The regulations in both the United States and Canada contain provisions by which the review of clinical research can be simplified. Determination of participant risk as minimal is a key consideration as to whether a given research project qualifies for “delegated review” in Canada or “expedited review” in the United States. Whenever engaging in the review of studies that are to take place in both countries, an REB/IRB should account for the nuanced differences in reasoning methods between the Canadian and US regulatory definitions of “minimal risk.”

Minimal Risk: US vs Canada

Minimal risk research in Canada is defined as research...Standards in the United States define minimal risk as:
“…in which the probability and magnitude of possible harms implied by the participation in the research is no greater than those encountered by participants in those aspects of their everyday life that relate to the research.”“The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine or psychological examinations or tests.”

Minimal Risk in Canada

In Canada, minimal risk research is defined by the Tri Council Policy Statement (TCPS) 2 as research:

“in which the probability and magnitude of possible harms implied by the participation in the research is no greater than those encountered by participants in those aspects of their everyday life that relate to the research.”

 

The REB (Research Ethics Board) in Canada must, in its assessment of the acceptable threshold of minimal risk, ensure that a given research study involving individuals and groups who live with relatively high levels of risk on a daily basis does not exacerbate their vulnerability.

In making an assessment of an acceptable threshold of minimal risk, the REB is to take a proportional approach. The level of review is determined by the level of risk presented by the research—a lower level of risk requires a lower level of scrutiny (delegated review); a higher level of risk requires a higher level of scrutiny (full board review). Ethical acceptability is predicated on a favorable balance of risks and benefits.  In its assessment of minimal risk, the REB ought to begin with an assessment of the magnitude and probability of harms in a way that accounts for their implications given the situational context and actual life risks of the study population.

Minimal Risk in the US

The US regulations define minimal risk as:

“the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine or psychological examinations or tests.”

 

A Key Difference

The Canadian regulations differ from the US regulations by defining minimal risk as relative rather than absolute. In Tri-Council Policy Statement (TCPS) 2, the harms and discomforts associated with minimal risk are rooted in the actual lives of the participants. The US regulations, on the other hand, do not tie the harms and discomforts ordinarily encountered in daily life to those experienced in the daily lives of the proposed subjects of research or any specific population. The notion of “harms and discomforts” in the US regulations reflect the “background risks” that are familiar and part of the routine experience of life for “the average person” in the “general population.” In 2008, the US Secretary’s Advisory Committee on Human Research Protections (SACHRP) suggested that “minimal risk” as defined in the regulations should be applied in a manner that recognizes that “risks” are procedure-specific and population-dependent and that the notion of “acceptably low risk is fixed.” The “fix” referring to the “average person” and the “general population.”

Managing Ambiguity

The US fixed standard of the estimation of risk as set against the “average person” and “general population” carries with it a degree of ambiguity given that both terms are abstractions. When reviewing pediatric research, the IRB is required to determine what constitutes a “minor increase over minimal risk.” However, the US regulations do not provide the IRB with precise definitions for any of these terms.

The Canadian regulations (TCPS 2) recognize that potential risks and benefits may be perceived differently by different groups and individuals in society. TCPS 2 does not specify the standard further and asks the REB to consider the diversity of values and experiences in society when making minimal risk estimates. The regulations require that the REB be guided more broadly by the principle of the Concern for Welfare of participants, which imposes an ethical obligation “to design, assess, and conduct research in a way that protects participants from any unnecessary and avoidable risks.”

Interestingly enough, TCPS 2 reflects the earlier guidance issued by SACHRP in 2008, which enjoined the IRB to “carefully consider the characteristics of subjects to be enrolled in the research including an evaluation of subject susceptibility, vulnerability, resilience and experience in relation to the anticipated harms and discomforts of research involvement.”

Estimating Risk in the US and Canada

A bone marrow biopsy in the US would be considered a risk of daily life for patients with certain types of leukemia. Given the US definition of minimal risk, the IRB must judge whether the risks introduced to these subjects by the research (three bone marrow biopsies over five days) are “greater than the risk of daily life for the ‘average person’ in the ‘general population.’” While the actual life of the leukemia patient provides bone marrow biopsy experience, the estimate of the probability and magnitude of harm introduced by a biopsy in a research study is not lowered by the actual experience of these patients. A bone marrow biopsy is not seen to be part of the experience of the average person in the general population. It is not considered a routine medical test, and thus its use in research remains greater than minimal risk.

In the Canadian regulations, the REB must determine whether the probability and magnitude of possible harms introduced by the research (three bone marrow biopsies in five days) is no greater than those already experienced by leukemia patients. A finding by the REB that the study is above minimal risk seems likely.

However in a group of elderly (up to 80 years of age) where participants are being asked to exercise, unsupervised, at home, as an adjunct to other study activities (filling out questionnaires) that would otherwise be considered to be minimal risk the prospect of discord between IRB and REB determinations exists.

The US regulations call for an assessment as to whether or not the specific exercise could be considered routine for the average person in the general population. The Canadian regulations on the other hand call for the assessment as to whether or not the study exercise routine exacerbates the vulnerability of this elderly population. In studies where estimates of risk imposed by the regulations in the US and Canada become discordant, it seems prudent to forego delegated or expedited review. For both in the US and Canada full board review ensures a wide and full consideration of risk and its proportion to any benefit associated with the research study.

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