The final version of this guidance will show what OHRP believes is true on this topic at this time. There are no rights being granted to any individual by this advice, and it does not have the power to bind the Office for Human Research Protections or the general public.
One should view OHRP guidance as merely suggestions unless certain exact regulatory demands are indicated. The necessity of following the Department of Health and Human Services’ regulation at 45 CFR Part 46 is implied by the use of the word must in the guidance provided by the Office of Human Research Protections. It is recommended by OHRP that one should use the word ‘should’ in their guidance, though it is not a requirement. If the requirements of the applicable laws and regulations are met, you can use a different method.
Date: October 20, 2014
Supplementary Background
On August 28, 2013, HHS convened a gathering to listen to the public’s input and thoughts on how a review board should assess the possible hazards related to research that involves participants randomly assigned to one or more treatments within the accepted standard of care for specific medical situations, and to determine which foreseeable risks should be shared with research participants as part of the informed consent process.
The opinions and ideas conveyed in the meeting, in the public remarks made, and those submitted in written form to the Department of Health and Human Services have been taken into consideration while creating this draft assistance.
A face-to-face conference and appeal for opinions from the public happened after a compliance review conclusion letter from OHRP’s probe into the ‘The Surfactant, Positive Pressure, and Oxygenation Randomized Trial’ (SUPPORT) clinical trial (http://www.hhs.gov/ohrp/detrm_letrs/YR13/mar13a.pdf).
After examining the case, OHRP established that participants taking part in the SUPPORT trial were not informed of selected risks involved with the interventions being tested adequately enough as needed by HHS guidelines for safeguarding of human test subjects.
The decision by OHRP regarding the SUPPORT trial spurred a number of inquiries, like: What dangers can come to study participants when looking into treatments that are common in clinical treatment and how can an IRB determine if these risks are predictable and accurate enough to communicate with participants in the informed consent process? Due to the varied opinions among the scientific, ethical and research circles on how the HHS rules for the defense of human subjects should be utilized for studies about the current standard of care treatments, OHRP is releasing this guidance with the goal of increasing understanding.
This guidance document examines studies intended to analyze the hazards of treatments or methods accepted as medical standards of care and makes it evident the OHRP believes several risks connected to the standard should be made clear to potential participants during the process of obtaining their informed agreement in esteem to 45 CFR 46.116(a)(2). This text focuses on particular risks likely to occur when conducting research that are associated with the reason why the research is being conducted, though it does not cover all conceivable risks.
Discussion of Public Comments
The Department of Health and Human Services asked for people’s thoughts on the matter of how a review board should evaluate any potential hazards associated with studies that include chances for randomization to one or more parameters of typical care, and what research risks need to be explained to participants in the process of informed consent. HHS was specifically interested in public input on the following questions:
How should an IRB assess the risks of standard of care interventions provided to subjects in the research context?
a. When should an Institutional Review Board consider the potential risks of a research project?
b. In which situation should an Institutional Review Board (IRB) decide not to take into account risks that are unrelated to the research?
c. Which evidence should an IRB take into account when assessing potential risks?
Many people argued in favor of informing potential participants of clinical trials about the risks associated with the usual treatment. It was widely believed that any type of risk, including those of the expected level of care, must be made known in order for prospective research participants and their guardians to be totally aware of what they will be getting into.
A number of people expressed that when included in a clinical study, the risks of regular medical treatments can be intensified. To reduce any possible harms, they suggested making data monitoring plans obligatory to observe and recognize any potential risks that may occur. The results derived from data security monitoring plans would find any potential dangers that could occur as a result of conducting the study.
People spoke out against including the potential hazards of utilizing medical care protocols within the dangers associated with regular or comparative effectiveness research. Lots of people expressed that it is incorrect to refer to the risks related to standard of care treatment as research risks as normally there is little to no corroborating proof to back them up.
Many small and large medical methods are based on the opinion of healthcare providers and have no substantial evidence to back them up. Those supporting this viewpoint argued that IRBs should not necessitate that any standard of care risks must be announced as research risks, instead, it should be included in the patient’s consent for treatment prior to enrolling them in the clinical trial.
OHRP concurs that any risks not caused by being a participant in a clinical trial should not be taken into account as hazards related to the research. The primary factor to consider is not whether the intervention being offered to individuals is up to par with accepted standards, but rather if the care they are receiving is different from what they would usually experience in non-research circumstances.
The potential dangers from having unequal treatment in the study belong to the people engaging in the experiment. Patients taking part in a study comparing how effective different standards of care are should be informed of the potential hazards associated with each of the treatments being compared.
The Office for Human Research Protections (OHRP) holds the belief that the disparity between receiving medical care and being involved in research should be made evident to subjects.
What factors should an IRB consider in determining that the research-related risks of standard of care interventions, provided to research subjects in the research context, are reasonably foreseeable and therefore required to be disclosed to subjects?
Various commentators proposed clarifying the term “standard of care” prior to elucidating the definition of “reasonably foreseeable risk”. It was suggested that “standard of care” should be understood as the accepted and suitable treatment or practice for a particular illness or situation which is recognized by medical experts and practiced commonly by medical practitioners.
Commenters drew attention to the need for evidence to support a prescribed standard of care. This proof may come in the form of an article, the results of an experimental trial, or specialist opinion, but the standards of practice may vary between the medical community and the associated risks accordingly.
Comments providing different interpretations of what is meant by “reasonably foreseeable risk” indicated the disagreement among medical and clinical research professionals on how this term should be understood.
Commenters brought up different types of standards and quantifiable measurements to identify any potential risks that could be predicted. The commenters put forth various amounts of evidence which consisted of clinical trial results, peer and literature reviews, professional experience, consideration of risk versus benefit, and existing risks for the relevant population.
Some people who commented suggested that reasonably probable dangers are those found in professional medical journals which affect 5% of patients or that have p-values less than 0.10 in at least one experiment.
A comment said that events which could potentially be dangerous but don’t have supporting evidence to be related to the action should not be considered foreseeable. However, some people disagreed with trying to make a definition for this.
The commenters were in agreement that any risks of the standard of care treatment should be revealed to prospective participants, but they disagreed on the exact spot in the informed consent form where this information should be included.
The Office for Human Research Protections (OHRP) believes that any research or other proof that is related to the accepted medical standards for treatment should be taken into account when figuring out if there are likely dangers to consider.
This guidance does not provide suggestions on how to determine the amount of risk that is anticipated. In relation to what risks should be seen as “reasonably foreseeable,” OHRP believed that the least amount of identified dangers linked to a standard of care that are being assessed for the aim of the research should be thought of as “reasonably foreseeable.” The fundamental purpose of the Common Rule is to enable prospective participants to make informed choices about participating in research.
If a risk is substantial enough for the federal government to allocate public funds to determine its scope or characteristics, then potential participants should be informed of this risk in order to make an informed decision about whether they are willing to be exposed to it.
It would not be appropriate to have both the federal agency that is paying for the research and the researchers carrying out the investigation be informed of a certain danger without informing the participants of the same risk, while still claiming that their permission to take part was obtained in a meaningful manner.
When is evaluating a risk in a research study considered to be a “purpose” of the research study?
The motivations for conducting research are the goals or objectives which influence how the research is designed and why it should ethically be done. An investigation is usually conducted and arranged when conducting a research study to determine if, how much, and what kind of injury may be taking place when assessing a risk. The people behind the conception and implementation of the research are aware of the potential of causing harm, as the investigation aims to determine the extent to which that harm could or would not happen. Those taking part in the study should be informed of any possible risks they may face.
When researching and assessing standards of care, it is important to only evaluate ways that risk can be present in studies which compare standards, and these risks should be important enough to warrant doing the study in the first place.
The objective of these studies should not be interpreted as necessarily including every potential result that could be assessed during the investigation, but rather those that are the main reasons for carrying out the study.
No research study is meant to assess any risks that are completely obscure or unrecognized. For the research to be intentional in providing proof of a specific danger, the assessment of the risk must be counted as a goal of the research.
As an example, a research study can be designed to include enough participants so that the collected data can provide statistically relevant results regarding a certain risk. Thus, the evaluation of the risk is considered to be one of the aims of the research.
Are the risks of research associated with the purposes of studies of standards of care “reasonably foreseeable risks” that must be disclosed to prospective subjects in the informed consent process?
Prospective subjects must be made aware of the potential risks associated with the research, allowing them to factor this information into making an informed decision about participating. People who are asked to agree to take part in this experiment could have opinions as to the level of danger they are willing to put themselves in. The regulations include the following requirement for the disclosure of risks as part of the informed consent process:
An enumeration of potential hazards or discomfort that may be experienced by the study participant.
In general, when assessing the potential hazards associated with an accepted standard of care in a study, the Office for Human Research Protections (OHRP) considers these risks to be “reasonably foreseeable,” and therefore they should be reported to the participant in the informed consent documents as per 45 CFR 46.116(a)(2).
OHRP has held that if there is valid reasoning for examining a hazard related to a standard of care, then that risk must be seen as conceivable and, in turn, a “reasonably foreseeable” danger for which the regulations apply.