Minimal risk in research

In research regulations regarding human participants, such as the US CFR (45 CFR 46.102(i))5 and the Tri-Council Policy Statement of Canada (TCPS2) (Chapter 2.B),7 risks may be considered below minimal risk when the likelihood and seriousness of harm or discomfort are comparable with those of daily life. In research regulations, such as the International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS Guidelines) (Guidelines 4 and 9)6 as well as in the US CFR (45 CFR 46.102(i)),5 risks are considered within minimal risk when the risks are not above the risks of routine clinical (physical and psychological) examinations. Similar concepts of minimal risk are employed across other national and international regulations with some differences1 such as Guidelines on Ethics for Medical Research2 or Additional Protocol to the Convention on Human Rights and Biomedicine Concerning Biomedical Research.3

The risks of daily life or routine clinical examinations as thresholds embedded in the minimal risk in research standard has received much scrutiny, including commentators inquiring whose daily life or routine clinical examinations should be referenced and why risks in daily life or routine clinical examinations should serve the role as a low risk standard.1 ,4 ,17 Although these discussions largely focus on research with children in non-therapeutic situations and do not specifically discuss its relevance as a threshold in relation to informed consent,4 ,17–19 they may provide insight into how a low risk standard could be determined.

Two interpretations of minimal risk are discussed widely in the literature.1 ,4 ,17 The absolute interpretation of minimal risk provides the same standard for everyone by referring to risks in daily life or routine clinical examination of an average healthy person.1 ,4 ,17 The relative interpretation of minimal risk leads to different standards across persons depending on what kind of risk that particular person lives with.1 ,4 ,17 The relative interpretation has been criticised as it may label high-risk procedures as minimal-risk procedures if the participant lives with high daily risk such as living in an unsafe neighbourhood or routinely requiring a high-risk clinical intervention.1 ,8 ,20 However, those who support the relative interpretation indicate that it can consider cultural and societal norms18 and that potential abuse may be addressed by ethics review committee (ERC) members who have fiduciary duties to participants,18 which is stipulated, for example, in the TCPS2 (p.23, Chapter 2-B). Nonetheless, leaving much to ERC discretion may potentially lead to exploitation of participants8 ,20 particularly when ERC members are influenced by the value of research or the prestige of the investigators.19

Next, it is a normative choice to determine that risks in daily life or routine clinical examinations are relevant to serve the roles of minimal risk.1 ,18 The daily life standard has been criticised for involving higher risks compared with the routine clinical examination standard.1 ,4 ,17 Daily life involves a variety of harms, ranging from very trivial to highly serious with various possibilities.1 ,4 ,8 ,17 By contrast, routine clinical examinations for healthy persons may involve very low physical risks1 ,4 ,17 although these examinations may involve potentially high psychosocial risk due to personal information collected prior to such examinations if not kept confidential.12 ,20

Comparing minimal risk standards across research regulations, Kopelman1 concludes that the absolute interpretation of the routine clinical examination standard is more justifiable than others as it sufficiently excludes high risks. She articulates that some concern regarding potentially serious psychosocial harm due to inappropriate disclosure of private information may be extremely low due to clinicians’ compliance with fiduciary duties.1 Kopelman1 also proposes that the routine clinical examination standard should rather be understood as risks involved in these examinations per se and not information collected alongside these examinations.1 Similarly, Resnik8 proposes to employ only the routine clinical examination standard. He argues that rather than flexibility, the clarity of the standard and consistency in its application should take priority to secure fairness or justice. On the other hand, Freedman et al18 argue that the daily life standard is morally justifiable as (1) research risks are substitutive due to people's exposure to daily risks while not participating in research and (2) daily risks are socially acceptable.18 The first point is criticised as daily risks are usually associated with some purpose or benefits whereas research does not guarantee any benefit to the participant.4 Indeed, the total benefit gained from the same time frame may likely decrease particularly in research without potential therapeutic benefits to participants. The second point is also criticised as what is socially acceptable may not necessarily be clear1 and daily risks are not always socially acceptable but simply unavoidable.4 Perhaps, a socially acceptable standard is what may be justifiable.

Informed consent and minimal risk in research

Informed consent, independent ethics review and special protection to vulnerable populations are among the basic requirements in conducting ethically sound research.21 Among these requirements, informed consent enables a person to protect oneself through the opportunity to receive information and to give or not give consent.9 ,22 Although a person has a basic right not to be researched upon without informed consent,23 alteration to the informed consent process in minimal risk research can occur if other criteria are satisfied, such as ERC approval, very low likelihood of a particular adverse consequence and impracticality of obtaining consent (45 CFR 46.116(c); TCPS2, Article 3.7; CIOMS, Commentary on Guideline 4). Further regarding information provision, research regulations stipulate extensive risk disclosure, that is, reasonably foreseeable risk (TPCS2, Article 3.2, 45CFR46.116(a,2), CIOMS Guideline 5(9)), discomfort (45CFR46.116(a,2), CIOMS Guideline 5(9)) and inconvenience (CIOMS Guideline 5(9)). However, there are debates over the extensiveness of information provision depending on the research procedures and context, which largely revolve around information that is meaningful for the participant's decision-making.24–28

Informed consent in clinical practice

Informed consent is an essential part of standard of care in clinical practice.29 Unlike clinical research, there has been little focus in clinical practice on below what risk level a potential complication of a therapeutic or diagnostic procedure need not be discussed with a patient. However, circumstances seem to exist which allow clinicians to proceed with certain clinical procedures with implicit consent, suggesting that conditions for not requiring formal consent or risk disclosure may exist.9 ,14 ,30–35

Application of minimal risk in research to clinical contexts

Although concepts of information provision and consent in the research context are not always analogous to the clinical context, there are important learnings from the large literature on minimal risk in research that may be useful to clinical practice well beyond the circumstances in which implied consent is widely used.9 ,14 ,30–35 In this section, we explore how the concept of minimal risk in research may be applied to clinical practice, particularly regarding guiding clinicians as to what information should be discussed with the patient, regarding particular therapeutics and procedures and health promotion.

Current criteria regarding information provision to the patient generally do not refer to a specific low risk standard. A clinical minimal risk concept comparable with minimal risk in research may assist clinicians in determining the low health risks that need to be discussed and those that do not. A clinical minimal risk concept may be particularly important for family physicians who need to address a wide range of health risk factors beyond clinical procedures and therapies. For example, in prescribing acetylsalicylic acid, which side effects in adult men in addition to gastrointestinal problems should a clinician disclose to the patient? In women who are pregnant or planning pregnancy, must a clinician discuss potential but not yet proven risk of household products such as flame retardants and plasticisers? A clinical minimal risk concept may enhance the patient’s informed choice regarding numerous health risks above a minimal risk standard and also save clinician time and resources by providing guidance as to what low-risk factors need to be discussed.

In terms of information regarding clinical procedures, the elements of disclosure and the reasonable patient standard may be suitable particularly for procedures that are deemed the standard of care as recommended in professional practice guidelines or resulting from legal cases. For less common clinical procedures, the subjective standard of disclosure may also be used as it enables clinicians to identify necessary information through communication with the patient as well as the patient's medical and social backgrounds. However, considering the time constraints of clinicians’ practice,11 implementing a clinical minimal risk concept could further facilitate the process of determining risks to be discussed and those that require discussion only if raised by the patient. A clinical minimal risk concept may complement currently employed criteria regarding clinicians’ risk disclosure in identifying whether a particular risk should be discussed for the patient's informed decision-making.

A clinical minimal risk concept may also have a role in evaluating a variety of risks in the patient's everyday life such as unhealthy diet, substance use or exposure to environmental chemicals, some of which remain uncertain in terms of their potential harm or are not necessarily addressed by clinical guidelines. Needless to say, it is ideal if all risk factors are evaluated at the level of professional bodies, regulatory agencies or society in general. Nonetheless, regulatory responses may not necessarily be timely enough for all potential health risks that are emergent while patients may be anxious about numerous risk factors through the media. Regarding some of these risks, it could be in the patient's best interest to be informed about them particularly if they potentially have significant consequences on health, that is, clearly above minimal risk, and if they are avoidable although uncertainties and the lack of regulatory recommendations should be communicated. Concerning these miscellaneous health risks, a clinical minimal risk concept may be used together with the existing criteria to guide clinicians.

Applying the discussions of absolute versus relative interpretation of minimal risk in research,1 ,4 ,6 ,17–20 the relative interpretation of minimal risk may be problematic if a patient lives with high daily risk due to factors such as environment, occupation, recreation activities or health status as it suggests that higher risks in clinical care are minimal risks and thus need not be disclosed. For example, if a person with a serious illness requires a high-risk procedure on a regular basis, the relative interpretation may determine that a different procedure involving a similar level of risk can be performed without disclosing specific risks of the procedure. Likewise, people with a high-risk occupation may not be informed about some risk factors that are communicated to most people. Thus, the absolute interpretation that sets common criteria for everyone may work better as the relative interpretation identifies any risk in a particular person's everyday life as minimal risk for that person, which results in them not being informed about those risks or equally high risks.

Regarding moral justification of the daily life standard, the argument that risks are substitutive18 may suit better with clinical procedures as they usually have benefits to the patient as do activities in daily life. Limiting the scope of discussion to a simplified risk–benefit calculation, the relative interpretation of the daily life standard may be morally justifiable in determining what amounts to minimal risk in clinical care. Nevertheless, the risk substitution justification may result in different standards across persons depending on each person’s daily life, which is not desirable for guiding clinicians’ information provision about particular low risks. Also, the elusiveness of the daily life standard1 ,4 ,8 ,17 should be cautioned against when applied to clinical practice. Moreover, justification based on the claim that daily risks are socially acceptable18 may fail to appropriately identify risks that should be discussed with the patient. We contend that the absolute interpretation of the daily life standard is a better model for information provision in clinical care, with some modification required to improve clarity and to ensure exclusion of high risks. An example model may be risks in a healthy adult’s daily life at home in a safe neighbourhood.

Moral justification of the routine clinical examination standard based on its adequate exclusion of high risk1 and fairness due to less ambiguities in risk assessment8 pertains to the clinical context. In fact, the routine clinical examination standard, particularly its absolute interpretation, overlaps with some of the criteria in current clinical practice as routine clinical examinations for healthy persons usually fall under procedures that do not require risk disclosure or explicit consent. Considering the similarities between the routine clinical examination standard and extant clinical criteria for information provision, the routine clinical examination standard appears justifiable in the clinical context for the reasons indicated in the research context. This standard may be useful as it succinctly clarifies a component of existing criteria for clinicians’ risk disclosure.