Metadata of the chapter that will be visualized online

Metadata of the chapter that will be visualized online Chapter Title

The Relationship of Benefits to Risks in Psychiatric Research Interventions

Copyright Year

2014

Copyright Holder

Springer Science+Business Media Dordrecht

Corresponding Author

Family Name

Helmchen

Particle Given Name

Hanfried

Suffix

Abstract

Division/Department

Klinik für Psychiatrie und Psychotherapie

Organization/University

Charité – Universitätsmedizin Berlin

Street

Eschenallee 3

Postcode

140505

City

Berlin

Country

Germany

Phone

030–8040 2887

Email

[email protected]

The risk-benefit evaluation of a research intervention is only probabilistically possible and is open for contextual influences, because the criteria of benefits and of risks are often only insufficiently quantitatively defined. The question remains whether it is at all possible and, if so, how individual benefits and risks can be balanced against societal benefits and risks. Algorithmic attempts to structure the evaluation process should standardize the evaluation. However, for now, only a pragmatic solution will validate the result in three steps (researcher, ethics committee, potential research participant).

Comp. by: JNagalakshmi Stage: Revises1 Chapter No.: 60 Date:30/7/13 Time:10:06:26 Page Number: 1

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Hanfried Helmchen

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Contents

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Type, Magnitude, and Likelihood of Benefits and Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

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Abstract

The risk-benefit evaluation of a research intervention is only probabilistically possible and is open for contextual influences, because the criteria of benefits and of risks are often only insufficiently quantitatively defined. The question remains whether it is at all possible and, if so, how individual benefits and risks can be balanced against societal benefits and risks. Algorithmic attempts to structure the evaluation process should standardize the evaluation. However, for now, only a pragmatic solution will validate the result in three steps (researcher, ethics committee, potential research participant).

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Introduction

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Every physician must consider the expected benefits in relation to the potential risks of his/her diagnostic, therapeutic, prophylactic, etc., intervention for the patient. This up to now mostly implicit estimation has become more explicit

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This paper is based on Chap. 3 Ethische Grundvoraussetzungen klinischer Forschung, 3.1 Nutzen und Risiken in Helmchen H (ed) Ethik psychiatrischer Forschung (2013) Springer, Heidelberg H. Helmchen Klinik f€ur Psychiatrie und Psychotherapie, Charite´ – Universit€atsmedizin Berlin, Berlin, Germany e-mail: [email protected] J. Clausen, N. Levy (eds.), Handbook of Neuroethics, DOI 10.1007/978-94-007-4707-4_60, # Springer Science+Business Media Dordrecht 2014

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during the past decades by the medical obligation to inform the patient in order to gain his/her consent. This is particularly valid in the case of off-label use of interventions or quasi-experimental procedures in the individual patient, the so-called attempts at healing (Heilversuche). Moreover, especially in research interventions, the researcher has to consider explicitly his/her arguments for the acceptability, i.e., the justification and reasoning, of his/her planned research application to an ethics committee (Europarat 2005). Several regulations specify that the potential risk must have been assessed adequately and can be dealt with satisfactorily (World Medical Association 2008). Without these prerequisites, a research intervention is not permissible even if a subject with the capacity to consent consents to participate. However, this does not mean that risky interventions or those without potential individual benefit cannot be justified ethically in consenting subjects, e.g., healthy volunteers in phase 1 trials. Thus, reasons must be given for an acceptable benefit-risk relationship. But it is difficult to find an acceptable benefit-risk relationship,1 or it will be seen as impossible: “risk-benefit ratios often cannot be calculated, even roughly; and that even if they could, ethical experiments don’t need to have favorable riskbenefit ratios” (Rajczi 2004). The final report of the American National Bioethics Advisory Commission reads as follows: “An IRB may approve a research proposal only if it judges that the risks are reasonable in relation to potential benefits. This judgment may be an IRB’s single most important and difficult determination, because it ensures that when research participants voluntarily consent to participate in a research study, they are offered a ‘reasonable choice’” (cit. Simonsen 2009). Unfortunately, as the report continues, “current regulations do not further elaborate how risks and potential benefits are to be assessed, and little additional guidance is available to IRBs” (Wendler and Miller 2007). This has to do primarily with the estimation of benefits to risks in the participating individual. But it is also an estimation of the individual benefits and risks to those for society. However, there is a doubt that it is possible at all to estimate the relationship of these individual benefits and risks to the potential benefits and risks for society other than qualitatively and personally. But there is “not at all an operational criterion for the decision that this benefit or harm for the individual is of greater magnitude than benefit or harm for society. Furthermore, there is no way to calculate the social value against the individual risk without further assumptions.” (Wiesing 2011). Therefore, H€uppe and Raspe avoid terms which may “suggest a comparability of the extreme heterogeneous potentials of benefits and risks” (H€ uppe and Raspe 2011).

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“The wording ‘fair balance’ is occasionally used by the European Court of Human Rights when there is a reasonable relationship between legitimate but conflicting interests, typically between the individual and the society at large.” (Simonsen 2009).


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Example 1

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Compare the potential societal benefit of sequencing the human genome for possible targets of therapeutic interventions with the (minimal) individual risk of participants for discrimination and stigmatization by a misuse of their individual genetic data. Ethically it seems important that on the one hand such research interventions are without potential individual benefit and, furthermore, the confidentiality of the individual genetic data cannot be guaranteed with certain (Maier et al. 2013), and on the other hand, it is not for sure that the modern sequencing methods will reach their promised objectives.

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Example 2

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The individual benefit of recovery from an illness as quickly as possible may clash with the social value of gain of knowledge if, e.g., the patient’s recovery may be delayed because he/she belongs to a purely placebo group.

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In these examples, the gain of general knowledge for the benefit of future patients as members of society can be understood as a social benefit (Emanuel et al. 2000). Raspe relates the term “societal benefit” in a much broader sense to other “beneficiaries: the whole explanatory knowledge of medicine, population health, health insurance and their financial stability. . .” (Raspe 2012). However, to judge the relationship of such benefits to risks may be much more difficult than that between the defined benefits and risks of a specific medical intervention both for the individual research participant and the societal benefits and risks.

Furthermore, a basic difficulty exists insofar as potential risks and benefits can be determined only as probabilities, e.g., as “probable,” “possible,” or “not to be excluded.” Moreover, these probabilities vary among individuals, e.g., with regard to every day risks, or among ethics committees. Due to the fact that unequivocal criteria of the extent of benefits and risks as well as clear algorithms for the evaluation of their mutual relationship do not exist (Rid et al. 2010), the justification of a benefit-risk relationship can be influenced by individual dispositions (characters or prejudice) as well as by the current social situation of the evaluator, the physician, the patient, the potential research participant, and members of the ethics committee (Rid et al. 2010). At least the evaluator should be aware of this and reflect such possible background influences on his/her preconceptions: e.g., a society-oriented evaluator (or the researcher) could estimate the societal benefit of the expected gain of knowledge more highly and the potential burdens of the proband less than a more individualistic or research skeptical evaluator (or treating physician) might do. Rid et al. state six reasons for the unreliability of such intuitive judgments among others that they do not consider systematically existing empirical data and that they are subject to personal bias, e.g., by rating lower the risks of interventions familiar to


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Also interactions have to be considered among individual and societal benefits and risks. This is valid not only for research interventions but also for everyday medical interventions. Thus, societal risks such as burdens on insurance companies should also be considered on the individual level, because, in order to save resources for the community, medical services may be applied only in an effective and economically efficient mode and their benefit must be proven according to the state of the art (SGB V) (Deutscher Bundestag 2010).

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the evaluator than the risks of interventions with which he/she is not familiar, and that therefore the estimates of acceptable risks vary in a broad range among ethics committees (Rid et al. 2010; Shah et al. 2004). Because of these difficulties of judgment, research ethics committees tend to avoid comprehensive evaluations of the risk-benefit relationship and focus on other aspects of the research project, such as the informed consent process, as Simonsen found in a 3-year observational study of Norwegian research ethics committees (Simonsen 2012).2 However, because researchers and ethics committees must estimate the benefitrisk relationship of a research project in order to account for legal regulations, they should communicate the reasons for their estimates with regard to their comprehensibility. And, where applicable, they should say that “defined risks are not acceptable, namely in the sense that they are not negotiable” (Wiesing 2011). In any case it is the task of the researcher to convey the significance of probabilities and particularly those of the benefit-risk estimation in a mode that can also be understood by the potential research participant. In view of the uncertainty of risks that can be calculated only as probabilities, decisions will be made logically statistically according to the prevailing opinion, but in fact however intuitively heuristically (Gigerenzer 2006). The question of whether such knowledge of the psychology of intuitive decisions will be helpful requires future investigations. The evaluation of the acceptability of the benefit-risk relationship is specifically important in research interventions with patients whose capacity to consent is impaired by a mental illness, because the risk of exploitation of such vulnerable subjects may be larger than in patients who are competent to give informed consent. A careful evaluation also includes an understanding of the uncertainties in assessing potential benefits and risks that should be considered for both the individuals participating in research and other current or future patients (society). Thus, benefits and risks are to be evaluated primarily with regard to individual subjects who participate in a research intervention. In cases with more than minimal risks on the individual level benefits and risks are to be considered with regard to society too.

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In order to make clear the determinants of such estimations, Rid et al. recently proposed a procedure for a standardized evaluation of risks, which will be considered in the following (Rid et al. 2010).

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Literature on the lack of rules and on the difficulties of benefit-risk estimates of research projects can be found in (H€ uppe and Raspe 2011) and in (Rid et al. 2010).


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Type, Magnitude, and Likelihood of Benefits and Risks

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The comparability of benefits and risks as well as the evaluation of the benefit-risk relationship requires a: • Definition of specific types • Graduation (or even quantification) • Estimation of the probability of occurrence of benefits and risks

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Benefits

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Individual Versus Social Benefit The social benefit of clinical research in psychiatry consists in the gain of knowledge for the improvement of the treatment and care of mentally ill patients. Basically it can be seen as urgently desirable, because mental diseases are widespread and the need for research is great as opposed to the necessary scientifically proven knowledge for optimal psychiatric action. However, the estimation in the individual case depends: • On the one hand upon the probability of an unequivocal gain of knowledge, i.e., upon the quality of the scientific method • But on the other hand upon the relevance of the expected gain of knowledge for psychiatric action Due to the conviction of liberal western societies expressed legally and also in the Declaration of Helsinki, } 6 (World Medical Association 2008) that no human being is obliged to donate himself/herself to society, the practice of clinical research will be dominated less by its societal benefit than by the individual benefit of the patients participating in research.

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Individual benefit comprises both: • The subjectively determined well-being in the sense of a self-experienced and self-evaluated benefit • The more intersubjectively (“objectively”) evaluated “best interest” of the patient as a benefit seen from the outside, so to speak an objectively, externally judged benefit This differentiation is significant insofar as in case of a patient not competent to consent, the substituted consent by an authorized person must be guided by wishes of the patient expressed beforehand, e.g., by an advance directive, for the well-being of the patient. If no information exists about such personal wishes, the substitute must decide in the best interest of the patient (Heinrichs 2007). Patients themselves see the benefit of participating in research in that they will: • Receive a better treatment that will be more effective than the available standard therapy or will act more quickly or will have fewer side effects • Satisfy altruistic feelings of solidarity with other similarly ill patients (Rosenbaum 2012)


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H. Helmchen Most respondents continue to participate in the ESPRIT study in hopes of benefiting personally. The majority also recognized that by participating in ESPRIT they were contributing to helping others; they experienced pride regarding this contribution and considered it an important reason to continue to participate. (Magnus and Merkel 2007; Wendler et al. 2008)

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• Receive money or other advantages (Sofaer et al. 2007)

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Further motivational factors are: • To receive more information about one’s own illness and its characteristics. • To feel self-determined. • The hope that other people will understand better their mental state. • Particularly in the mentally ill without the capacity to consent, the motivation of the caretakers is important; this has been evidenced in research interventions which have aimed for an improvement of the quality of life of the patients and/or for an attenuation of the burdens of the caretakers (Connell et al. 2001; Mastwyk et al. 2002).

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Specifications of Benefit Benefit can be defined only in relation to something: • Societal benefit of research is related to the gain of knowledge. In this case, the “essentiality” of the gain of new knowledge towards the existing knowledge plays an important role (s. below). • Individual benefit, e.g., can be assessed as an attenuation of symptoms or of suffering or of an augmentation of the quality of life or functional improvement. Compared with clearly defined and well-ascertainable phenomena such as some symptoms, it is more difficult to operationalize the attenuation or increase of more complex phenomena such as suffering or quality of life; but such an operationalizing would be a prerequisite or at least a support for the assessment of the size of the benefit. However, many of the following terms, which specify and grade benefits and risks by the dimensions of size and probability, are not clearly defined or are not at all definable and thus are open to subjective interpretations. Such specifying criteria of benefit are: • “Direct” or “immediate” benefit will be used synonymously. However, “direct” benefit can be understood as a causal effect of the intervention, “immediate” benefit by contrast as an effect in a timely connection. “Direct” suggests that “indirect” forms of benefit may also exist, e.g., if the development of a new effective therapy is based on the knowledge of the cause of the illness that was found during an earlier research intervention in a patient with an illness of long duration. “Few existing accounts disagree over how this crucial concept of ‘direct’ benefit should be defined. This disagreement raises concern over whether those who cannot consent, including children and adults with severe dementia, are being adequately protected.” It is suggested “that the extant definitions of direct benefits either provide insufficient protection for research subjects or pose excessive obstacles to appropriate research” (Friedman et al. 2010, p. 60).


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• “Therapeutic research” as potentially beneficial for the patient participating in research had been compared to “nontherapeutic research” without potential individual benefit. However, this distinction is questionable, because the border between both types of research is often not clear: “A therapeutic research study may prove that the experimental intervention is ineffective, in which case undergoing the experimental condition would be not beneficial to the subjects. Conversely, a non-therapeutic study may be associated with benefits for the subjects, such as more attention from health care workers. etc.” (Welie and Berghmans 2006, p. 69). This is particularly valid with regard to the “therapeutic misconception,” i.e., that the research participant misunderstands the research intervention as a mere therapeutic intervention (Vollmann 2000). Therefore, the ethically unequivocal terms “with” or “without” potential individual benefit should be preferred. • As “collateral” benefit, a benefit will be termed that cannot be ascribed causally to the research intervention but to other aspects of the study performance and study participation, e.g., an “inclusion benefit” by an intensive medical monitoring (H€ uppe and Raspe 2011). • “Important,” “essential,” or “significant” benefit are particularly vague terms and are thereby open for different interpretations. Thus, the Explanatory Report (Nr. 87) to the Additional Protocol of the European Council defines “essential” as an “essential extension of the scientific understanding of a disease” (Europarat 2011). The circularity of this explanation shows the difficulty in defining the term “essential” clearly, unequivocally, and practically. Aside from a broad understanding of the contents of the field in which “essential” insights can be gained, i.e., new knowledge of causes, treatment, and prevention of a disease, the term “essential” itself remains unclear. Is it necessary for new knowledge, in order to be viewed as “essential”: • To be not less than a breakthrough, i.e., knowledge that opens new possibilities for action? • To be a breakthrough only with an immediate impact or also with a delayed effect? • To be – with regard to formal criteria – proven at least and on which level? On the other side, the vagueness of such terms opens a necessary range for interpretations, because the newness of knowledge progress and its practical usefulness are difficult to judge and are only seldom quickly recognizable. • Because it is the objective of research to gain new knowledge, every research surpasses an exclusively individual benefit and is oriented supraindividually. Insofar the extent of the individual benefit, i.e., the self- interest, must be related to the benefit for others, i.e., other person’s interests (“Fremdn€utzigkeit”). Hence, the potential individual benefit (benefit, potential individual) is largest if the research participant can expect such benefit for himself/herself during the ongoing study (group 1 of the statement of the Central Ethics Committee of the German Board of Physicians (Zentrale Ethikkommission bei der Bundes€arztekammer 1997)); it will be less in studies with only future benefit (group 2) and


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will be at most questionable in research with expected benefit mainly for the group of patients to which the research participant belongs by age or disease (group 3). Such “group-specific” research will be differentiated from research with benefit exclusively for others (group 4). In the framework of clinical research “group-specific” benefit as benefit for others means improved medical knowledge for the optimization of diagnostics, therapy, or care for other patients with the same disease or in the same age group. This can be the sole benefit of a research intervention with only questionable or no potential individual benefit for the participant of a research intervention, e.g., in a validation of a diagnostic measure or in a study of possible conditional or risk factors or causes of a disease. In order to prevent an excessive use of the term “group benefit,” it has been proposed to define further beneficiaries not only by disease, age, and gender but additionally by the “inclusion and exclusion criteria on which the study is based” (H€ uppe and Raspe 2011). • The “size,” “extent,” “magnitude,” or “strength” of a benefit however defined could be graded as “questionable,” “slight or recognizable,” or “unequivocal or strong.” • “Prospective” or “potential” benefit indicates an anticipation or expectation of a benefit. Because it is a determination of a likelihood, the occurrence of a benefit should at least be graded as “possible” or “probable.”

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Risks

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If a subject participates in a necessary or even legally required research intervention for the benefit of all, he/she must be protected against the risks of this intervention. Protective norms are also related to gradings of risks. Various normative rules describe the content, extent, and the mode of protection of research participants against risks, e.g., declarations such as the best known one of Helsinki in 1964 with the following revisions by the World Medical Association (World Medical Association 2008), national research laws, and particularly the first internationally binding instrument for biomedical research, the European Convention on Human Rights and Biomedicine (1997) (Europarat 1997) and its Additional Protocol (2005) (Europarat 2005).

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Individual Versus Societal Risks Individual Risks (Risks, Individual) The term risk comprises both: • Rather “objective” endangering of the individual research participant, e. g., with unwanted accompanying effects of the intervention, for example, unwanted side effects of an investigational drug or risks of blood taking for research purposes, but also prolongation of suffering or worsening of the disease due to withholding a specific treatment in a placebo group, in a broader understanding also


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dispositions for unwanted effects such as (pharmaco)genetic or allergic inclinations belong to this group of risks. • Rather “subjective” burdens and inconveniences, e.g., by the methodological rigor of the research procedure or feared risks of stigmatization especially in depressive or drug-dependent patients, which may demotivate potential research participants. Because of the subjective dimension of risks and unwanted effects, potential research participants should be examined particularly for their susceptibility to physical or psychic burdens that may be related specifically to the research intervention. Thus, e.g., the magnetic resonance imaging (MRI) has no objective risks, but may indeed – in claustrophobic patients – become a subjective burden that leads to a termination of the intervention. For risks that are specific for the intervention and that have large relevance for the further life of the patient, he or she must be informed independently of the probability of occurrence.

Societal Risks (Risks, Societal) However, societal risks should also be considered, e.g., if research interventions have considerable risks or do not follow precisely the normative prescriptions and thereby lead to incidents that undermine the necessary trust of the public or of potential research participants. This can protract or even prevent the recruitment of research participants. But not executing a research project may also present a societal risk, e.g., if the lack of knowledge must urgently be eliminated, in order to contain and treat an acute threat to health such as an infectious epidemic or to substitute an ineffective measure by an effective one.

Specifications of Risks (Risks, Specifications of) • Magnitude, extent, or strength of risks are graded by a broad range of terms, such as “without the danger of injury,” “minimal risk,” “minor increase of minimal risk,” “not negligible risks,” “serious risk for health,” “potentially irreversible damage,” and “risk of inacceptable dimension” (Helmchen 2002). • Absolute upper limits of risks are irreversible impairments and death. Standard upper limits for research with patients incompetent to give informed consent are “no more than minimal risk” or with minors even “minor increase of minimal risk” (Wendler 2008). • “No more than minimal risk” is a decisively limiting criterion for research with patients incompetent to give informed consent. However, there are different interpretations of “minimal risk”: – US regulations permit ethics committees to approve a research intervention in patients incompetent to give informed consent only if “it poses no more than ‘minimal’ risk, defined as the risks encountered in daily life or during the performance of routine examinations or tests” (Wendler 2008, p. 467). But “in the absence of empirical data, IRB members may assume they are familiar with the risks of daily life and with the risks of routine examinations and tests and rely on their own intuitive judgment to make these assessments.


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Yet intuitive judgment of risk is subject to systematic errors, highlighting the need for empirical data to guide IRB review and approval of pediatric research. . .Current data on the risk of mortality in healthy children suggest IRBs are implementing the federal minimal risk standard too cautiously in many cases” (Wendler et al. 2005). On the other hand, this concern has led to a warning against a softening of the “minimal risk” concern (Gefenas 2007). – Furthermore, standards of minimal risk vary with regard to the risks of everyday life with age (Wendler 2009). With children there are other standards than with older persons. Because of these difficulties, it has been proposed that the standard of everyday life be eliminated (Resnik 2005). – However, there has been an attempt to objectify the standard of everyday life by considering the magnitude and likelihood of injuries in sports and in car driving, i.e., two common everyday activities (Rid et al. 2010). With regard to the criterion “routine examinations,” the Central Ethics Committee of the German Federal Board of Physicians commented that the standard of minimal risk is present “e.g., when taking small amounts of body fluids or tissue in the framework of diagnostic measures or surgery without additional risks for the patient. Defined somatic investigations also belong to this standard (e.g., sonography, transcutaneous tissue measurements) or psychological investigations (e.g., interviews with questionnaires, tests, observations of behavior)” (Zentrale Ethikkommission bei der Bundes€arztekammer 1997).

• “Minor increase above minimal risk”: this standard was introduced in the USA for research with children. However, it remains unclear what “minor increase” means (Wendler and Emanuel 2005). Accordingly other countries did not follow this line. Also the ambiguity of this criterion has led ethics committees to different interpretations and to a call “for a national consensus on the interpretation of federal regulations” (Fisher et al. 2007). • Research without potential individual benefit in patients incompetent to give informed consent will be seen either – according to German law – as inadmissible or – according to the European Convention on Human Rights and Biomedicine (1997) – as ethically acceptable only as an exception and when limited by the criterion “no more than minimal risk,” if at least a group-specific benefit can be expected and if the consent of the research participant will be substituted by an authorized person.

Proposals for Grading During the past 15 years, the grading of benefits and risks has been intensified more systematically: • Thus, a taxonomy of benefits and risks according to their magnitude or severity has been proposed (Helmchen et al. 1995) (see Table 60.1). • The following table had been developed as an advanced categorization that contains the essential variables of evaluation of the German Drug Law (Deutscher Bundestag 2004) (see Table 60.2).


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t1:1

Table 60.1 Taxonomy of benefits and risks according to their magnitude (Translated in English and modified from Helmchen and Lauter 1995, S. 47f.)

t1:2

Risks 1 No or at most minimal risk 2 Mild increase of minimal risk 3 Unequivocal more than minimal risk 4 Risk with irreversible consequences Benefits 1 No or at best questionable benefit 2 Benefit only for the public good (benefit without potential individual benefit) a. Only by extension or safeguarding of existing knowledge b. By qualitative new knowledge 3 Benefit for both the public good and the individual research participant (intervention with potential individual benefit) a. Only by quantitative improvement of existing standards b. By qualitative innovative treatments

t1:3 t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14

t2:1

Table 60.2 Grading of risks and the essential evaluation variables of the German Drug Law (AMG) (Translated in English from Terwey (2007), S. 138, Table 24)

t2:2

Risk No risk Minimal risk Minimal increase above minimal risk More than minimal increase above minimal risk

Vulnerability Not vulnerable Vulnerable Children

Chance Patient Group specific Science Short termed Patients who are Science Long not competent to termed give consent

Scientific quality GRADE High Moderate Low

Evidence SIGN A B C

Very low

D

t2:5

A B C

t2:6

D

t2:7

GRADE grading of recommendations assessment, development and evaluation SIGN Scottish Intercollegiate Guidelines Network Each of the five columns shows an order from a lower to a higher grade or from general to more specific items. However, the columns should not be seen as completely correlated to each other. Thus, e.g., in the risk column lines C and D are related only to children. “Chance” means the objective of the research intervention, i.e., the chance of a benefit for the individual research participant or at least for the group of patients with the same age or illness condition of the research patient, or the research results are expected to be applied currently (short termed) or are more of a basic nature with perhaps applicable findings in the future (long termed)

t2:3 t2:4

397 398 399 400 401 402

• Rid et al. (2010) produced after consultation with experts an empirically based scale of seven grades of injury and illustrated each grade with specific examples of the consequences of the injury and its duration and treatability (Rid et al. 2010) (see Table 60.3). • Recently further proposals have been published in order to adapt control and monitoring of clinical research to the level of risk. Thus, a model of risk

Moderate Uncomplicated bone fracture Moderate insomnia for 1 month

Significant Ligament tear of knee with Moderate pain that interferes with pursuing permanent instability some minor life goals (e.g., exercise); permanent instability precludes vigorous exercise and requires adaptation (e.g., seek new types of exercise)

t3:10

t3:13

Requires surgery and rehabilitation

Requires some medication and wearing a cast Can require lifestyle changes and medication

May require medication, rest, or both

Tear, hours to days; rehabilitation time following surgery, weeks to months

Fracture pain, hours; recovery, weeks to months Weeks intermittently

Several days

Hours

Bruise or abrasion pain, minutes to several hours; healing, 10 days

Can require cleaning and coverage

May require medication, rest, or both

Minutes to several hours

Duration

May require medication

Treatment

12

t3:14

t3:12

t3:11

Moderate pain, inability to pursue some minor life goals (e.g., play sports) Annoying experience, inability to pursue some minor (e.g., meet friends) and some major (e.g., work) life goals

Common cold

t3:9

t3:8

Small Headache

Moderate pain, inability to pursue some minor (e.g., 1 day hiking) and some major (e.g., attend school) life goals Discomfort, inability to pursue some minor (e.g., visit museum) and some major (e.g., work) life goals

Examples and details of harms Examples of harms by magnitude Effect/disability Negligible Mild nausea Discomfort; can interfere with ability to pursue some minor life goals (e.g., eat) Skin bruise or abrasion Mild pain

Table 60.3 Magnitude of harms scale with illustrative examplesa (From Rid et al. 2010 with permission of JAMA)

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Major Psychotic episode

Rheumatoid arthritis

Loss of finger

Severe Major depression

Paraplegia

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Depressive episodes with hopelessness/ worthlessness, loss of interest in usual activities, isomnia, and eating; can preclude performance of some daily life activities and some minor and major life goals; often baseline anxiety and low mood Inability to perform some activities of daily life, inability to pursue many minor (e.g., hiking) and some major (e.g., having children) life goals, often distressing transition period

Terrifying distortions of reality, changes in personality that undermine relationships, precludes performance of daily life activities and many minor and major life goals Daily episodes of serious pain and permanent stiffness, unable to pursue some minor (e.g., vacation) and some major (e.g., work) life goals, sometimes unable to perform some activities of daily life Destabilizes hand, interferes with many activities of daily life, interferes with some minor and major life goals, requires adaptation, distressing transition period

Often intense pain and physical exhaustion, inability to perform activities of daily life and to pursue essentially all minor and major life goals

Requires daily support and close clinical observation; requires major adaptation

Requires medication; requires adaptation of some major life goals (e.g., relationships)

None

Requires aggressive medication, physiotherapy, requires major adaptation

Requires medication, can require adaptation of some major life goals (e.g., work)

Permanent

Decades

Permanent

Years

Weeks to a month

Weeks

(continued)

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Intensive care for several weeks (assuming no sequelae)

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The Relationship of Benefits to Risks in Psychiatric Research Interventions 13

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Permanent

Duration

Important factors that influence the magnitude of a harminclude associated experience (no sensory, nuissance, uncomfortable, distressing, suffering); burden of efforts to mitigate condition (low/moderate/high, weeks/months/permanent); inability to perform activities of daily life (partial/complete); inability to realize life goals (minor/major life goals, some goals in one category/some goals in both categories/all goals in one or both categories); duration (minutes/ hours/day/weeks to months/years/permanent, intermitten/continuous); potential to adapt to new (residual) condition (minor/moderate/major adaptation, impossible to adapt); and burden of adaptation period (low/moderate/high). The examples were chosen based on input from 43 international experts in clinical research, research ethics, and risk assessment. The example have an illustrative function to show how the harm scale might be applied. Factors not mentioned in the description of an example are considered not relevant. It is assumed that the given harms occur in otherwise healthy, normal, average individuals (adults), which implies that the selected examples might fall into a different category on the harm scale in individuals who are not healthy, normal, or adults. No examples of economic or social harms are given due to their strong context dependence

a

Examples and details of harms Examples of harms by magnitude Effect/disability Treatment Catastrophic Severe dementia Precludes performance of daily life activities Requires full-time care and essentially all minor and major life goals, adaptation impossible, distressing transition period Death

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Table 60.3 (continued)

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60 403 404 405 406 407 408 409 410 411 412 413 414 415 416

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estimation was introduced in 2010 into the discussion of the revision of the EU directive on clinical research that proposes to determine the two dimensions of severity and likelihood of impairments of health for defined groups of risks (sponsor and experience; product class; stage of development: pre- or postmarketing approval; scientific newness; characteristics of patients; method of trial) (Hartmann and Hartmann-Vareilles 2012). The German ADAMON project (Brosteanu et al. 2009) and the British community project(MRC/ and DH/ 2011) provide risk-adapted monitoring and control of clinical trials in three classes of risks with different intensity of control (and the bureaucratic effort). To date, however, such proposals up to now are almost nothing more than constructs that can at most be useful for a rough structuring of the evaluation of the acceptability of benefits and risks of a research intervention and particularly of their relationship to each other. How much they can indeed achieve needs empirical validation.

Empirical Procedures for the Evaluation of the Benefit-Risk Relationship • In contrast to the abovementioned proposals, such an empirical study of a more differentiated three-stage taxonomy was done ex post from all research applications of the year 2006 at the university hospital in L€ubeck (H€uppe and Raspe 2011): “At the first step of analysis the identified consequences were differentiated according to their effects (positive or negative) in chances of benefit and risks of injury (with regard to addressee, relation to the study, relevance, extent, likelihood of occurrence, start of occurrence, sustainability, level of evidence).” “The second step of the analysis outlines the chances of benefit and risks of damages with regard to the respective addressee or concerned person into three partial quantities”: potential self- benefit or self-injury; group benefit or group injury; benefit for others or injury for others. In step 3 of the analysis the detailed assessment of the features of individual chances of benefit and risks of injury” with regard to the criteria named under step 1 was carried out. Subsequently it was stated by two steps of balancing “whether the entire balance yields a net benefit”.” In order to reach a concluding positive point balance a net benefit must be found.” Such a “proceduralisation of the analysis of chances and risks can increase the transparency of the performed processes of analysis and comparison. The communication among researchers and ethics committees and among the members of the ethics committee will be facilitated in controversial research projects, the standardization and harmonisation of the consulting processes of the ethics committees will be supported.

• Recently the estimated risks of two research interventions, an allergy test and a liver biopsy, were compared with empirically assessed risks of everyday activities. In the first example, the magnitude and the likelihood of occurrence of the risks of allergy testing are below those of comparable everyday activities (e.g., sports or work), i.e., seem to be acceptable (Fig. 60.1).

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However, the liver biopsy as a research intervention is ethically questionable because some of its risks are above comparable everyday activities (Fig. 60.2).


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H. Helmchen Transient pain Risk estimate Daily life

Estimated Likelihood of Harm, per 100000

105 104

Local allergic reaction

Epicutaneous allergy skin testing a by strength of evidence Weak

103

Strong

Mild systemic allergic reaction

102 10

Moderate systemic Severe systemic allergic reaction allergic reaction (intubation)

1 10−1 10−2

Death

10−3 Negligible Small (eg, bruise) (eg, common cold)

Moderate (eg, bone fracture)

Significant (eg, ligament tear)

Major (eg, loss of finger)

Severe (eg, paraplegia)

Catastrophic (eg, death)

Magnitude of Harm

Fig. 60.1 Estimated risks of epicutaneous allergy skin testing (per 100,000): transient pain (negligible), approximately 100,000; local allergic reaction (negligible), approximately 50,000; mild systemic allergic reaction (small), 11–30; moderate or severe systemic allergic reaction (moderate or significant), 2–5; and death (catastrophic), approximately 0 (1 case report). Daily life risks in the United States (per 100,000): bruise (negligible), approximately 100,000 (all age groups); common cold (1 day [small]), approximately 22,000 (children); bone fracture or dislocation (surfing contest [moderate]), approximately 70 (adults); complete ligament tear of knee (sports practice [significant]), approximately 8 (adolescents); loss of 1 finger (workday in service sector [major]), approximately 0.008 (adults); paraplegia (day of skiing [severe]), approximately 0.03 (all age groups); and death (riskier car trip [catastrophic]), approximately 0.2 (adolescents/adults).aSpan of elongated data markers indicates range of estimated risk (From Rid et al. (2010) with permission of JAMA) 447 448 449

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This is a considerable step towards an empirical foundation of risk assessment. However, it is an open question whether it will gain acceptance because it is a very elaborate procedure.

Contextual Influences An acceptable or reasonable benefit-risk relationship is understood usually as a justified relationship between benefits and risks. At the same time, it should be considered that the estimation of a benefit-risk relationship as justified also depends upon normative values.

456

Example

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In studies with potential individual benefit but more than minimal risks, e.g., trials of new methods of vaccination, it must be decided whether the benefitrisk relationship is ethically acceptable in patients not competent to give

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Risk estimate Daily life

Transient mild pain Postprocedure pain

Estimated Likehood of Harm, per 100000

105 10

4

10

3

10

Anxiety

Percutaneous liver biospy a by strength of evidence Weak

Immediate postprocedure pain

Major hemorrhage

Superficial kidney puncture

1 10−1

Subcutaneous emphysema

Intermediate Strong

Hemobilia Major hemorrhage (interventional) (interventional)

2

10

17

Death

Gallbladder perforation Sepsis (ICU) Sepsis Hematothorax

Colon perforation

Pneumothorax Hemobilia Pleural effusion

10−2 10−3

Negligible Small (eg, bruise) (eg, common cold)

Moderate (eg, bone fracture)

Significant (eg, ligament tear)

Major (eg, loss of finger)

Severe (eg, paraplegia)

Catastrophic (eg, death)

Magnitude of Harm

Fig. 60.2 Estimated risks of percutaneous liver biopsy (per 100,000): anxiety (small), 31,000; transient mild pain (negligible), approximately 100,000; immediate postprocedure pain (small), approximately 3,000; postprocedure pain (small), approximately 10,000–20,000; superficial kidney puncture (small), 3 subcutaneous emphysema (small), 1 pleural effusion (moderate), 21 hematothorax (moderate), 18–63 pneumothorax (moderate), 8–35 major hemorrhage requiring transfusion (moderate), 160–733 hemobilia requiring conservative treatment (moderate), 6–50 sepsis requiring antibiotic treatment (moderate), 9 major hemorrhage requiring interventional radiography/surgery (significant), 67 hemobilia requiring interventional treatment (significant), 6–50 sepsis requiring intensive care unit (ICU) treatment (significant), 9 gallbladder perforation (significant), 12–22 colon perforation (significant), 4 death (catastrophic), 0–40. For daily life risks see Figure 60.1 legend.aSpan of elongated data markers indicates range of estimated risk (From Rid et al. (2010) with permission of JAMA)

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informed consent and with currently untreatable disease conditions such as advanced stages of Alzheimer disease (analogous to the reasoning for experimental treatment in patients with final stages of cancer). Some family members might view the risk of burdens for the patient as considerable and are not convinced of the chance of a remission and therefore hope for a peaceful end for the patient; other relatives – in harmony with a possible advance directive or presumptive will of the patient – or also members of the ethics committee might estimate the potential benefit of an attenuation of symptoms or a prolongation of life to be much greater than the potential burdens.


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Thus, for now it remains largely a personal evaluation of the participants judging the ethical acceptability of a research intervention. This evaluation is filled with uncertainties and is thereby open to contextual influences. But “what cannot be objectified can at least be controlled by procedures: one attempts to distribute difficulties onto several shoulders and hopes that the collectivity of judgments may lead to a result that is more acceptable. However, the basic difficulties of a balance between benefits and risks are not solved by this but are only regulated by procedure” (Wiesing 2011). In order to control and to minimize these contextual influences, a three-step procedure will be formulated here: 1. The researcher must give his/her reasons for considering that the relationship of potential risks and burdens to the expected benefit of a planned research project is acceptable, i.e., that it is reasonable and justified. 2. The appropriate ethics committee must investigate this relationship and the evaluation of the researcher with regard to ethical and legal norms, if necessary with additional professional expertise. It should communicate its reasons – at least in research with patients not competent to give informed consent – not only in cases of rejection but also in cases of approval of the research plan and particularly with regard to the ethical argumentation of the researcher. 3. Finally the potential research participant or his/her authorized substitute must evaluate the reasons of the institutionally acceptable established benefit-risk relationship of the planned research intervention with regard to his/her own idiosyncrasies, values, and interests; after that he/she can consent if he/she feels that the benefit-risk relationship seems to be acceptable for himself/herself.

495

Conclusion

496

The evaluation of the benefit-risk relationship of a medical research intervention is only probabilistically possible and is open for contextual influences, because the criteria of benefits and of risks are often only insufficiently quantitatively defined. Whereas in a medical standard intervention the benefit-risk estimation is focused almost only on the individual, in a research intervention the societal benefit-risk evaluation must be added. The question remains whether it is at all possible and, if so, how individual benefits and risks can be balanced against societal benefits and risks, particularly if the research intervention contains more than minimal risks. Only in the past decade researchers have begun to investigate determinants of the benefit-risk evaluation in ethics committees, to develop evaluation procedures (Curtin and Schulz 2011), and to systematize in a framework (Rid and Wendler 2011). Algorithmic attempts to structure the evaluation process should standardize the evaluation. However, for now only a pragmatic solution will be possible that will validate the result in three steps (researcher, ethics committee, potential research participant).

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Cross-References

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▶ Compulsory Interventions in Dangerous Mentally Ill Persons ▶ Ethical Implications of Social Interventions in Mentally Ill Persons ▶ Strengthening Self-Determination in People with a Mental Illness

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