SACHRP Recommendation on Interpretation

Approved by SACHRP March 20, 2024

Background

When human subjects research is halted, suspended, or has its IRB approval lapse, the institutional review board (IRB), the investigator(s), the institutional official, or a regulatory agency with oversight of the research may wish to consider whether continuing some or all research procedures or interventions is in the best interest of the subject(s). The HHS regulations at 45 CFR part 46, subpart A (i.e. the Common Rule) do not address continuation of research or delivery of research intervention(s) in these cases; nevertheless, the “best interests” issue is often raised in cases when research stops unexpectedly. However, the term “best interests” is not defined in regulation or guidance, leaving stakeholders in the position of making decisions that may be inconsistent and not necessarily well-supported.

Human subjects research can be interrupted or stop prematurely for a number of reasons. Examples of the circumstances in which research can end prematurely or be suspended include:

A DSMB (data safety monitoring board) recommends the termination of a study due to concerns related to safety, efficacy, or futility.
A lack of financial resources to support the continuation of the research.
A sponsor decides to end a clinical trial for commercial reasons.
A sponsor decides to terminate a clinical trial early due to poor enrollment of subjects or other implementation-related issues.
Investigators discontinue their participation due to lack of interest, retirement, completion of a fellowship, etc. This includes single sites that are part of a multi-site trial.
Compliance-driven decision by an IRB, institutional leadership, or regulatory bodies to suspend or terminate some or all research activities. This includes actions such as the suspension of a Federalwide Assurance (FWA) that cause all research at a given location to be suspended even if the immediate issue that led to the suspension was not due to problems in all research.
One or more stakeholders fail to obtain necessary continuing approvals.

Excluded from consideration in this document are issues related to the availability of research interventions after the completion of the research, which is commonly referred to as “post-trial access.” The recommendations in this document are focused on the disposition of subjects in ongoing human subjects research and are intended to inform relevant stakeholders in the research enterprise, including regulators, Institutional Review Boards, investigators, and sponsors. Together, these stakeholders share responsibility and control for the implementation of human subjects research, including the management of research that has been suspended or terminated. Resolving issues related to suspensions and terminations will frequently require collaboration across stakeholders.

A determination that continuing or resuming participation of one or more subjects in research that has been suspended or terminated means that the relevant stakeholders have determined that ongoing participation is acceptable. It does not mean that there is an obligation or requirement to allow continuation of participation.

Defining “Best Interests”

The Belmont Report introduces the principle of beneficence by stating that “Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being.” A complementary statement appears in the fourth general principle of the Declaration of Helsinki which pronounces that “It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including those who are involved in medical research” and also “While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.” Combining these concepts, “best interests” may be defined in broad terms as the interests of the individual as they relate to their personal health and well-being. While the regulations do not include language regarding best interests, there is the requirement that IRBs have policies that allow investigators to implement changes to protocols without prospective IRB approval when necessary to eliminate apparent immediate hazards to the subject. (45 CFR 46.108(3)(iii)). This is echoed in FDA guidance on disruptions in ongoing clinical research due to disasters and public health emergencies.¹

While the issue of best interests is often discussed in the context of biomedical research / clinical trials, it should be acknowledged that there may be non-biomedical research where it is in the best interests of subjects to continue in research that has been suspended or terminated.

There are a number of types of benefits that subjects may experience during their participation in research that might trigger best interest considerations. This may include psychological benefit as a factor in determinations of best interests. Subjects who are in research studies that are being suspended or terminated may believe that they are receiving benefit from their participation, even when the subjects have been randomized to placebo or where clinical data from the research indicates that the intervention is ineffective or perhaps harmful. It is inevitable that there will be clinical trials that are stopped due to negative overall results (either at the planned interim analysis or at the final analysis) even though there may be perceived benefit by persons who want to continue receiving the intervention.

In the context of individuals who lack capacity to make decisions in the clinical care context, an objective best interests test guides decision-making for people who never had capacity to make decisions for themselves, including children. Legally, it is generally a consideration of whether the benefits outweigh the burdens. In the context of research, it may be necessary to distinguish between a “best interests” standard i.e., benefits outweigh burdens and situations in which someone has a compelling interest in maintaining access to interventions or procedures that are only available through participation in research.²

The other context in which best interests is used in cases relating to medicine is when a provider has put his/her/their own interests above the interests of the patient. This expresses a concern about the fiduciary duty that physicians and other clinicians owe to patients. Whether the duties owed by researchers to research subjects should be considered fiduciary is debated in the literature. In the conduct of research, the research requirements for extra tests and procedures are not necessarily advancing the best interests of the patient-subject. This is permissible in the research context because of the informed consent of the subject to participate in research. However, investigators still must provide for subject safety, but they are not expected to put the patient-subject’s interests above all else.

Analysis of “Best Interests”

Stakeholders in the research enterprise who have a part in deciding if subjects’ continued participation is warranted in research that has been suspended or terminated must consider whether it is in the subjects’ best interests to resume participation in some or all research procedures. This analysis should be rooted in the principles of beneficence and non-maleficence and the requirements that efforts are made to secure the well-being of subjects and not unnecessarily expose them to harm. Factors that should be considered when making a best interests determination include:

The reason for the suspension or termination.
Whether subjects will continue to receive direct benefit (e.g., clinical benefit) if allowed to continue.
The impact of the suspension or termination on the health and wellbeing of subjects.
Whether the benefit requires the resumption of some or all research procedures.
The risks to the subject associated with the resumption of some or all research procedures.
The availability of resources to safely resume some or all research procedures.
The ability to obtain the same care or treatment outside of the research context.
The need for continued collection of safety data or subject monitoring.

For example, the IRB, in consultation with the investigator and the subjects’ treating physicians (if not the investigator), may need to determine whether it is in the best interests of currently enrolled subjects to (a) continue receiving the interventions that were being administered to subjects under the research project, (b) be transferred to another institution engaged in the research so that participation of the subjects in the research may continue, or (c) be transitioned to medical management outside of the research context. Continuation of subjects on interventions that were being administered under the research project may be appropriate at least temporarily, for example, when those interventions hold out the prospect of direct benefit to the subjects or when withholding those interventions poses increased risk to the subjects or would have a negative effect on their health and wellbeing.

In some circumstances, such as in the context of a therapeutic relationship, researchers may have a duty to transition subjects into other clinical care following an unexpected stoppage of a trial when it is not possible to continue some or all research interventions and procedures.

Additional Considerations

While one or more stakeholders may determine that it is in the subjects’ best interests to resume research, there may be legal, contractual, or financial barriers that need to be addressed to ensure there are adequate resources available to support the resumption of activities. This includes adequate resources to ensure proper monitoring in trials that may pose a risk to subjects.

In situations where the suspension or termination of research activities is due to a serious compliance issue on the part of an investigator, the IRB will need to consider whether it is feasible and appropriate to resume some or all study activities. The nature of the noncompliance and its impact on participant safety will factor into this review. When the suspension or termination was issued by a different stakeholder such as the institution or a regulatory body, resuming research activities and the conditions under which research may resume will need to be negotiated among these stakeholders.³

There are also situations where research is suspended or terminated at the institutional level, for example the suspension of an institutions Federalwide Assurance (FWA) that results in the suspension of all research covered by the FWA even when the issues that led to the suspension of the FWA were unrelated to all of the covered research. In such cases a consideration of why a particular study has been suspended may need to be considered as part of the best interest determination.

When research is suspended or terminated due to circumstances where the principal investigator, the entire research team, or the research site / institution refuse to continue their involvement in the study, options such as transferring subjects to another site or identifying a geographically similar location to conduct the research may provide a pathway for subjects to continue with minimal interruption. In these cases the subject transfer must be amenable to the subject as well as the sponsor, the receiving site, and the IRB.

In situations where the suspension or termination of research activities is due to sponsor’s insolvency, it may not be possible to resume research activities regardless of whether it is in the best interest of subjects to continue. For example, IRBs have no authority to compel a sponsor to continue a trial, just as they have no authority to compel a sponsor to provide an investigational product through the use of expanded access or right to try mechanisms. At the same time, it may be in participants’ best interests for the insolvent sponsor to return data and specimens (voluntarily given by participants) including copies and remaining samples to the researchers so that some value may result from the research, such as the ability to perform further testing and analysis of unused specimens or for use in future research. While IRBs may not have authority to compel this, they or their institutions may consider how to support researchers and participants for best-interest reasons.⁴

Finally, there may be circumstances where access to experimental drugs or devices may be possible outside of the research through expanded access.⁵ The provision of experimental interventions through an expanded access mechanism may be considered when it is appropriate and when relevant stakeholders such as the sponsor are willing to make the intervention available through expanded access.

Informed Consent

In general, informed consent documents provide minimal information regarding unplanned interruptions in or premature termination of research beyond language that indicates that the subject’s participation could end at any time because the research has been ended or because the investigator has determined that it is in the subject’s best interest to discontinue participation. However, the potential for the unplanned interruption or termination of research may need to be addressed in the informed consent materials and process when it is appropriate given the nature of the research or when there are ramifications from discontinuation that will need to be addressed beyond the research. For example, research involving implantable devices should be explicit about the impact of study termination, including responsibility for managing ongoing servicing and maintenance or explantation of the device. At a general level, template consent language may be augmented with language that more completely describes general reasons why research may be discontinued prematurely.

Notification to subjects related to a suspension or termination of research would include “new information” potentially affecting their continuing participation. The nature of the information presented should be calibrated to the issue affecting the research. For example, a delay in shipment of study drug to sites may disrupt participation and require notification to current subjects due to the impact on procedures such as specifically timed infusions, but this delay would not apply to subjects who have completed all procedures related to the delay. However, notification may be applicable to all subjects, current and former, if the delay in shipment was due to problems with the study drug that could have an impact on subject safety, such as improper manufacturing of the study drug.

If there is a decision made to resume some or all research procedures for some or all subjects, then it is necessary to inform subjects, who are continuing, of any changes that might be necessary and obtain their informed consent to the revised research. The revised consent information should be explicit regarding what has changed with respect to the subject’s participation and why, as well as including changes in the risks and benefits to continued participation.

Investigators must make their best effort to be respectful and transparent to the subjects who have volunteered for their studies. The principle of “respect for persons” obligates the research team to inform present subjects about the interruption, the reason for the interruption, and as stated above, the next steps. Researchers and IRBs should receive training and education to ensure they understand the wide breath of variables to consider in determining when current and/or former subjects should be notified regarding the new information.

Questions Posed by OHRP for SACHRP to Consider:

When should IRBs, investigators, or institutions consider the “best interests” standard for research that is stopping, or being stopped, prematurely?

IRBs, investigators, or institutions should consider the “best interests” standard for research that is stopping, or being stopped, prematurely when research is providing demonstrable direct benefit to subjects or a subset of subjects and the research intervention is not reasonably available outside of the research. When the research is stopping prematurely due to issues of subject safety, even when individual subjects believe that they are obtaining benefit through their participation, the consideration of an individual’s best interests can include an examination of the facts and circumstances relevant to an individual’s participation. However, it would be unethical to allow individuals to continue participating in research that is known to be harmful.

What issues should be considered by an IRB, institution, or other oversight body to make a “best interest” determination?

The issues for consideration will vary depending on the nature of the research, the reason for the suspension or termination. At a minimum stakeholders should consider:

The reasons for the suspension or termination
The likelihood of the research resuming
The availability of resources, including funding, research staff, adequate facilities and investigational product to support the resumption of some or all research activities
The need for additional monitoring or other enhanced oversight activities
Subjects’ interest in ongoing participation in research that may differ in significant ways from that which they originally provided consent

Is a “best interest” determination ever justified if subjects can obtain the same care or treatment outside of the research? Should access to care, or barriers to access, be part of the considerations?

Usually no. When the same clinically important care or treatment can be obtained by subjects outside of the research, the issue of best interests is generally satisfied because there are options for obtaining the care and treatment options being provided through research. However, all parties should be engaged to ensure a careful transition of subjects from the research study to clinical care. While barriers to access may be a legitimate concern, it is not a reasonable standard in and of itself for justifying best interest determinations. However, if access to healthcare, e.g., transportation to the clinical site, is part of the research then it may be appropriate to put measures in place to mitigate any negative impact of losing access to non-research healthcare because of the suspension or termination.

Should “best interests” determinations be made on an individual, group (e.g. study arm), or study-wide basis?

Best interests determinations may be made on an individual, group or study-wide basis. The primary intent of the best interests determination is to prevent harms that result from the suspension or termination of research and extend direct benefit to subjects at the individual level. Whether that determination should be extended to the group level or study-wide can vary depending on the nature of the research activity.

If a study has not yet enrolled or begun to involve research interventions, is a “best interest” determination ever justified?

No, best interests should not be a factor in research with no active subjects. Allowing subjects to enroll in research where the sponsor, investigator, institution or IRB has determined that the research will not be allowed to continue is disingenuous and potentially goes against the best interests of potential subjects. Moreover, if the intent of the proposed research is to determine the safety or effectiveness of an intervention, it may not be possible to know whether the research intervention will have a positive effect on subjects with respect to the disease or condition being studied.

Is a “best interest” determination ever justified for a placebo-controlled study, where the placebo is the absence of potentially beneficial interventions?

No. If “best interests” are limited to a subject’s therapeutic response to a research intervention, then allowing continuation of the placebo arm in suspended or terminated research is not justified. While there will be individual subjects who experience a placebo effect, continuation of the placebo for clinical purposes is not consistent with typical standard of care.⁶ This aligns with the FDA’s position that there is no prospect of direct benefit from the placebo intervention or procedure.⁷ (Also see response to question 4 above.) In the case of behavioral research or studies with a lifestyle or other non-medical component, where basic education or a basic, common intervention is deemed the “placebo” for comparison, this should not be a concern as the comparison is the equivalent of a standard of care and not a true placebo. However, if the placebo is only part of the intervention or there are other significant interventions included in the placebo arm, it may be appropriate to take this into account.

Are considerations such as lost time or effort on the part of participants, or lost research compensation, ever appropriate justifications for a “best interest” determination?

No. Considerations such as lost time or effort and lost research compensation may be important to participants, but should not be considered as factors when determining whether continuation of research interventions or procedures is in a subject’s best interest. Moreover, depending on the circumstances under which a research study was suspended or terminated, there may not be a source of funding for participant compensation.

Is a therapeutic relationship between the study investigator(s) and the participants an appropriate justification for a “best interest” determination?

No. A therapeutic relationship between a clinician and a patient may be established in the context of clinical research, or it may exist prior to a patient making a decision to participate in research being implemented by the clinician. Such relationships, whether or not preexisting, should not be determinative of whether continued participation in research is in the subject’s best interest. When the research investigator is also a subject’s clinical care provider, they may have relevant input to aid in making a determination that continuation is in a subject’s best interest, but this relationship is not in and of itself a justification for continuation. There may also be scenarios where the patient/clinician relationship is hard to disentangle from the research.

When a “best interest” determination is made to allow one or more participants to continue in the research, should data collection toward the scientific objectives continue? What about other ancillary research procedures?

The primary factor when deciding which research procedures and data collection activities should continue is what the expected outcome is for the research activity. If the interruption in research is expected to be temporary, then collecting data and performing all research procedures for the duration of the suspension serves both the best interests of the individual subject and the best interests of science. However, when the research activities are terminated or expected to be terminated, collecting additional scientific data beyond what is necessary for subject safety or conducting other ancillary research procedures that do not have a direct impact on subject best interests should be discontinued.

Additional scenarios:

Device investigations, where a device has been implanted in human subjects and explanting or removing the implanted device poses more risks than continuing the research.

Depending on the reason for the suspension or termination, the IRB and other stakeholders may consider leaving the device in place when the risk of explant is high. However, when a device manufacturer becomes insolvent and can no longer pay for research-related activities, there may need to be an analysis of the impact of leaving the device in place, even when it reaches a point where the device no longer functions. In cases where leaving a non-functioning device in place presents a lower risk that an explant procedure, consideration can be given to leaving the device in place. However, subjects with the device would need to be adequately informed and consent to leaving the device in place or allowing a high-risk explant procedure, and this information is of importance to subjects irrespective of when their participation is expected to end.

Research includes a behavioral therapeutic component, or a potentially beneficial educational intervention.

The analysis for non-biomedical trial scenarios such as behavioral or educational research should largely mirror the analysis for clinical research. The IRB should consider what is the direct benefit that subjects are receiving from the intervention or procedures, and the harms of stopping them early. Other factors such as the availability of funding, the presence of a research team, and issues related to research compliance are also factors.

Research where ongoing procedures are needed to assess safety of interventions the participant already experienced.

Concerns for the safety of participants should be a primary concern when deciding if participants should be allowed to continue with procedures that are needed to assess safety. When safety is an issue, measures to either ensure ongoing access to the procedures related to safety or a transition to non-research safety oversight must be in place.

Research that has been suspended as part of a broader action e.g., suspension of an FWA.

Determinations regarding the resumption of research activities for studies suspended as part of a broad compliance action should be negotiated between institutional leadership, the IRB and the regulatory agency responsible for the suspension. In such cases the best interest of subjects is a relevant concern, particularly in cases where the research would not otherwise have been suspended. Relevant stakeholders should consider whether issues related to the suspension are relevant to the research in question and whether subjects are at greater risk of harm if they are denied access to the research.

Endnotes

¹ https://www.fda.gov/media/172258/download

² Beauchamp and Childress, Principles of Biomedical Ethics (New York: Oxford University Press, 2009) pp. 138-39.

³ The conditions for resumption of research will vary depending on the reason for the suspension, and could include measures such as increased monitoring, more frequent reporting, and additional training of research personnel.

⁴ Consideration should be given to prospectively addressing this in contracts ahead of starting research.

⁵ Expanded access is a regulatory pathway for a patient with a serious or immediately life-threatening disease or condition to gain access to an investigational medical product for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. Because the use is considered investigational the use must be reviewed by an IRB.

⁶ Placebo-controlled studies may pose additional challenges, such as unblinding to determine what arm subjects had been randomized to.

⁷ FDA draft guidance “Ethical Considerations for Clinical Investigations of Medical Products Involving Children”

SACHRP Recommendation on Interpretation of the Best Interests Standard for the Retention of Subjects in Human Subjects Research that Has Been Suspended or Terminated