Attachment B: Recommendations on Regulatory Issues in Cluster Randomized Studies

SACHRP RECOMMENDATIONS ON REGULATORY ISSUES IN CLUSTER RANDOMIZED STUDIES

Approved October 26, 2016

Executive Summary:  Recommendations

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

1.   OHRP policy on analysis of research projects for exempt status

Under current OHRP policy, if any arm of a study is research requiring IRB review, as opposed to research that is exempt under 45 CFR 46.101(b)(1) through (6), then all of the arms must be considered to be non-exempt research.  In the context of a CRT, therefore, if all clusters in a CRT qualify as exempt research, then the research ought to be considered exempt.  SACHRP recommends that OHRP confirm this interpretation of existing OHRP policy as applied to CRTs.

1.   Assessment of whether individuals in a cluster are human subjects

SACHRP recommends that it is acceptable to find that the individuals in a cluster or a level of a cluster are not human subjects if the definition of a human subject is not met.   This will most often occur in professional cluster designs, in which individuals are randomized by reference to the professional who provides services to them.  In these circumstances, when the individuals in one cluster or level of a cluster will be receiving the same services that they would have received regardless of the study, then there will be no intervention with them and, depending on the study design, no collection of their identifiable data. 

2.   Risk assessment for waiver or alteration of consent

SACHRP recommends that it is acceptable for IRBs to make independent risk determinations for individual clusters.  In other words, it should be acceptable under current regulations that one cluster might involve minimal risk to subjects while another cluster in the same protocol may be judged to involve more than minimal risk to subjects.  This is important for purposes of determining minimal risk in the context of waiver or alteration of consent.

SACHRP recommends that it is appropriate to consider the risk level of each arm of the study independently, and that the research as a whole is not required to present minimal risk in order for a waiver or alteration of consent to be granted in one cluster or several clusters of a study.

SACHRP previously recommended that when applying the 45 CFR 46.116(d), IRBs should be able to allow consideration of whether the component of the research related to the  proposed waiver or 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  https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2013-january-10-letter-attachment-d/index.html.

3.       “Delayed” consent
SACHRP recommends that IRBs must consider whether not obtaining consent at the time of randomization exposes the subjects to an unacceptable level of risk or an unacceptable restriction on autonomy.  The potential subjects should be given the opportunity to consent at the first opportunity.  Under the HHS regulations, IRBs should consider whether not obtaining consent at the time of randomization is justified using an alteration of consent under 45 CFR 46.116(d). 

4.       FDA-regulated clinical investigations
The FDA definition of a human subject includes controls.  As a result, in FDA-regulated clinical investigations that use a CRT design, it is not possible to waive consent in individual clusters (unless the research involves an emergent condition).  The FDA definition of a human subject at 21 CFR 56.102(e) is “an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient.”  The previous SACHRP recommendation on Cluster Randomized Trials recommended, “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.”  SACHRP reiterates that recommendation here.

5.       Prior SACHRP recommendation on CRTs
SACHRP recommends that the previous SACHRP recommendation on CRTs, approved by SACHRP March 13, 2014, be retired and removed from the current SACHRP recommendations to avoid confusion.

Outline of Discussion:

A.       Background

1.       Definition of a CRT
2.       Scientific Rationale for CRT Design

B.       Specific Issues

1.       Analysis of Whether an Activity is Not Research - Quality Improvement Projects and Public Health Projects
2.       Determining Who is a Subject in a CRT
3.       Institutional Engagement in Research
4.       Exempt Research

C.       Consent Issues in CRTs

1.       Waiver or alteration of consent
2.       Consent cannot be obtained until after randomization
3.       Voluntary participation
4.       Penalty or loss of benefits from refusal to participate
5.       Use of Deception to aid blinding

D.       The Role of Gatekeepers

E.        Subparts B, C, and D

F.        Flow Chart for Regulatory Assessment of CRTs

G.        Sample Cases

A.      Background

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 usually offers few or no scientific advantages over an individually randomized trial.

However, CRTs can be scientifically appropriate for the study of contextual and multilevel relations (such as students in classrooms in schools, or patients in clinics).  A CRT has the statistical advantage that treatment effects are estimated within clusters so that variance among clusters can be estimated separately from variation in treatment effects and variation among clusters does not increase the variation in the estimated average treatment effect.

When there is wide variation among clusters (e.g. among research sites), CRTs can provide superior statistical power to detect treatment effects—and in that context expose fewer research subjects to research risks (see below).  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 discussion 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 the individual-cluster example 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 the individual-cluster example 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.

When clusters vary greatly (e.g., due to demographics or treatment implementation at sampled sites) a CRT may be preferable to individual randomization for statistical power and to assess mediation of treatment effects.

Several principles come into view.  First, statistical power decreases as the variation of the treatment effect (e.g., across study sites) increases.  Second, although both individuals and clusters contribute to power, clusters are more crucial than individual participants when there is substantial variation among clusters.  Third, the importance of individual study subjects in increasing power depends strongly on the variance of the treatment: the larger this variation component, the less important individuals are for increasing power. In general, power is increased more easily in this context by increasing the number of clusters rather than the number of individuals sampled in the cluster.  Having a large number of clusters is particularly important when the site-by-treatment variation is large.

Disadvantages

The CRT design is generally less statistically efficient than an individually randomized design.  Since characteristics of individuals in the clusters are not independent, each individual provides less independent information for analysis.  Due to this intraclass correlation, CRTs generally require a larger sample of individuals to achieve the same power as an individually randomized study.

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.  . 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.

In summary, research with randomly sampled individuals is generally preferable to CRT designs.  However, when clusters differ substantially, a CRT can provide more statistical power to detect treatment effects while minimizing the number of individuals sampled for the study to achieve a level of statistical power.  This is because in that context the CRT provides more statistical precision—and minimizes the number of subjects exposed to the research risks.  CRT research designs can also enable analysis of contextual and multilevel factors that mediate the treatment effects.  A large treatment-by-site variance component cries out for understanding of the characteristics of sites that can account for the large variation in the impact of the treatment effect.

Summary

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 exist. 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".

B.       Specific Issues

Analysis of Whether an Activity is Not Research

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. The use of a CRT design does not determine in and of itself whether or not a given project meets the definition of research.  Certain activities that use cluster randomized design will meet the definition of research, while others will not.  (The related issue of whether or not a project is research involving human subjects is discussed below.)  Two common examples of cluster randomized projects that do not meet the definition of research are quality improvement projects and public health projects.

Quality Improvement (QI) Projects

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 ore 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 a clinical investigation of a device.

The OHRP FAQs also provide a second example of QI activities that do not meet the definition of research.  The HHS regulations for the proctection 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 decide to vary vaccination delivery practices among schools, providing required vaccinations directly and on-site in one set of schools, while 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 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. 

Identifying Subjects in CRTs

HHS Regulations

After determining that a project is research, the next step is to determine whether it is research that involves human subjects.  In applying the regulations to CRTs, the step of determining which individuals meet the definition of a human subject under 45 CFR 46 and the FDA regulations can be challenging.  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 also important to note that for the purpose of defining “intervention” or “interaction,” the term “data” is not the same as “identifiable private information.” Also, the term “data” is not limited 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 through an intervention.  Also, in many CRT designs, individuals experience the research intervention by virtue of their being a member of the cluster, but data are not collected directly about all of the individuals within that cluster.  For instance, in a CRT looking at the effectiveness of HIV prevention strategies with randomization on a community-wide basis, the study design might require collection of data from only 20 percent of the individuals affected by the intervention in order to prove the efficacy of the intervention, even though the entire cluster is affected by the intervention.  SACHRP believes that the HHS definition of a research subject should be interpreted such that the cluster member individuals from whom no data or identifiable private information is collected are considered subjects and afforded appropriate protection under the human subject protection regulations.  This falls within the intent of the regulations to protect human subjects. 

In certain cases, such as professional cluster designs, it can be difficult to determine 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?”  Guidance from OHRP and FDA 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.

FDA Regulations

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.  However, it is important to note that under FDA regulations, persons in a control arm qualify as subjects.

Institutional Engagement 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 cluster-cluster example above 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. It is also important to make the analysis of engagement in research for each cluster, as a given institution may or may not be engaged in research for a given cluster.

Exempt Research under 45 CFR 46.101(b)(1) through (b)(6)

The CRT design does not in and of itself determine whether the criteria are met.  CRTs can be exempt research under all of the exemption categories if they meet the exemption criteria.  Under current OHRP policy, if any arm of a trial is research that requires IRB review, as opposed to research that is exempt under 45 CFR 46.101(b)(1) through (6), then all of the arms must be considered to be non-exempt research.  If all clusters in a CRT qualify as exempt research, then the research can be found to be exempt.

C.       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 the HHS 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.

Definitions that affect waiver of consent and waiver of documentation of consent

Under the HHS regulations for waiver of consent, at 45 CFR 46.116(d), there are two key terms that significantly affect the analysis of waiver of consent for CRTs.  They are “practicably” and “minimal risk.”

Definition of “practicably.”  A central issue that arises in the question of whether a waiver of consent, or a waiver of certain elements of consent, is allowable under 45 CFR 46.116(d) is what factors satisfy the requirement that the “research could not practicably be carried out without the waiver or alteration?”

First, as a threshold criterion, in order to find that the research could not practicably be carried out without the waiver or alteration, it has to be true that the study cannot reasonably be conducted in a different manner whereby consent can be obtained. 

There are then several types of criteria that can be put forth as satisfying the requirement that the research could not practicably be carried out without the waiver or alteration.  For ease of reference, these have been labelled as a) and b).

a)       The most common criterion of not being practicable historically has been that it is administratively infeasible.  Common circumstances that cause consent to be administratively infeasible include large numbers of subjects, or the fact that many subjects are difficult to contact because, for instance, they have been lost to follow up or represent a unique population such as the homeless.   It is important to note that large numbers in and of itself is not sufficient if there is opportunity to interact with each subject. 

b)       A second criterion of not being practicable is that obtaining consent will undermine the scientific validity of the research because the inability to contact enough subjects to seek consent to participate, or full disclosure of the study purpose, will skew the population to the extent that the data are no longer reliable.  SACHRP supported this position in a previous recommendation, “SACHRP Letter to HHS Secretary, January 31, 2008.”  Possible reasons that the data could be skewed may be: the inclusion of only those subjects who can be contacted to seek consent would prohibit conclusions to be drawn, bias the sample, cause the results to lose statistical power, or cause a Hawthorne-like effect (whereby research modify or improve an aspect of their behavior in response to their awareness of being observed).  The expectation that too many potential subjects would refuse to participate does not constitute impracticability.  An important subset to consider is when a waiver or alteration of an element of consent, rather than a complete waiver of consent, would be necessary to preserve the integrity of the research data.  For instance, in some studies it might be necessary to obscure the nature of the arms of the study in order to avoid altering subject behavior.

In CRTs, practicability often becomes an issue because the assignment to the intervention has already been made, or the intervention has already happened, before it is possible to identify individual subjects and obtain their consent.  In these cases, it is not practicable to obtain prospective consent because the randomization and exposure have already occurred before consent can be obtained.  Subjects should be given the opportunity to consent at the first opportunity.  In most cases the research will be such that the subjects at that point can refuse to consent to the use of their data in the research, even though they have been randomized and also perhaps exposed to the intervention.  The end effect is that the IRB, through the use of the regulatory waiver of consent at 116(d), may have to approve a delayed consent process.  It will be important that this use of the waiver of consent regulations not be referred to as “deferred consent,” as discussed in the 1993 OHRP guidance “Informed Consent--Legally and Prospectively Obtained.”  

Definition of “minimal risk.”  A second issue that comes up with waiver of consent under 45 CFR 46.116(d) and waiver of documentation of consent under 45 CFR 46.117(c) is the definition of minimal risk, which arises in a far broader context than just CRTs, but often arises in CRTs.  For example, if hospitals are randomized to use different antibiotic soaps, is the research minimal risk?  Similarly, if surgical centers are randomized to having surgeons who are receiving extra training or not, is the research minimal risk?  If pre-k programs are randomized to having snacks with extra vitamins or not, is the research minimal risk? If elementary schools are randomized to having counselors who receive special training in anti-bullying interventions or not, is the research minimal risk?

There are several approaches to interpreting whether risk is minimal or above minimal.  A common framework is to contrast absolute versus relative levels of risk.  In an absolute approach, the risk of the research is assessed as compared to the objective standard presented in the regulations, the risks of daily life or routine exams.  In a relative approach, the risk of the research is compared to the level of risk the subjects in the study population will face in their daily life or the treatment of their disease.  Thus, if a subject has cancer and will have chemotherapy, then the risks of an experimental chemotherapy agent are assessed in comparison to the risks of standard chemotherapy, and the research may be minimal risk if those risks are judged equivalent.  In considering the definition of minimal risk in past recommendations, SACHRP has consistently put forward an absolute approach.  (See SACHRP Chair Letter to HHS Secretary Regarding Recommendations, July 28, 2005 and SACHRP letter to HHS Secretary: Recommendations related to waiver of informed consent and interpretation of “minimal risk,” January 31, 2008.)  In the draft guidance “Disclosing Reasonably Foreseeable Risks in Research Evaluating Standards of Care,” OHRP outlined an approach for determining which risks are in fact research risks in comparative effectiveness research, dependent on whether each individual subject will face potentially different risks than he or she might face without enrollment, and this approach can also be used to identify research risks in CRTs.  If those risks are above minimal risk, then the cluster or level must be found to be more than minimal risk.  SACHRP continues to recommend an absolute approach to defining minimal risk in this recommendation.

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?

One issue that arises in CRTs is that clusters of potential subjects may be randomized on a group basis without being approached for consent prior to the randomization.  In these cases, IRBs should consider whether subjects should be asked if they will allow the use of the data collected at the earliest possible opportunity where such consent is required.  At that point, depending on the study design, subjects may also exercise their right not to participate in the research going forward.  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.  However, the IRB must consider whether not obtaining consent at the time of randomization exposes the subjects to an unacceptable level of risk or an unacceptable restriction on autonomy.  The potential subjects should be given the opportunity to consent at the first opportunity.  Under the HHS regulations, IRBs can consider whether or not obtaining consent must be justified as an alteration of consent under 45 CFR 46.116(d). 

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. 

Penalty or Loss of Benefits from Refusal to Participate

Another regulatory issue that can arise is that subjects must be informed that “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.”  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, which was a loss of a benefit to which she was otherwise entitled.  OHRP agreed with her complaint, and the study was stopped.  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.

D.      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. 

E.       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 it has been established who the subjects are and what the risk levels are, then the application of Subpart D will proceed as normal. 

F.       Flow Chart for Regulatory Assessment of CRTs

SACHRP proposes the following flow chart as a tool to apply the HHS and FDA regulations to CRTs, with the purpose of identifying whether each cluster (and each level of each cluster, as applicable) is research involving human subjects, is exempt research, is research requiring IRB review, and whether consent is necessary or may be waived.

OHRP Policy on Analysis of Research Projects

Under current OHRP policy, if any arm of a trial is research that  requires IRB review, as opposed to research that is exempt under 45 CFR 46.101(b)(1) through (6), then all of the arms must be considered to be non-exempt research.  If all clusters in a CRT qualify as exempt research, then the research can be found to be exempt.

Assessment of whether or not the individuals in a cluster are human subjects

SACHRP recommends that OHRP confirm that it is acceptable for IRBs to find that the individuals in a level of a cluster are not human subjects if the definition of a human subject is not met, even when other individuals in other clusters or levels of the same cluster are human subjects.   This will most often occur in professional cluster designs.  This is in contrast to the approach to exemptions described above.

Risk assessment for control arms that receive no change in treatment or circumstances and waiver of consent

SACHRP recommends that OHRP confirm that it is acceptable for IRBs to make independent risk determinations for individual clusters, in other words, that one cluster might involve minimal risk to subjects while another cluster in the same protocol involves more than minimal risk to subjects.

SACHRP believes that it is appropriate to consider the risk level of each cluster, and each level of a cluster, of a study independently, and that the research as a whole does not have to be minimal risk in order for a waiver of consent to be possible in one cluster or level of a cluster.

FDA Regulated Clinical Investigations

Finally, it is important to note that the FDA definition of a human subject includes controls, and as a result in FDA regulated clinical investigations that have a CRT design, it is not possible to waive consent in individual clusters (unless the research involves an emergent condition).  The FDA definition of a human subject at 21 CFR 56.102(e) is “an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient.”  The previous SACHPR recommendation on Cluster Randomized Trials recommended, “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.”  SACHRP reiterates that recommendation here.

Flow Chart for Consideration of the Application of HHS and FDA Regulations to CRTs

In each case, the following systematic approach is used for the assessment of each cluster and level of individuals (teachers, students, physicians, patients, etc.) in each arm of the protocol.  The questions start with an assessment of whether the research meets the definition of an FDA regulated clinical investigation, because if so then the control arms involve subjects and consent cannot be waived except for research in emergent conditions.

Questions (must be asked in order):

1.  Is the cluster a “clinical investigation” as defined by FDA? [see 21 CFR 56.102(c)]

The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

a.        If No, continue to #2.
b.       If Yes, skip to #5.

2.  Does the cluster involve “human subjects” as defined by HHS? [see 45 CFR 46.102(f)]

The answer is Yes, if one or more of the following are true:

·         Does the investigator obtain data through intervention with living individuals?

·         Does the investigator obtain data through interaction with living individuals?

·         Does the investigator obtain identifiable private information about living individuals?

a.        If No, informed consent is not required. [STOP]
b.       If Yes, continue to #3.

3.  Can consent be waived or altered for the subjects in the cluster? [see 45 CFR 46.116(d)]

The answer is Yes, if all of the following are true:

·         The research involves no more than minimal risk to the subjects

·         The waiver or alteration will not adversely affect the rights and welfare of the subjects

·         The research could not practicably be carried out without the waiver or alteration

·         Whenever appropriate, the subjects will be provided with additional pertinent information after participation

a.        If No, informed consent is required.  Continue to #4.
b.       If Yes, informed consent is not required. [STOP]

4.  Can documentation of consent be waived for the subjects in the cluster? [see 45 CFR 46.117(c)] 

The answer is Yes, if either of the following is true:

·         The only record linking the subject and the research would be the consent document, the principal risk would be potential harm resulting from a breach of confidentiality, and each subject will be asked whether the subject wants documentation linking the subject with the research and the subject’s wishes will govern; or

·         The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

a.        If No, written documented informed consent is required. [STOP]
b.       If Yes, documentation of informed consent is not required (e.g., oral or online consent without a signature). [STOP] 

5.  If this is an FDA regulated clinical investigation, can documentation of consent be waived for subjects in the cluster? [see 21 CFR 56.109(c)(1)]

The answer is Yes, if the following is true:

·         The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

a.        If No, written documented informed consent is required. [STOP]
b.       If Yes, documentation of informed consent is not required (e.g., oral consent or online consent without a signature). [STOP]

It is also important to note that for any cluster a given institution may or may not be engaged in research.

G.      Case Studies

The following examples of cluster randomized trials are presented to provide illustrative examples.  For each case, we present analysis of whether consent cannot be waived because the trial is an FDA regulated clinical investigation, then for HHS regulated research whether a waiver of consent (including waiver of elements of consent) or waiver of documentation of consent under HHS 45 CFR 46 could be allowed, followed by analysis of whether waiver of documentation of consent under FDA 21 CFR 50 could be allowed.  The cases are organized into three categories: 

  • Cases that obviously require consent in all arms,
  • Cases that clearly can be conducted with a waiver of consent under 45 CFR 46.116 for all arms, and
  • Cases where it is uncertain whether consent is necessary in at least one arm.

Cases That Require Consent in All Clusters

Case 1 – FDA regulated, consent required in all clusters

Hospitals are randomized to have neuro-surgery done with either standard current procedures for surgery or an investigational new computer-controlled surgery device.  Hospitals are randomized due to the cost of installing the device and training users and to avoid contamination among hospital staff as to preference for one method or the other.

Analysis of investigational device cluster

Questions (must be asked in order):

  1. Is the cluster a “clinical investigation” as defined by FDA? [see CFR 56.102(c)]
    The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

a. If No, continue to #3.
b. If Yes, skip to #5.

Answer: Yes
Analysis:  The protocol is an FDA regulated clinical investigation.  Therefore, all of the individuals in both clusters, the investigational and the control cluster, are human subjects, and consent cannot be waived for either cluster. 

5.       If this is an FDA regulated clinical investigation, can documentation of consent be waived for subjects in the cluster? [see 21 CFR 56.109(c)(1)]
          The answer is Yes, if the following is true:

·         The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

  a.  If No, written documented informed consent is required. [STOP]
  b.  If Yes, documentation of informed consent is not required (e.g., oral consent or online consent without a signature). [STOP]

                          Answer: No.  The research involves more than minimal risk.  Documented consent is required for this arm.
                         Analysis of control cluster

Questions (must be asked in order):

  1. Is the cluster a “clinical investigation” as defined by FDA? [see CFR 56.102(c)]
    The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

                           a. If No, continue to #2.
                           b. If Yes, skip to #5.

                           Answer: Yes

5.      If this is an FDA regulated clinical investigation, can documentation of consent be waived for subjects in the cluster? [see 21 CFR 56.109(c)(1)]
        The answer is Yes, if the following is true:

·         The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

   a.  If No, written documented informed consent is required. [STOP]
   b.  If Yes, documentation of informed consent is not required (e.g., oral consent or online consent without a signature). [STOP]

                          Answer: Yes.  The subjects’ care will not be altered from standard of care, thus the only risk is a breach of confidentiality.  Therefore, a waiver of documentation of consent is possible.   This will not affect blinding due to the cluster randomized design.

Case 2 Not FDA regulated, consent required in all clusters

After School Drug Testing Program

The two-year study was conducted in 11 high schools.  Participating schools were randomly assigned to one of two clusters:  Schools that designed and implemented a drug and alcohol testing policy; and schools that had designed a policy but agreed to defer the drug testing until the study had concluded.

Athletes in the cluster of drug and alcohol testing schools were exposed to random testing throughout the academic year.  If an athlete tested positive for drug use, the results were reported to parents or guardians, and counseling was mandatory.  In addition, the athletes completed confidential questionnaires at the beginning and end of each school year.   The questionnaires asked about alcohol and drug use and student attitudes about drug testing, and were used to help establish the results.  Athletes in the cluster at schools that did not implement the drug and alcohol testing completed the same confidential questionnaires at the beginning and end of each school year.   

Cluster 1 - Athletes receiving drug and alcohol testing and questionnaires

Questions (must be asked in order):

1.       Is the cluster a “clinical investigation” as defined by FDA? [see CFR 56.102(c)]
          The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

a.  If No, continue to #2.
b.  If Yes, skip to #5.

Answer: No

  1. Does the cluster involve “human subjects” as defined by HHS? [see 45 CFR 46.102(f)]
    The answer is Yes, if one or more of the following are true:

·         The investigator obtains data through intervention with living individuals

·         The investigator obtains data through interaction with living individuals

·         The investigator obtains identifiable private information about living individuals.

a.  If No, informed consent is not required. [STOP]
b.  If Yes, continue to #3.


Answer: Yes.  The cluster involves both interventions (testing) and interactions (questionnaires).

3.       Can consent and assent be waived or altered for the subjects in the cluster? [see 45 CFR 46.116(d)]
         
The answer is Yes, if all of the following are true:

·         The research involves no more than minimal risk to the subjects

·         The waiver or alteration will not adversely affect the rights and welfare of the subjects

·         The research could not practicably be carried out without the waiver or alteration

·         Whenever appropriate, the subjects will be provided with additional pertinent information after participation

a.  If No, informed consent is required.  Continue to #4.
b.  If Yes, informed consent is not required. [STOP]

Answer: No.   Is practicable to obtain consent and assent. 

4.        Can documentation of consent be waived for the subjects in the cluster? [see 45 CFR 46.117(c)]
          
The answer is Yes, if either of the following is true:

·         The only record linking the subject and the research would be the consent document, the principal risk would be potential harm resulting from a breach of confidentiality, and each subject will be asked whether the subject wants documentation linking the subject with the research and the subject’s wishes will govern; or

·         The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

a.    If No, written informed consent is required. [STOP]
b.   If Yes, documentation of informed consent is not required (e.g., e.g., oral or online consent without a signature). [STOP]

Answer: No.   117(c)(1) The consent form is not the only record linking the subject because they are also collecting identifiers and notifying other individuals about the results.   117(c)(2) Written consent is normally required outside of the research context for drug testing.

Result:  Written consent and assent are required in this cluster

Cluster 2 – Cluster of athletes receiving questionnaires about drug and alcohol use (but not drug testing)

Questions (must be asked in order):

1.       Is the cluster a “clinical investigation” as defined by FDA? [see CFR 56.102(c)]
          The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

a.  If No, continue to #2.
b.  If Yes, skip to #5.  

Answer: No.  

2.       Does the cluster involve “human subjects” as defined by HHS? [see 45 CFR 46.102(f)]
         The answer is Yes, if one or more of the following are true:

·         Does the investigator obtain data through intervention with living individuals?

·         Does the investigator obtain data through interaction with living individuals?

·         Does the investigator obtain identifiable private information about living individuals?

                      a. If No, informed consent is not required. [STOP]
                      b. If Yes, continue to #3.
      
                     Answer: Yes.   The confidential questionnaires are interactions.

3.       Can consent and assent be waived or altered for the subjects in the cluster? [see 45 CFR 46.116(d)]
         The answer is Yes, if all of the following are true:

·         The research involves no more than minimal risk to the subjects

·         The waiver or alteration will not adversely affect the rights and welfare of the subjects

·         The research could not practicably be carried out without the waiver or alteration

·         Whenever appropriate, the subjects will be provided with additional pertinent information after participation

a.        If No, informed consent is required.  Continue to #4.
b.       If Yes, informed consent is not required. [STOP]

Answer: No.   It is practicable to obtain assent and consent.

4.       Can documentation of consent and assent be waived for the subjects in the cluster? [see 45 CFR 46.117(c)]

The answer is Yes, if either of the following is true:

·         The only record linking the subject and the research would be the consent document, the principal risk would be potential harm resulting from a breach of confidentiality, and each subject will be asked whether the subject wants documentation linking the subject with the research and the subject’s wishes will govern; or

·         The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

a.        If No, written informed consent is required.
b.       If Yes, documentation of informed consent is not required (e.g., e.g., oral or online consent without a signature). [STOP] 

Answer: No.   117(c)(1) The consent form is not the only record linking the subject because they are also collecting identifiers with the questionnaires, which are confidential but not anonymous.   117(c)(2) written consent is normally required outside of the research context for questionnaires about drug testing and illegal drug and alcohol use. 

5.       If this is an FDA regulated clinical investigation, can documentation of consent be waived for subjects in the cluster? [see 21 CFR 56.109(c)(1)]

c.        If No, written informed consent is required. 
d.       If Yes, documentation of informed consent is not required (e.g., e.g., oral or online consent without a signature). [STOP]

Answer: N/A.  

Result: Assent and Consent are required for this cluster.


Case Where Consent Can Be Waived for All Clusters.

Case 3

A study is designed to test the effectiveness of a comprehensive, community-oriented approach to influence excessive drinking behaviors. The intervention will be delivered at the community-level. Twenty communities with populations between 50,000 and 250,000 in the USA and Canada will be randomly assigned to intervention or control.  The intervention includes public education using mass media and organized community events, promotion of policies to restrict the sale of alcohol to youth, and the development of drinking cessation resources and activities in each community.   In the control cluster there are not interventions.   Outcomes will be measured through records review of health care facilities and alcohol treatment facilities, with appropriate confidentiality and data security provisions in place.  

Questions (must be asked in order):

Intervention Cluster

  1. Is the cluster a “clinical investigation” as defined by FDA? [see 21 CFR 56.102(c)]
    The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

a.        If No, continue to #2.
b.       If Yes, skip to #5.

Answer: No.  The educational interventions and record reviews do not involve a test article.

  1. Does the cluster involve “human subjects” as defined by HHS? [see 45 CFR 46.102(f)]
    The answer is Yes, if one or more of the following are true:

·         Does the investigator obtain data through intervention with living individuals?

·         Does the investigator obtain data through interaction with living individuals?

·         Does the investigator obtain identifiable private information about living individuals?

     a.        If No, informed consent is not required [STOP]
     b.       If Yes, continue to #3.

                       Answer: Yes, there is an intervention in the community, and the investigators obtain identifiable data through intervention with living individuals, through the records review of health care facilities and alcohol treatment facilities.  

  1. Can consent be waived or altered for the subjects in the cluster? [see 45 CFR 46.116(d)]

The answer is Yes, if all of the following are true:

·         The research involves no more than minimal risk to the subjects

·         The waiver or alteration will not adversely affect the rights and welfare of the subjects

·         The research could not practicably be carried out without the waiver or alteration

·         Whenever appropriate, the subjects will be provided with additional pertinent information after participation

    a.        If No, informed consent is required.  Continue to #4.
    b.       If Yes, informed consent is not required .  [STOP]

Answer: Yes, these conditions are satisfied.  The cluster involves minimal risk, waiver of consent will not adversely affect the rights and welfare of the subjects, it is not practicable to obtain consent because the entire population has the possibility of encountering the interventions, and it is not practicable to obtain consent for the records reviews due to the large number of subjects whose records are reviewed.  The analysis stops here.  [STOP]

Control Cluster

Questions (must be asked in order):

  1. Is the cluster a “clinical investigation” as defined by FDA? [see CFR 56.102(c)]
    The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

  1. If No, continue to #2.
  2. If Yes, skip to #5.

Answer: No.  The record reviews do not involve a test article

  1. Does the cluster involve “human subjects” as defined by HHS? [see 45 CFR 46.102(f)]
    The answer is Yes, if one or more of the following are true:

·         Does the investigator obtain data through intervention with living individuals?

·         Does the investigator obtain data through interaction with living individuals?

·         Does the investigator obtain identifiable private information about living individuals?

  1. If No, informed consent is not required. [STOP]
  2. If Yes, continue to #3.

Answer: Yes, because identifiable private information is reviewed during the records reviews. 

  1. Can consent be waived or altered for the subjects in the cluster? [see 45 CFR 46.116(d)]
    The answer is Yes, if all of the following are true:

·         The research involves no more than minimal risk to the subjects

·         The waiver or alteration will not adversely affect the rights and welfare of the subjects

·         The research could not practicably be carried out without the waiver or alteration

·         Whenever appropriate, the subjects will be provided with additional pertinent information after participation

  1. If No, informed consent is required.  Continue.
  2. If Yes, informed consent is not required. [STOP]

Answer: Yes, these conditions are satisfied.  The cluster involves minimal risk, waiver of consent will not adversely affect the rights and welfare of the subjects, it is not practicable to obtain consent due to the large number of subjects with whom there is no intervention or interaction , and it is not practicable to obtain consent for the records reviews due to the large number of subjects whose records are reviewed.  The analysis stops here.  [STOP]

Cases Where the Requirement for Consent Can be Waived in One Cluster but is Required in Another Cluster.

Case 4

A cluster randomized trial was used 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 were defined as the clusters and 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.  Clinics 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.   Outcome is measured by a review of patients’ medical records to look for prescription of anti-smoking medications, referrals to counselling, and documentation that subjects have reported quitting.  The intent of this activity is to publish the results and affect public policy.

Analysis with Tool:  Two clusters, each with two levels; intervention cluster physicians, intervention cluster patients, control cluster physicians, control cluster patients.

Intervention Cluster Physicians

Questions (must be asked in order):

1.       Is the cluster a “clinical investigation” as defined by FDA? [see CFR 56.102(c)]
         The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

a.        If No, continue to #2.
b.       If Yes, skip to #5.

Answer:  No.  The enhancements and records reviews do not involve a test article.

2.       Does the cluster involve “human subjects” as defined by HHS? [see 45 CFR 46.102(f)]

         The answer is Yes, if one or more of the following are true:

·         Does the investigator obtain data through intervention with living individuals?

·         Does the investigator obtain data through interaction with living individuals?

·         Does the investigator obtain identifiable private information about living individuals?

a.        If No, informed consent are not required. [STOP]
b.   If Yes, continue to #3.

Answer.  Yes.  Physicians are human subjects in this cluster because the enhancements are interactions for research purposes.

3.       Can consent be waived or altered for the subjects in the cluster? [see 45 CFR 46.116(d)]
         The answer is Yes, if all of the following are true:

·         The research involves no more than minimal risk to the subjects

·         The waiver or alteration will not adversely affect the rights and welfare of the subjects

·         The research could not practicably be carried out without the waiver or alteration

·         Whenever appropriate, the subjects will be provided with additional pertinent information after participation

a.        If No, informed consent is required.  Continue to #4.
b.       If Yes, informed consent is not required. [STOP]

Answer:  No.  It is practicable to obtain consent because there are e-mails to clinicians and a practice visit by an investigator to encourage use of the enhancements.

4.       Can documentation of consent be waived for the subjects in the cluster? [see 45 CFR 46.117(c)]

         The answer is Yes, if either of the following is true:

·         The only record linking the subject and the research would be the consent document, the principal risk would be potential harm resulting from a breach of confidentiality, and each subject will be asked whether the subject wants documentation linking the subject with the research and the subject’s wishes will govern; or

·         The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

a.        If No, written informed consent is required. [STOP]
b.       If Yes, documentation of informed consent is not required (e.g., e.g., oral or online consent without a signature). [STOP]

Answer:  Yes.  117(c)(2) The enhancements present no more than minimal risk, and receiving emails and practice visits would not normally require consent outside of the research context. The analysis stops here. [STOP]

Intervention Cluster Patients

Questions (must be asked in order):

1.       Is the cluster a “clinical investigation” as defined by FDA? [see CFR 56.102(c)]
         The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

a.        If No, continue to #2.
b.       If Yes, skip to #5.

Answer:  No.  The patients will not be involved in an experiment that involves a test article.

2.       Does the cluster involve “human subjects” as defined by HHS? [see 45 CFR 46.102(f)]
         The answer is Yes, if one or more of the following are true:

·         Does the investigator obtain data through intervention with living individuals?

·         Does the investigator obtain data through interaction with living individuals?

·         Does the investigator obtain identifiable private information about living individuals?

a.        If No, informed consent is not required. [STOP]
b.        If Yes, continue to #3.

Answer:  Yes.  Outcome is measured by a review of patients’ medical records to look for prescription of anti-smoking medications, referrals to counselling, and documentation that subjects have reported quitting.   Also, there is an intervention in that the patients’ environment is manipulated.

3.       Can consent be waived or altered for the subjects in the cluster? [see 45 CFR 46.116(d)]

         The answer is Yes, if all of the following are true:

·         The research involves no more than minimal risk to the subjects

·         The waiver or alteration will not adversely affect the rights and welfare of the subjects

·         The research could not practicably be carried out without the waiver or alteration

·         Whenever appropriate, the subjects will be provided with additional pertinent information after participation

a.        If No, informed consent is required.  Continue to #4.
b.       If Yes, informed consent is not required. [STOP]

Answer:  Yes.    It is not practicable to obtain consent, because obtaining consent could cause a Hawthorne like effect that could skew the results if the patients’ consent is obtained.  [STOP]

Control Cluster Physicians

Questions (must be asked in order):

1.       Is the cluster a “clinical investigation” as defined by FDA? [see CFR 56.102(c)]
         The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

a.        If No, continue to #2.
b.       If Yes, skip to #3.

Answer:  No.  The control physicians are not involved in an experiment involving a test article.

2.       Does the cluster involve “human subjects” as defined by HHS? [see 45 CFR 46.102(f)]
          The answer is Yes, if one or more of the following are true:

·         Does the investigator obtain data through intervention with living individuals?

·         Does the investigator obtain data through interaction with living individuals?

·         Does the investigator obtain identifiable private information about living individuals?

a.        If No, informed consent is not required. [STOP]
b. If Yes, continue to #3.

Answer: Yes.  Control physicians are human subjects because information will be obtained about their prescription of anti-smoking medications, referrals to counseling, and documentation practices.

3.       Can consent be waived or altered for the subjects in the cluster? [see 45 CFR 46.116(d)]
         The answer is Yes, if all of the following are true:

·         The research involves no more than minimal risk to the subjects

·         The waiver or alteration will not adversely affect the rights and welfare of the subjects

·         The research could not practicably be carried out without the waiver or alteration

·         Whenever appropriate, the subjects will be provided with additional pertinent information after participation

a.        If No, informed consent is required.  Continue to #4.
b.       If Yes, informed consent is not required. [STOP]

Answer: Yes.  The study is minimal risk and it is not practicable to obtain consent because it might contaminate behavior and thus affect the validity of the research.  The analysis stops here. [STOP]

Control Cluster Patients

Questions (must be asked in order):

1.       Is the cluster a “clinical investigation” as defined by FDA? [see CFR 56.102(c)]
         The answer is Yes, if the following is true:

·         It is an experiment that involves a test article and one or more human subjects that either meets the requirements for prior submission to FDA under sections 505(i) or 520(g) of the Food, Drug, and Cosmetic Act; or need not meet the requirements for prior submission to FDA under the sections noted above, but the results of which are intended to be later submitted to or held for inspection by FDA as part of an application for a research or marketing permit.

a.        If No, continue to #2.
b.       If Yes, skip to #5.

Answer:  No.  The patients will not be involved in an experiment that involves a test article.

2.       Does the cluster involve “human subjects” as defined by HHS? [see 45 CFR 46.102(f)]
         The answer is Yes, if one or more of the following are true:

·         Does the investigator obtain data through intervention with living individuals?

·         Does the investigator obtain data through interaction with living individuals?

·         Does the investigator obtain identifiable private information about living individuals?

a.        If No, informed consent is not required. [STOP]
b. If Yes, continue to #3.

Answer:  Yes.  The investigators obtain identifiable private information when they review the patients’ medical records. 

3.       Can consent be waived or altered for the subjects in the cluster? [see 45 CFR 46.116(d)]
         The answer is Yes, if all of the following are true:

·         The research involves no more than minimal risk to the subjects

·         The waiver or alteration will not adversely affect the rights and welfare of the subjects

·         The research could not practicably be carried out without the waiver or alteration

·         Whenever appropriate, the subjects will be provided with additional pertinent information after participation

a.        If No, informed consent is required.  Continue to #4.
b.       If Yes, informed consent is not required. [STOP]

Answer:  Yes.  The intervention involves the patients of over 250 physicians in 13 clinics, and the only intervention is a review of the medical records without other intervention or interaction, and there is concern about a Hawthorne-like effect.  .  The analysis stops here. [STOP].

SACHRP hopes that these case examples are useful to the agencies and to interested individuals.

Content created by Office for Human Research Protections (OHRP)
Content last reviewed