, or administrative purposes.”

This type of QI activity could be conducted using a cluster randomized design.  For instance, two hospitals could be randomized, with one hospital implementing a practice to improve the quality of patient care, while the other hospital does not implement the practice.  Examples could include having nursing staff wash their hands once an hour, or having two additional nursing staff working on each shift.  The fact that this was done using a cluster randomized design would not in and of itself cause this activity to be research under 45 CFR 46.

Similarly, this type of cluster randomized QI activity involving FDA regulated products may not meet the definition of a clinical investigation.  For example, a hospital could use one type of approved air mattress for burn victims in one wing of a burn unit, and a different approved air mattress in the other wing, and then collect patient satisfaction information about each mattress based on noise level.  As another example, the purpose of such a trial could be to provide data on cost effectiveness rather than to establish the safety or effectiveness of the mattresses.  In both cases, this trial would not meet the FDA definition of clinical investigation of a device.

The OHRP FAQs also provide second example of QI activities that do not meet the definition of research.  The HHS regulations for the protection of human subjects in research (45 CFR part 46) do not apply to quality improvement activities if their purposes are limited to: “(a) delivering healthcare, and (b) measuring and reporting provider performance data for clinical, practical, or administrative uses.”  A cluster randomized design could be used to deliver different healthcare methods on two floors of a hospital.  For example, the floors could be randomized to using one brand of catheter on one floor and a different brand on the other floor for the purpose of addressing the observation that medical providers are reluctant to make use of a newer, less expensive model at the hospital because they are concerned that the catheter will not be as cost effective.  As long as the data collected is used for clinical, practical, or administrative uses, the project would not qualify either as research under 45 CFR 46.  As long as the purpose is not to collect safety or efficacy data about the devices, it also is not a clinical investigation under 21 CFR 56 or 812.

Public Health Projects

Public health authorities often will try various methods of public health interventions, varied across neighborhoods or other jurisdictional units, in an effort to determine the most effective or efficient interventions.  In certain cases, these activities will not meet the definition of research because they are not intended to produce generalizable knowledge.  For example, within one city jurisdiction a health department that provides school nursing services may determine to vary vaccination delivery practices among schools, providing required vaccinations directly and on-site in one set of schools, but in other schools requiring parents to seek vaccinations from public health clinics or private physicians.  The public health authority then can compare vaccination rates among the schools, all in order to understand whether on-site vaccination services best achieve acceptable vaccination rates among school children.  Similarly, delivery of STD and HIV screening services, and community promotion of those services, can be varied by clinic and neighborhood, in order to determine the most effective and efficient use of limited screening resources.

In these cases and others, the purpose of varying the intervention among service delivery sites and neighborhoods is not to derive generalizable knowledge, even though aggregated experiences, if accompanied by adequate data gathering, might give rise to publishable findings that are generalizable knowledge.  Instead, the purpose of these interventions –which typically are discretionary public benefit interventions, not interventions dictated by patient “rights” to care and services – is to promote the most optimal allocation of limited public health resources.  Randomization is done at a level far beyond the individual patient because (1) such a design is more efficient than individual randomization and moreover (2) the public health authority’s own success and failure is measured on an aggregate, not individual patient, level.  Thus, such public health activities are most often regarded not as “research,” but as the delivery of an acceptable range of public health interventions, grouped and then measured by service delivery site or neighborhood. Recipients of public health services are generally not thought to be required to undergo a consent process regarding the variant of service that they are receiving.  However, whether a public health intervention qualifies as research must be determined on a case by case basis.  The fact that an activity is a public health intervention does not automatically exclude it from also meeting the regulatory definition of research.  

Which Institutions are Engaged in Research?

After it has been determined that a project is research and that it is research involving human subjects, the next threshold issue is to determine which institutions are engaged in the research.  When an institution is engaged in research, then the institution is required to oversee the research in compliance with HHS regulations, including issues such as IRB review, informed consent, and registration with OHRP.  In cluster randomized trials, it can be difficult to determine which institutions are engaged in research, particularly in studies such as the example involving a community smoking cessation program.  An analysis must be performed for each institution involved in a CRT to determine if it meets the criteria of being engaged in research.  The OHRP guidance document “Engagement of Institutions in Human Subject Research” provides criteria for determining if given institutions are engaged.  It may be necessary to first determine which participants in the research are subjects, as discussed below, before being able to apply some of the criteria in the guidance.

Can CRTs meet the definition of exempt research under 45 CFR 46.101(b)(1) through (b)(6)?

Yes, CRTs can be exempt research under all of the exemption categories if they meet the exemption criteria.  The CRT design does not in and of itself determine that the criteria are met or not.

Who is a subject?

An essential issue in the application of the regulations to CRTs is determining who meets the definition of a human subject under 45 CFR 46 and the FDA regulations.  The potential subjects include medical providers, their patients, teachers, their students, and individuals who are the targets of the cluster randomized research activities.  Under 45 CFR 46, the definition of a human subject is:

(f) Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains

(1) Data through intervention or interaction with the individual, or
(2) Identifiable private information.

Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes.  Interaction includes communication or interpersonal contact between investigator and subject.  Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record).  Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.

It is important to note that the definition includes a disjunctive “or” between the two sub-clauses, such that an individual becomes a subject if either the investigator obtains data through intervention or interaction with the individual, or if the investigator obtains identifiable private information about the individual even when there is not an intervention or interaction.  Either condition suffices to make the individual a subject; both conditions do not have to be satisfied.

It is important to note that for the purpose of defining intervention or interaction, the term “data” does not refer only to identifiable data.  Collecting aggregate data from a population or sub-population exposed to a research intervention, such as general infection rates across hospitals or lead blood levels, meets the definition of obtaining data about a living individual.  Even though you are only measuring data from a sub-population, all of the exposed individuals are subjects.  This falls within the intent of the regulations.  

In certain cases, such as professional cluster designs, a difficult issue is determining which individuals are subjects.  To provide direction on how to make this determination, it is important to elucidate the meaning of the phrase “manipulations of the subject or the subject’s environment” in the definition of an “intervention.”   The regulation states that “Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes.”  SACHRP recommends that a “but for” test may be helpful in interpreting this phrase.  The “but for” test in its most simple form asks “but for the existence of X, would Y occur?”  The “but for” test is used in law to establish causation for the purpose of determining liability, for instance by considering whether an injury would not have occurred but for the defendant's negligent act.  For the purposes of determining whether an individual will be a subject in a professional cluster design study, the “but for” test can be articulated, “but for the existence of the research, would the environment still be manipulated in this same way if the research didn’t take place?  When the individual’s environment has a reasonable possibility of being manipulated by the existence of the research, then the individual is a research subject.  For the purposes of medical research, the test can be phrased, “but for the existence of the research study, would the subject’s medical care be manipulated in the same way if the research didn’t take place?”  The guidance should instruct IRBs to consider a short chain of events that could lead to manipulation of the subjects’ care, rather than thinking of attenuated chains of unlikely events that could lead to the manipulation of the subject or the subject’s environment.  

It is important to note that if the activity is not research, then the application of the “but for” test is moot.  It only answers the question of whether the research manipulates the individuals’ environment, not other activities, such as QI projects, insurance policy changes, or changes in hospital staffing for budget reasons.

The FDA regulations (which apply to “clinical investigations”) provide a different definition of a human subject.  “Human subject means an individual who is or becomes a participant in research, either as a recipient of the test articles or as a control.  A subject may be either a healthy human or a patient.”  (21 CFR 56.102(e)).  For devices, human subject also includes an individual “on whose specimen an investigational device is used” (21 CFR 812.3(p)).  The application of the FDA definition of a human subject to CRTs is not as complicated as the application of the HHS definition.  It is important to note that under FDA regulations, persons in a control arm qualify as subjects.

To illustrate the process for determining whether providers, their patients, teachers, their students, and other individuals are research subjects, we provide several examples.  

Antibiotic Ointment versus Antibacterial Soap in ICU:  Consider a CRT in which ICUs are randomized to the use of either antibiotic ointment or antibacterial soap on the patients to prevent the spread of staph infection.  The purpose is to study the safety and efficacy of the products.

Are the ICU patients subjects under 45 CFR 46 in this proposed study?  Yes, the ICU patients are subjects under 45 CFR 46.  The research involves interaction with the patients because they are exposed to different products used in the ICU to prevent the spread of staph infection.

Are the ICU patients subjects under FDA regulations?  Yes, the ICU patients are subjects under the FDA regulations because the safety and efficacy of medical products are being tested in the research, and it qualifies as a clinical investigation that requires IRB review.  It is likely it would not need an IND, because if fits under the IND exception at 21 CFR 312.2.  However, that does not alleviate the need for IRB review and oversight.  In addition, consent cannot be waived because this is an FDA regulated study.  If a subject doesn’t agree to participation, then their data cannot be used for the study purposes.  In some cases, such as this one, the patient may end up being exposed to the research intervention because it is the only intervention available at that site.

Strategy Training of Psychiatric Care Staff and Physicians for Reduction of Seclusion, Restraint, and Aggressive Behavior:  Inpatient psychiatric acute care units for patients with serious mental illness are randomly assigned to one of three approaches to manage aggressive behavior on the unit: the first approach provides medical staff with classroom training emphasizing the value of reducing the use of seclusion and restraint use; the second arm provides medical staff with training focused on methods of early identification of aggressive behavior, de-escalation and intervention using alternatives to seclusion and restraint where possible; and the third arm involves no intervention in standard practice.  The measured outcomes will be episodes of patient seclusion, application of restraint, and episodes of aggressive behavior by patients.  The researchers who provide the intervention also interview the medical staff at the end of the study about their views on the effectiveness of the intervention, and record identifiable information about the medical staff’s application of the techniques being taught in the first and second arm.  In the third arm, there are interviews with the medical staff to gather their views on standard techniques.

Are the medical staff subjects under HHS regulations?  Yes, the medical staff are subjects under 45 CFR 46 because the researchers interact with the medical staff to obtain research data about the staff.

Are the patients subjects under the HHS regulations?  Yes, the patients are subjects under 45 CFR 46 because their environment is manipulated by the research.  If the research did not exist, the patients in the first and second arm would receive different care than if it did exist.  In addition, if the researchers gather private identifiable information about the patients, then they would be research subjects on that criteria as well.

Are the medical staff subjects under the FDA regulations?  No, the medical staff are not subjects under the FDA regulations because they are neither recipients of FDA regulated test articles nor controls.

Are the patients subjects under the FDA regulations?  No, the patients are not subjects under the FDA regulations because they are neither recipients of FDA regulated test articles nor controls.  However, if the use of FDA regulated drugs were part of the applied techniques, or if the safety or efficacy of an FDA regulated device were being studied, then the patients would be research subjects under the FDA regulations.  In this case, however, the interventions did not include FDA regulated products.

Smoking Cessation Study:  In the smoking cessation example of a CRT above, communities are randomized to be exposed or not to a smoking cessation campaign.  

Are the members of the communities all subjects under 45 CFR 46?  Yes, the community members are subjects under 45 CFR 46, because their environment is manipulated by the presence of the smoking cessation campaign.  However, as discussed below, this research will qualify for a waiver of consent because the manipulation involves minimal risk.

There are research designs under which certain groups of individuals will not meet the definition of a subject.  For instance, consider a study in which school counselors are randomized by school to use one of two different checklists of criteria to detect possible cases of child abuse.  The effectiveness of the two different checklists will be tested only by interviews and surveys with the school counselors.  There will be no effort to measure any rates of child abuse detection or follow up in the community, and no contact with the students in the schools.  In this case, the students are not research subjects because no data is obtained about them through intervention or interaction, and no private identifiable information is collected, even though their environment has potentially been manipulated.  Each proposed CRT research project requires a careful analysis as to whether the various levels and clusters of participants are research subjects.   Even if certain clusters of individuals are found not to meet the definition of research subjects, the IRB or institution may wish to consider whether there are issues of unacceptable risks, lack of informed consent, or other issues affecting that cluster population.

Identifying the Risks and Benefits of the Research

The criteria for IRB approval require that IRBs determine that risks are minimized and that the risk/benefit ratio is appropriate.  In addition, subjects must be informed of risks and benefits as part of the consent process.  The risks and benefits to the subjects in each level and cluster must be considered (e.g., randomized medical providers and their patients).  

One issue that arises is that there is not uniformity in the regulated community in designating which risks are in fact research risks.  The regulations direct that, “in evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research).”  This is a clear cut issue when an investigational new product is being tested, but it is not as clear when the research involves a registry, a phase IV study, arms in which standard of care is provided, or public health interventions.  In many RCTs, there is not uniformity as to identify the risks of the research, particularly in those arms that involve standard of care interventions.  Some IRBs will consider the risks of a standard of care arm as the risks of the research, and also consider the benefits of that arm as research benefits.  Other IRBs will consider the risks of a standard of care arm as not being research risks, and the benefits as not being benefits of research.  

In the example involving the randomization of ICU units to antibiotic ointment or antibacterial soap, the use of both approved products fall within standard of care.  The risks include the fact that one product may cause more adverse events, such as skin irritation to the soap or allergic reaction to the antibiotic, or that one product may not be as effective in preventing the spread of staph infection and subjects may develop treatment-resistant staph infection.

For another example of the risks involved in CRTs, consider a study of community-based study to address the recognized problem of post-partum hemorrhage in rural Indonesia.  One hundred villages will be randomized to either be provided with misoprostol, an inexpensive drug to treat post-partum hemorrhage, or have no access as a matter of local standard of care. In the active arm of the study, pregnant women will be asked to consent to participate in the research, and will receive tablets of misoprostol in a small baggy with directions on use presented in pictures.  After they have their children, the women in the active arm will be interviewed to see if they had postpartum bleeding and used the misoprostol.  In the control arm of the study, pregnant women will be identified by professional surveyors, but there is no intervention in their care and they will not be asked to provide consent. After they have their children, the women’s level of postpartum bleeding will be determined by professional surveyors.  In the active arm, the women face the risks of misoprostol, particularly if they take it while still pregnant prior to the birth of the infant.  In the control arm, the women face the risks of untreated postpartum bleeding as they would have if the research did not exist.  This illustrates that there can be above minimal risk in CRTs.

Informed Consent and Waiver or Alteration of Consent in CRTs

The HHS and FDA regulations require that research subjects consent to their participation in research unless a waiver of consent is acceptable.  The standards for waiver of consent under the two sets of regulations differ.  Under HHS regulations, there are certain waivers of consent possible.   Under the FDA regulations, distinct waivers of consent are possible.  The most common of these waivers is 45 CFR 46.116(d), whereby consent can be waived if four conditions are met:

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

In addition, 116(d) can be used to alter the consent such that certain information is not disclosed.
However, FDA has not adopted the 116(d) regulatory criteria for waiver of consent.  Therefore, to determine if consent can be waived or altered, there first must be an analysis of which regulations apply, and then for each cohort of subjects, appropriate regulatory analysis must be applied in order to determine if consent may be waived under the applicable regulations.

The CRT is a design that requires careful justification. There are usually cogent reasons to adopt a CRT: in the case of cluster-cluster and professional-cluster trials, the reasons are usually obvious; in the case of individual-cluster trials, individual randomization is possible — at least in principle — but contamination, efficiency, or political factors argue for the use of a CRT.  The use of a CRT does not change the general presumption that individual informed consent is required, unless conditions to justify a waiver of consent obtain.  According to the Ottawa Statement, "an inappropriate reason to adopt a CRT is the mistaken belief that the need to seek informed consent can be avoided by using cluster randomization."

When IRBs approve a waiver of consent for a CRT, the IRB, institution and investigator may wish to consider whether it would be appropriate to perform community outreach to provide knowledge to the affected population of existence of research.  This does not substitute for informed consent from individuals, but may be respectful of autonomy in those cases where the IRB has made the finding that the research meets the regulatory criteria for waiver of approval.

Is it acceptable to obtain consent after randomization?
The IRB must consider whether the delay in obtaining consent exposes the subjects to an unacceptable level of risk or an unacceptable restriction on autonomy.  Under the HHS regulations, IRBs can consider whether the delay in obtaining consent must be justified as an alteration of consent under 45 CFR 46.116(d).  One issue that arises in CRTs is that clusters of potential subjects will be randomized on a group basis before being approached for consent.  In these cases, when consent is required and feasible, the investigators must obtain consent at the earliest possible opportunity.  At that point, subjects may exercise their right not to participate in the research or not to allow the use of data collected.  However, the right not to participate will depend on the study design.  In some cases, it may not be possible to decide not to participate, because for instance the randomized intervention is the only treatment available.   An example of this is the research described above in which subjects are randomized by ICU to be cleansed with either an antibiotic ointment or antibacterial soap.  If a subject doesn’t agree to participation, then their data cannot be used for the study purposes.  In some cases, such as this one, the patient may end up being exposed to the research intervention because it is the only intervention available at that site. This issue does not automatically cause the research to be unacceptable from a regulatory perspective.  The potential subjects have been given the opportunity to consent at the first opportunity.

Voluntary participation; opportunity to decline participation
Another issue that arises with CRTs is that when the intervention is administered at the level of the cluster, such as the community or the institution, the subjects often may not have an opportunity to decline participation after their group has been randomized because the entire cluster is affected.  For instance, in the smoking cessation example above, subjects located in the communities randomized to either have the smoking cessation campaign or not have no choice as to whether to participate.  They will either be exposed to the campaign or not.  

Refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.
Another regulatory issue that can arise is that subjects must be informed that their refusal to participate in the research will not lead to any penalty or loss of benefits to which they are otherwise entitled, and that the same applies if they discontinue participation.  In the SATURN study, school districts were randomized to having or not having after drug testing programs for after-school sports.  One potential subject complained that if she did not participate in the research and be tested for illegal drugs then she could not participate in after-school sports.  IRBs must always consider whether this situation applies in any CRT study.

When can incomplete disclosure through an alteration of consent be used in a CRT to avoid contamination?
45 CFR 46 also allows for alterations of consent, and this approach is commonly used to allow deception in certain types of research in order to strengthen the validity of the research.  This same technique can be used in a CRT if the criteria at 45 CFR 46.116(d) for an alteration of consent are met.  As one example, a study design may be such that if subjects are told about both arms of a study, then it could contaminate the results.  In this case, if the 116(d) criteria are met then information about the other arm can be withheld.


In an FDA regulated study, it is also acceptable to withhold certain information in the initial consent process if the withholding is essential to ensure blinding.  This would not be considered deception, just as blinding is not considered deception.  However, it would usually be appropriate to disclose the withheld information to the subject at such point as it is no longer necessary for the blinding.

Subparts B, C, and D

If the CRT involves the protected subject populations that are addressed in 45 CFR 46 Subparts B, C, and D, then the IRB must apply those regulatory criteria.  
For instance, if the research involves pregnant women, fetuses, neonates of uncertain viability, or non-viable neonates, then Subpart B must be applied.  Once the subjects are identified and the risks assessed, then the application of Subpart B should be straightforward.  As a useful standard for determining whether these populations are involved, it is acceptable to not consider these groups to be included unless the investigator or IRB has direct knowledge that any of the subjects are pregnant or otherwise meet the definitions, as long as the research is of minimal risk to them.  If the research would be of more than minimal risk to these subjects, then the research should be modified to ensure those risks are acceptable or to exclude these populations.  If the investigator or IRB learn that these populations have become enrolled, then the IRB should consider whether their continued participation is acceptable under the regulatory requirements.  

If the research involves prisoners, then Subpart C must be applied.  Once the subjects are identified and the risks assessed, then the application of Subpart C should be straightforward.  As a useful standard for determining whether these populations are involved, it is acceptable to not consider these groups to be included unless the investigator or IRB has direct knowledge that any of the subjects are prisoners.  If the investigator or IRB learn that these populations have become enrolled, then the IRB should consider whether their continued participation is acceptable under the regulatory requirements.  [The earlier SACHRP recommendations on incidental inclusion of prisoners in research apply here as well.]  

For subpart D, once you have established who are subjects and what the risk levels are, then the application of Subpart D will proceed as normal.  

The Role of Gatekeepers

As with any research project, researchers performing CRTs must obtain the agreement of gatekeepers such as nursing home directors, school principals, and other officials to conduct research at a given organization.  However, as a regulatory matter, that permission cannot substitute for the informed consent of the subjects in a CRT, or an IRB approved waiver of consent.  

Recommended Modifications to the Regulations

RECOMMENDATION 1. SACHRP recommends that certain modifications to the regulations would allow the ethical conduct of CRTs and other research designs to proceed.  First, an earlier SACHRP recommendation was that when applying the 45 CFR 46.116(d), IRBs should be able to use a component analysis approach to allow consideration of whether the proposed alteration of consent is of minimal risk, rather than whether the research as a whole is minimal risk.  This earlier recommendation is available in the SACHRP January 2013 letter to the Secretary, Attachment D, section d(1), available on line at http://www.hhs.gov/ohrp/sachrp-committee/recommendations/2013-january-10-letter-attachment-d/index.html.

RECOMMENDATION 2. Second, we recommend that FDA adopt the provisions for waiver of consent that exist under 45 CFR 46.116(d).  This would allow for certain minimal risk research under FDA regulation to be conducted with this waiver of consent when the criteria are met.

RECOMMENDATION 3. Third, we recommend the following change to the HHS definition of a research subjects:

(f) Human subject means a living individual (1) who receives a research intervention about which data are collected about humans, or (2) about whom an investigator obtains identifiable private information.

Intervention includes both physical procedures (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes. Interaction includes communication or interpersonal contact between investigator and subject.  Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record).  Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.

The purpose of this change is to remove the necessity to collect data to cause an individual to become a human subject.  Rather, just an interaction or intervention for research purposes would be sufficient.  It is important to note that this could end up including research staff as being subjects.

Conclusion

We offer these recommendations to help the Secretary provide advice on the application of U.S. regulations to cluster randomized trials.

Attachment B. Recommendations on Assurances and Engagement, As Approved

Note: Italic font indicates areas that were revised by SACHRP during the meeting.

RECOMMENDATION 1:  SACHRP recommends that 45 CFR 46.103 be revised or reinterpreted, in its entirety, as follows:

46.103 Assuring compliance with this policy -- research conducted or supported by any Federal Department or Agency.

(a) Departments and agencies will conduct or support research covered by this policy only if the institution receiving the grant, contract, or cooperative agreement has provided an assurance, and only if that institution has certified to the department or agency head that the research has been reviewed and approved by an IRB, and will be subject to continuing IRB review.

(b) The assurance shall be provided by an individual authorized to act for the institution and to assume on behalf of the institution the obligations imposed by this policy and shall be filed in such form and manner as the department or agency head prescribes.

(c) Certification of IRB approval is required when the research is supported by a federal department or agency and not otherwise exempted or waived under §46.101(b) or (i). Institutions shall certify within 30 days after receipt of a request for such a certification from the department or agency, that the application or proposal has been approved by the IRB.  If the certification is not submitted within this time limit, the application or proposal may be returned to the institution.

RECOMMENDATION 2:  SACHRP recommends that the items currently specified to be included in assurances under 45 CFR 46.103(b)(1-5) be addressed in other sections apart from the assurance process, as they are under counterpart FDA regulations.

RECOMMENDATION 3:  SACHRP recommends that the assurance of compliance required under 45 CFR 46.103 be provided through the grant-making process, as one of multiple “Representations and Certifications” already made by institutions when they apply for federal grants, contracts or cooperative agreements.  The intent of this recommendation is to replace the current Federalwide Assurance (FWA) as the model for providing assurance.

RECOMMENDATION 4:  SACHRP recommends that sub-awardees not be required to provide separate assurances of compliance, but that collaborating research sites (including prime, subs and unfunded sites) have the discretion and responsibility to negotiate the terms of agreements amongst themselves, depending on the circumstances of the project and the nature of collaboration.  These agreements should address, among other obligations and oversight mechanisms, the number and location of IRBs needed to review the research.  Sub-awardees should identify the responsible Institutional Official who is legally authorized to commit the institution to the terms of these agreements.

Attachment C: Current Version of 45 CFR 46.103 with Changes Tracked, as Approved

46.103 Assuring compliance with this policy -- research conducted or supported by any Federal Department or Agency.

(a) Each institution engaged in research which is covered by this policy and which is conducted or supported by a federal department or agency shall provide written assurance satisfactory to the department or agency head that it will comply with the requirements set forth in this policy. In lieu of requiring submission of an assurance, individual department or agency heads shall accept the existence of a current assurance, appropriate for the research in question, on file with the Office for Human Research Protections, HHS, or any successor office, and approved for federalwide use by that office. When the existence of an HHS-approved assurance is accepted in lieu of requiring submission of an assurance, reports (except certification) required by this policy to be made to department and agency heads shall also be made to the Office for Human Research Protections, HHS, or any successor office.

(a) Departments and agencies will conduct or support research covered by this policy only if the institution has provided an assurance approved as provided in this section, and only if the institution has certified to the department or agency head that the research has been reviewed and approved by an IRB provided for in the assurance, and will be subject to continuing review by the IRB. Assurances applicable to federally supported or conducted research shall at a minimum include:
(1) A statement of principles governing the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects of research conducted at or sponsored by the institution, regardless of whether the research is subject to Federal regulation. This may include an appropriate existing code, declaration, or statement of ethical principles, or a statement formulated by the institution itself. This requirement does not preempt provisions of this policy applicable to department- or agency-supported or regulated research and need not be applicable to any research exempted or waived under §46.101(b) or (i).
(2) Designation of one or more IRBs established in accordance with the requirements of this policy, and for which provisions are made for meeting space and sufficient staff to support the IRB's review and recordkeeping duties.
(3) A list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc., sufficient to describe each member's chief anticipated contributions to IRB deliberations; and any employment or other relationship between each member and the institution; for example: full-time employee, part-time employee, member of governing panel or board, stockholder, paid or unpaid consultant. Changes in IRB membership shall be reported to the department or agency head, unless in accord with §46.103(a) of this policy, the existence of an HHS-approved assurance is accepted. In this case, change in IRB membership shall be reported to the Office for Human Research Protections, HHS, or any successor office.
(4) Written procedures which the IRB will follow (i) for conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution; (ii) for determining which projects require review more often than annually and which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review; and (iii) for ensuring prompt reporting to the IRB of proposed changes in a research activity, and for ensuring that such changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject.
(5) Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB; and (ii) any suspension or termination of IRB approval.

(c) The assurance shall be executed provided by an individual authorized to act for the institution and to assume on behalf of the institution the obligations imposed by this policy and shall be filed in such form and manner as the department or agency head prescribes.

(d) The department or agency head will evaluate all assurances submitted in accordance with this policy through such officers and employees of the department or agency and such experts or consultants engaged for this purpose as the department or agency head determines to be appropriate. The department or agency head's evaluation will take into consideration the adequacy of the proposed IRB in light of the anticipated scope of the institution's research activities and the types of subject populations likely to be involved, the appropriateness of the proposed initial and continuing review procedures in light of the probable risks, and the size and complexity of the institution.

(e) On the basis of this evaluation, the department or agency head may approve or disapprove the assurance, or enter into negotiations to develop an approvable one. The department or agency head may limit the period during which any particular approved assurance or class of approved assurances shall remain effective or otherwise condition or restrict approval.

(c) Certification of IRB approval is required when the research is supported by a federal department or agency and not otherwise exempted or waived under §46.101(b) or (i). An institution with an approved assurance shall certify that each application or proposal for research covered by the assurance and by §46.103 of this Policy has been reviewed and approved by the IRB. Such certification must be submitted with the application or proposal or by such later date as may be prescribed by the department or agency to which the application or proposal is submitted. Under no condition shall research covered by §46.103 of the Policy be supported prior to receipt of the certification that the research has been reviewed and approved by the IRB.  Institutions without an approved assurance covering the research shall certify within 30 days after receipt of a request for such a certification from the department or agency, that the application or proposal has been approved by the IRB. If the certification is not submitted within thisese time limit, the application or proposal may be returned to the institution.

Attachment D: Recommendations on Certificates of Confidentiality (COC), as Approved

Note: Italic font in text (apart from titles) indicates areas that were revised by SACHRP during the meeting. 

Introduction

Certificates of Confidentiality (COC) help researchers protect the privacy of human research participants enrolled in sensitive research.  They protect against compulsory legal demands, such as court orders and subpoenas, for identifying information or identifying characteristics of a research participant.  COCs were first implemented in the 1970s in order to protect research subjects while conducting research on illegal drug use.  In 1974 the protection was expanded to include "mental health, including research on the use and effect of alcohol and other psychoactive drugs," and in 1988 the protection was expanded to the protection of health research generally.

The current statute enabling COCs is 42 U.S.C. §241(d), which says:

The Secretary may authorize persons engaged in biomedical, behavioral, clinical, or other research (including research on mental health, including research on the use and effect of alcohol and other psychoactive drugs) to protect the privacy of individuals who are the subject of such research by withholding from all persons not connected with the conduct of such research the names or other identifying characteristics of such individuals. Persons so authorized to protect the privacy of such individuals may not be compelled in any Federal, State or local civil, criminal, administrative, legislative, or other proceedings to identify such individuals.

NIH has established a central website, the Certificate of Confidentiality Kiosk, available on line at http://grants.nih.gov/grants/policy/coc/.  It provides valuable information on how to obtain a COC.
Current Certificate of Confidentiality System

Several agencies within Health and Human Services (HHS) issue COCs, including NIH, CDC, FDA, HRSA, IHS, and SAMHSA.  The NIH has a predominate role in this system.  Within NIH the entities that can issue COCs include, FIC, NCCAM, NCI, NCATS, NEI, NHGRI, NHLBI, NIA, NIAAA, NIAID, NIAMS, NICHD, NIDA, NIDCD, NIDCR, NIDDK, NIEHS, NIGMS, NIMH, NINDS, NINR, NLM, and the Magnuson Clinical Center.  Each of these entities has independent authority to issue a COC, and to make decisions as to requirements, standards and processes for issuance.  
When research is protected under a COC, the researchers can refuse to respond to legal requests for "involuntary disclosure" of the names and other identifying information about research subjects.  The protection of the COC applies permanently, and applies retroactively to data collected in a study prior to obtaining the COC.

However, there are four exceptions to the COC protections, as described at http://grants.nih.gov/grants/policy/coc/:  

1. Voluntary disclosure of information by study participants themselves or any disclosure that the study participant has consented to in writing, such as to insurers, employers, or other third parties;

2. Voluntary disclosure by the researcher of information on such things as child abuse, reportable communicable diseases (http://grants.nih.gov/grants/policy/coc/cd_policy.htm), possible threat to self or others, or other voluntary disclosures provided that such disclosures are spelled out in
the informed consent form;

3. Voluntary compliance by the researcher with reporting requirements of state laws, such as knowledge of communicable disease, provided such intention to report is specified in the informed consent form (see Attachment D, which sets forth PHS policy on reporting of communicable diseases); or

4. Release of information by researchers to DHHS as required for program evaluation or audits of research records or to the FDA as required under the federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et seq.)

Researchers may request a COC for any research involving the collection of personally identifiable, sensitive information.  The definition of sensitive information includes but is not limited to “information relating to sexual attitudes, preferences, or practices; information relating to the use of alcohol, drugs, or other addictive products; information pertaining to illegal conduct; information that, if released, might be damaging to an individual's financial standing, employability, or reputation within the community or might lead to social stigmatization or discrimination; information pertaining to an individual's psychological well-being or mental health; and genetic information or tissue samples.”  Identifying information includes “name, address, social security or other identifying number, fingerprints, voiceprints, photographs, genetic information or tissue samples, or any other item or combination of data about a research participant which could reasonably lead, directly or indirectly by reference to other information, to identification of that research subject.”   

Additional criteria for issuance of a COC are that the research has been approved by an IRB operating under an FWA or reviewing FDA regulated research.  The consent form for the research must include language describing the COC and the protections it affords.  It Is not required that a study be supported with  NIH or other federal funding in order to be eligible for an NIH COC, but a study must involve subject matter that is within the mission area of the NIH.

The submission process can vary depending on the issuing organization, but the application must always be signed by the PI and the institutional official.  Students and other non-faculty researchers can submit for a COC, and then a faculty advisor or other appropriate person must also sign the application.  The application process can take a few weeks or up to three months.  Researchers are encouraged to submit their application three months in advance.  NIH currently issues approximately 1,000 COCs per year.

Challenges of the Current System

There are perceived disadvantages to the current system for the issuance of COCs, ranging from procedural to substantive.  

The procedural issues are the most commonly voiced.  First, it can take up to three months for a COC to be issued, and this must take place after an IRB has reviewed the research and issued a complete approval or a conditional approval that is conditional only upon obtaining a COC.  Therefore, all of the other IRB issues have to be resolved prior to the investigator’s beginning the application process for the COC.  In addition to this timing issue, the IRB-approved consent form must “include a description of the protections and limitations of the Certificate of Confidentiality, including the circumstances in which the investigators plan to disclose voluntarily identifying information about research participants (e.g., child abuse, harm to self or others, etc.).”  Sometimes the entity issuing the COC does not think that the language in the consent form appropriately addresses the description of the COC, or the entity believes that other language in the consent form, such as statement that “absolute confidentiality cannot be guaranteed,” will unacceptably weaken the validity of the COC in the case of a legal challenge.  In these cases, the effort to get both the IRB and the issuing entity to agree to the new consent form language can add additional time to the process.  

The administrative process for application for a COC differs across some of the entities that issue COCs, and this can cause confusion and delays.

Another administrative feature that also can cause delays is the need to obtain the signature of the Institutional Official.  The IO is usually not involved in the day-to-day oversight of research at this level.  It would be more efficient if this signature were not required.  

When research is not funded by the NIH, it can be difficult for a researcher to find the most appropriate institute within NIH to which an application for a COC should be directed.  The researcher is asked to approach the NIH institute whose mission most closely coincides with the research being conducted.  However, the appropriate choice of institute is not always readily apparent.

In addition, it is sometime difficult for the researcher to contact the appropriate person or department within NIH to discuss the application process.  

For multi-site research, both NIH and FDA are willing to issue COCs that cover all sites in the research.  However, it is often difficult to ensure that every site is appropriately registered.  A procedural issue that can arise in FDA-regulated multi-site research is that pharmaceutical sponsors sometimes do not feel comfortable being the holder of a COC, and instead ask that each individual site apply separately.  

There are also issues that are substantive rather than procedural.  One is that at times an NIH institute will refuse to issue a COC if the research does not involve a subject matter that is “within a mission area of the NIH.”  Examples have included stem cell research under previous federal policy, physician-assisted suicide, or criminal recidivism.

There is often a lack of understanding among investigators and IRBs of the legal basis and effect of a COC.  This in turn can lead to lack of clarity as to when to seek a COC and what protections it provides.

Another substantive issue is that the legal history of courts supporting COC against subpoenas is limited to a few cases.  Thus, there is some uncertainty of whether a given COC will be upheld, and on what terms, if challenged in court.

There is also a problem with both overuse and underuse of COCs, stemming from the fact that their use is voluntary.  As a result, they are applied inconsistently to research where the extra protection is warranted; some research that should be conducted under a COC for the protection of the subjects, such as research on illegal activities, is not conducted under a COC, while at the same time some research that does not need a COC for subject welfare is conducted under a COC.  This also involves the fact that the description of “sensitive information” provided on the COC Kiosk is quite broad, so that research involving tissue samples or genetics can qualify even if the subject matter is not particularly sensitive.  IRBs spend considerable time debating whether a given study involves “sensitive information” that warrants the protection of a COC, and often come to inconsistent conclusions.

Another potential issue is that the enabling statute prevents the release of “the names or other identifying characteristics of such individuals,” but does not prevent the release of the de-identified research data.  In theory, with today’s technology and methodologies, it is possible that subjects could be re-identified using data provided by an investigator under effective legal order, such as zip codes, age, etc.  The statute does not explicitly prohibit such efforts at re-identification.  Another issue is that some agencies have different processes for protecting confidentiality of sensitive information, particularly DOJ and AHRQ.  DOJ requires a Privacy Certificate under 42 U.S.C. § 3789g for all research it funds, even if the research is minimal risk and does not involve sensitive information.  AHRQ has a statute protecting all identifiable information (42 U.S.C. § 299c-3(c)).  As with any variability in administrative processes, this causes some confusion when researchers and IRBs face different processes.

Advantages of the Current System

There are several advantages to the current system, many of which have been referenced above in the discussion of disadvantages.  The current system is voluntary, which allows IRBs and researchers to determine on a case by case basis whether or not the use of a COC is warranted based on the sensitivity of the data collected in the research.  The current system also permits a variety of entities to issue institutions, which can help to make the COC available to a wider array of researchers, particularly for non-HHS-funded research.   In many cases the COCs are issued in a timely manner.  Finally, many institutions have found them to be useful in preventing the release of the identities of subjects involved in sensitive information research, most often without having to go to court for a legal reading as to the authority of the COC.  Therefore, the current system is functional.  The purpose of this recommendation is to inquire as to whether the system can be improved, but SACHRP does want to make sure that its support of the system in general is noted.

Recommendations

SACHRP makes the following recommendations, which are grouped first as changes to enhance administrative efficiencies and second as substantive changes to the system.

Administrative Efficiencies

1. Improvement in turn-around time at the entities issuing COCs.  Sometimes it takes up to three months to obtain a COC.  Improvement of this situation would require an assessment of the administrative process at each entity that issues COCs, including an analysis of dedicated resources.  If certain entities were found to be consistently slower than others, they could be provided with additional resources or have the process shifted to another appropriate entity.  The current electronic system for application for COCs being piloted by NIH appears to be another mechanism that could improve the turn-around-time, as it forces the submitting institution to provide all of the necessary data with the initial application.  However, SACHPR notes that based on a sampling of the new electronic consent process, one entity with NIH has already imposed additional questions beyond the others in that process.  NIH should carefully consider whether such differences, which often lead to administrative inefficiency, are necessary.

2. Allow concurrent submission to the IRB.  The turn-around time could be improved by allowing concurrent submission with the IRB process, so that the two processes do not have to proceed sequentially.  In order for this to be effective, all of the issuing entities would have to agree on standard consent form language describing the COC, as currently some issuing entities will not allow consent form language that is acceptable to other entities.  The duties of IRBs and the entities issuing COCs are distinct, and a sequential system is not prohibited by the enabling statute.  FDA uses a process similar to this regarding the issuance of IDEs for clinical investigations of devices, wherein both an IRB approval and an FDA issuance of an IDE are necessary, but the sponsor can work on both processes concurrently.  

3. As an alternative to the above recommendation 2, allow the research to begin upon IRB approval, prior to receipt of the COC.  Some IRBs have taken the position that it is acceptable for a research project to begin when the IRB approval is issued, as long as the investigator has applied for the COC but has not yet received the COC.  In this situation, language in the consent form will have to reference that the COC has been applied for and note the protection will be retroactive, so that subjects are properly informed of the protections and limitations of the COC.  The protections of the COC are retroactive, so subjects’ identities will be protected, and it is very unlikely that a legal request for the identities would be made within the first three months of the conduct of the study.  Clarification of the acceptability of this practice would allow institutions to implement this process to improve the timeline for implementation of research.

4. Provide guidance on how IRBs can better inform researchers about the availability of COCs, as part of the application process.  The NIH Kiosk already has advice to investigators on how to efficiently file for a COC.  The issuing entities should determine whether additional advice should be provided to IRBs.  For instance, IRBs could be encouraged to include questions about COCs in their submission forms to help ensure that the need for a COC is identified earlier in the IRB process.

5. Remove the requirement for the IO to sign, and allow the institution to designate a responsible official who can commit the institution.  This would allow greater administrative efficiency, and would not weaken the statutory authority, as the enabling statute does not require an IO to be involved in the process.  Alternatively, provide clarity as to who can serve as the IO for the purpose of signature, particularly in small institutional settings such as doctor’s offices, or clarify the acceptability of delegation to other individuals within the institution.

Substantive Changes

6. Implement specific regulations regarding Certificates of Confidentiality through a formal rule making process, to allow for clarification of processes, legal effects and standards, and to facilitate substantive public input.  At the current time, as far as SACRHP can determine, there is an enabling statute but not regulations at the Code of Federal Regulation (CFR) level.  Such regulations could be used to implement many of the substantive changes suggested below in the process of interpreting the enabling statute.  

7. New regulations could provide more substantive guidance as to what data COC protects and does not protect.  At this point many investigators and IRBs are not aware of the finer points of what protections a COC provides, and there is a decided lack of clear legal precedents interpreting COC’s effects.  HHS should clarify what it believes the legal effect of a COC should be, so that courts would have an indication of agency intent as to the purpose and role of a COC.  This would help to indicate to investigators, institutions and IRBs when a COC is appropriate, and would also help courts in justifying support of a COC when presented with the issue.

8. Provide a more refined definition of “sensitive information.” This would provide researchers and IRBs with a better sense of when a COC should be sought and when a COC would be granted.  For instance, the current list of examples at the COC kiosk give the impression that any research with genetic samples or tissue samples is “sensitive,” which is not the case.

9. Revise the enabling statute or use the implementation of new regulations to allow researchers the right to refuse to provide de-identified data in addition to identities, when there is a possibility of re-identification using technology or matching with other data.  Currently, many researchers are concerned that they could be required to provide the de-identified research data, which could be re-identified.

10. Provide a description of the types of research for which NIH is unlikely to issue a COC, so that researchers and IRBs have advance notice for planning purposes.  Alternatively, NIH could revise its policy such that it will issue a COC if the research involves sensitive date regardless of whether the research involves or otherwise relates to a mission of the NIH.

11. Create a single issuing office.  This will increase consistency and efficiency, and would make it easier to establish contact with the administrative office.  Also, this would eliminate differences among the current issuing entities as to acceptable consent form language describing the COC.  Such a single office would need to be appropriately resourced based on the workload so that it is efficient.  The staff involved should be knowledgeable about the conduct of research and the administrative framework for the conduct of research in HHS.

12. NIH should consider whether the COC system could benefit from consideration of the recommendations of the HHS Office of the National Coordinator on electronic record systems.

Finally, it is worth noting that the July 2011 ANPRM entitled “Changes under consideration would ensure the highest standards of protections for human subjects involved in research, while enhancing effectiveness of oversight” recommended uniform protections for research information.  The experiences of the agencies in providing COCs would provide valuable historical knowledge for implementation of new requirements proposed under an NPRM.

Conclusion

COCs have performed a valuable function of assuring research subjects of an additional level of protection of their identified data.  Yet the standards for granting COCs are unclear; its legal effectiveness is largely untested, with no regulations on which a future court might rely in interpreting a COC; and the process is decentralized and confusing. Reform is needed, in order to maximize the resource that COCs can represent in protecting human subjects who are involved in sensitive research.

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