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Genomic and Personalized Medicine, 2nd editionby Ginsburg & Willard. DOI: http://dx.doi.org/

Copyright © 2012, Elsevier Inc.All rights reserved.

chapter

201310.1016/B978-0-12-382227-7.00005-7

Informed ConsentLaura M. Beskow

INTRODUCTIONThe process of informed consent is intended to ensure that prospective participants receive sufficient, comprehensi-ble information, under conditions free of coercion or undue influence, to make autonomous choices about taking part in research. Developing and implementing informed consent processes also helps to remind researchers of their ethical obligations to participants (Reilly et al., 1997).

These ideals can be difficult to achieve in practice, how-ever, because of the complexity of some types of research, the wide disparities among individuals in their ability to com-prehend and process complex information, and the tendency of some institutions to use consent documents to protect against institutional liability rather to protect participants (US Department of Energy, 2007). These challenges are com-pounded in genomic research because there is frequently a separation between specimen collections (and thus the informed consent process) and the actual research, which may involve hypotheses and methods not contemplated at the time of consent. In addition, the most common risks are dignitary (rather than physical), and the social risks are often group-based and implicate subjects and non-subjects alike. The benefits often involve broader societal concerns about advancing scientific knowledge as well as the prevention, diag-nosis, and treatment of disease (Rothstein, 2005).

This chapter provides a step-by-step guide to understanding when informed consent is needed, an overview and resources for crafting appropriate consent disclosures, and special consid-erations concerning consent for the research use of biospecimens collected in the course of clinical care and for research biopsies.

WHEN IS INFORMED CONSENT REQUIRED?US federal regulations for the protection of human research subjects define a “human subject” as “a living individual about whom an investigator obtains (1) data through intervention or interaction with the individual, or (2) identifiable private infor-mation” [45 CFR §46.102(f)]. The collection of biospecimens for genomic research constitutes “intervention or interaction with the individual.” Thus, as recommended by the National Bioethics Advisory Commission (NBAC):

when human biological materials are collected, whether in a research or clinical setting, it is appropriate to ask subjects for their consent to future use of their samples, even when such uses are at the time unknown.

(NBAC, 1999)

Also, because the study of stored biospecimens can both involve and generate private information about the persons

35

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from whom they were obtained, ethical and legal require-ments to protect human subjects apply to a broader range of research activities than many genomic investigators may real-ize. With only limited exceptions, any time human subjects are involved, informed consent must be obtained. To understand these requirements and possible exceptions, it is helpful to fol-low a sequential assessment:

1. Does the Research Involve Human Subjects?As noted, research involving the collection of biospecimens meets the definition of research involving “human subjects,” and requires informed consent. When research involves only the study of samples that were collected for purposes other than the currently proposed project, the parameters high-lighted in Figure 35.1, Box 1, are of central concern. If an Institutional Review Board (IRB) determines that the proposed research does not involve human subjects, informed consent is not required.

For several reasons, the fundamental issue in this determi-nation is the identifiability of specimens and associated data, i.e., the extent to which investigators involved in the research can link the materials to specific individuals. First, access to “identifiable private information” is a key component of the definition of “human subject.” Second, the potential harms in research using human biospecimens are primarily informa-tional. In other words, the main concerns are not usually about physical harms but rather about the misuse of information, including clinical and other personal data associated with the specimens, as well as results derived from research using the specimens. Misuse of such information could lead to employ-ment or insurance discrimination, stigmatization, psychologi-cal harm, or familial disruption. Thus, identifiability is a central component in the assessment of risk, which in turn is a deter-mining factor in the human subject protections that will apply.

Samples used in genomic research are often coded, meaning that direct identifiers are removed and replaced with a code that is linked back to identifying information through a key. Until 2004, coded samples and data were commonly con-sidered identifiable (through the key), and thus research using coded materials involved human subjects. More recently, the US Office of Human Research Protections issued guidance that altered this understanding (US Department of Health and Human Services, 2008). Under this guidance, when coded materials were not collected for the currently proposed pro-ject and the investigators involved in the research cannot readily ascertain the identities of the individuals, the research may be determined not to involve human subjects and thus would not require informed consent. Investigators involved in the research would be unable to readily ascertain individuals’ identities when, for example, the key linking the code to iden-tifying information is destroyed before the research begins, or when the holder of the key is prohibited from releasing the key to investigators involved in the research under any cir-cumstances, e.g., through an agreement with the researchers, a repository’s IRB-approved written policies and procedures,

or other legal requirements (US Department of Health and Human Services, 2008).

2. Is the Research Exempt from IRB Review?US federal regulations identify certain categories of human subject research as being exempt from IRB review. The cate-gory most often relevant to research involving biospecimens is:

research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly avail-able or if the information is recorded by the investiga-tor in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects

[45 CFR §46.101(b)(4), #542]

If an IRB determines that the proposed research is exempt – following an assessment of the kinds of factors highlighted in Figure 35.1, Box 2 – informed consent is not required. Although there are technical distinctions between research that does not involve human subjects and human subjects research that is exempt, both of these categories share a focus on whether researchers involved in the proposed project cur-rently have access to identifiable private information.

They also share a focus on the use of existing samples that were collected for purposes other than the currently pro-posed project. Although regulations allow research in both of these categories to proceed without obtaining consent, the issue of whether the research is consistent with the informed consent under which the specimens were originally collected is a significant ethical concern.

To address this concern, collections of existing samples must be evaluated on a case-by-case basis, with a focus on whether the proposed use of the sample is in keeping with the sample source’s likely understanding of how it would be used. Some consent documents contain language that explic-itly limits how samples can be used. For instance, uses may be restricted to the study for which samples were collected, spe-cific diseases or disease categories, certain types of analyses, certain individuals or groups of researchers, or certain time-frames. In some cases, these kinds of restrictions are stated so that they apply to all subjects who signed the consent form. Other times, subjects are allowed to make certain choices; for example, each subject may have been asked to decide whether his or her sample could be used only in the study for which it was collected or if it could also be stored for use in future stud-ies. In such cases, restrictions on the use of a particular sample would have to be tracked and evaluated on an individual basis.

In addition, according to NBAC (NBAC, 1999), general releases for research given in conjunction with consent to a clinical or surgical procedure must not be presumed to cover all types of research over an indefinite period of time. Investigators and IRBs should review existing consent docu-ments to determine whether the subjects anticipated and agreed to participate in the type of research proposed.

When is Informed Consent Required? n 407

Box 1. Are you conducting research involving human subjects?

True or False:

The samples I will study were not collected for my particular projectAnswer “true” only if the specimens were or will be collected for purposes other than your currently proposed research.

I will obtain the samples from a non-collaborating source Answer “true” only if the person or entity from whom you will obtain the samples will not be involved in your research.

I will have no access to identifying informationIf the samples you will use are coded, answer “true” only if you will be unable to ascertain individual identities because you have no access to the key that links the codes to identifying information.

I will have no contact or interaction with research participantsAnswer “true” only if you will have no contact – before, during, or after the research – with the persons whose samples you will study.

If you answered “true” to all of

these questions

Your research may not involve human subjects and therefore may not require informed consent. However, only the IRB can make an authoritative determination that your research does not involve human subjects.

If you answered “false” to any of these questions, your research likely involves human subjects.

Box 2. Is your human subjects research exempt from IRB review?

True or False:

The samples I will study are existingAnswer “true” only if the specimens will exist (“on the shelf” or in the freezer)at the time your protocol is submitted to the IRB.

I will obtain the samples from a non-collaborating source Answer “true” only if the person or entity from whom you will obtain the samples will not be involved in your research.

I will initially have access to identifying information, but will record it in such a way that I cannot identify the research subjects Answer “true” only if the information you recorded cannot be linked back to specific individuals because there are no identifiers or codes.

I will have no contact or interaction with research participantsAnswer “true” only if you will have no contact – before, during, or after the research – with the persons whose samples you will study.

If you answered “true” to all of

these questions

Your research may be exempt from IRB review and therefore may not require informed consent. However, only the IRB can make an authoritative determination that your research is exempt.

If you answered “false” to any of these questions, your research likely requires IRB approval and may require consent.

Box 3. If your human subjects research is not exempt, can the requirement toobtain informed consent be altered or waived?

True or False:

The research involves no more than minimal risk to the subjectsAnswer “true” only if the probability and magnitude of harm anticipated in the research are no greater than those ordinarily encountered in daily life.

The waiver or alteration will not adversely affect the rights and welfare of the subjectsAnswer “true” only if subjects’ privacy and confidentiality will be protected and the research topic would not commonly be considered personally or socially sensitive.

The research could not practicably be carried out without the waiver or alterationAnswer “true” only if your research could not be carried out without the ability to waive consent.

If you answered “true” to all of

these questions The IRB may waive or alter the requirement that you obtain informed consent from participants.

If you answered “false” to any of these questions, the IRB will likely require that you obtain informed consent from participants.

Figure 35.1 Steps to determining likely informed consent requirements.

408 CHAPTER 35 n Informed Consent

When proposed uses of existing samples are not consist-ent with the original consent documents, it is appropriate to consider obtaining new consent when identifying information is available. Simply removing identifying information so that the research meets a regulatory category that does not require consent is an approach that should only be used with cau-tion, for at least two reasons. First, the justification for the use of unidentified samples without consent is typically that sub-jects would likely not object and the risks to them are minimal. However, this justification is difficult to assert when subjects have signed consent documents that make contrary promises or when subjects have stated opposing preferences. Second, NBAC identified several concerns about de-identifying samples, including compromising the scientific merit of the research, reducing but not eliminating the risk of harm to individuals, rendering further contact with the individual impossible (e.g., if something serious about that person’s health was discovered), and individuals’ interest in avoiding uses of their specimens that they regard as morally objectionable (NBAC, 1999).

3. Does the Research Meet the Criteria to Waive the Requirement to Obtain Informed Consent?When research involves human subjects and is not exempt, informed consent must be obtained unless the following crite-ria are met [45 CFR §46.116(d) (Figure 35.1, Box 3)]:

(a) The research involves no more than minimal risk to the subjects

Although biospecimen collection can sometimes pose physical risks (see Special Considerations – Research Biopsies, below), the predominant risks associated with genomic research are informational. Determining whether these risks are no more than minimal requires an assess-ment of the likelihood that identifiable information could be inappropriately disclosed, as well as the probability and magnitude of the harm that could realistically result if such disclosure occurred (NBAC, 1999). Robust measures to safeguard confidential information are crucial to minimiz-ing risk in genomic research (Malin et al., 2010).

(b) The waiver or alteration will not adversely affect the rights and welfare of the subjects

According to NBAC, failure to obtain consent may adversely affect the rights and welfare of subjects in two basic ways (NBAC, 1999). First, subjects may be improperly denied the opportunity to choose whether to assume the risks that the research presents. Second, subjects may be harmed or wronged as a result of their involvement in research to which they had not consented.

(c) The research could not practicably be carried out without the waiver or alteration

“Practicable” does not refer to the most practical or easiest course of action (Brunelli and Zwelling, 2001), and insuf-ficient organization or funding for the research is not a valid justification for forgoing appropriate human subjects

protections (Botkin, 2001). The key question for this crite-rion is whether an important avenue of research would be blocked without the ability to waive consent (Botkin, 2001).

(d) Whenever appropriate, the subjects will be provided with additional pertinent information after participation

This “debriefing” requirement has a historic basis in behavioral studies involving deception. For other kinds of research, including research involving human biospeci-mens, this criterion may not be appropriate and may even cause harm (NBAC, 1999).

The preceding discussion is based on US regulations, and it is important to note that there is no international regula-tory framework or uniform approach to many basic issues of informed consent (Elger and Caplan, 2006; Knoppers, 2005; Maschke, 2005; Salvaterra et al., 2008; Swede et al., 2007). However, this discussion does reflect international norms with regard to the general need for some form of ethical over-sight for the collection, storage and research use of human biospecimens and data, informed consent for the prospec-tive collection of biospecimens for research, the protection of identifiable private information, and the ability to discontinue participation. Further, absent specific consent for each use of a participant’s biospecimen, there appears to be increasing emphasis on additional protections such as governance struc-tures (Capron et al., 2009; Fullerton et al., 2010) and custodi-anship models (O’Brien, 2009; Yassin et al., 2010) to promote accountability, transparency, and public trust in biospecimen research (Deschenes and Sallee, 2005; Maschke, 2006).

INFORMED CONSENT DISCLOSURES AND COMPREHENSIONWhenever informed consent is required for research, the ele-ments of information that must be provided to prospective par-ticipants include a statement that the study involves research; an explanation of the purpose, procedures, and duration; risks, benefits, and alternatives; confidentiality protections; an expla-nation of whom to contact with questions; and a statement that participation is voluntary and can be discontinued at any time (45 CFR §46.116). Translating these basic elements into consent disclosures appropriate for genomic research has been the subject of several in-depth reviews (Beskow and Dean, 2008; Beskow et al., 2010a; Deschenes et al., 2001; McGuire and Beskow, 2010; Wallace et al., 2009) and are summarized in Table 35.1 (see also Recommended Resources).

Obtaining consent, however, is not simply a matter of dis-closing information – ensuring comprehension of the informa-tion is vital to making sure the individual’s decision to participate is, in fact, informed. Numerous studies have documented prob-lems with consent comprehension. For example, in two sepa-rate studies that assessed biobank participants’ understanding (McCarty et al., 2007; Ormond et al., 2009), more than one-third of participants answered questions incorrectly regarding the

Informed Consent Disclosures and Comprehension n 409

T a b l e 3 5 . 1 Informed consent elements for genomic research

Purpose A description of the purpose of the research, including an explanation that it involves genetics and a statement concerning whether or not samples/data will be stored for future research

Biospecimen collection An explanation of how biospecimens will be obtained (e.g., through a blood draw or biopsy specifically for research purposes, collection of specimens left over following a procedure for a clinical purpose)

Information collection A description of the information that will be associated with the specimens, including basic information collected from participants (e.g., demographics, family health history), information obtained from medical records, and research data generated by analysis of the specimens

Duration of storage An explanation of the length of time specimens/data will be stored (which may be “unlimited”)

Researcher access When materials will be stored and/or shared for future research, a description of who may be allowed to study the materials (e.g., researchers from other academic institutions, commercial companies) and the process by which access decisions will be made (e.g., scientific review, ethics review)

Large-scale data sharing An explanation of sharing that may occur outside the control of the researcher/entity that originally collected the specimens and data (e.g., the database of Genotypes and Phenotypes, dbGaP)

Recontact When applicable, an explanation that participants might be recontacted, for example to obtain updated information, to collect a new specimen, or for recruitment into additional research

Risks A description of reasonably foreseeable risks, including physical risks associated with biospecimen collection, as well as privacy/confidentiality risks (leading to the possibility of psychosocial harm); group harm may also be possible when the research involves socially defined groups. For research involving storage of materials for future use, it may be appropriate to include a statement that there may be other risks currently unforeseen

Confidentiality protections

A description of the steps taken to protect participants’ privacy and confidentiality, such as coding of specimens/data, limiting access to identifying information, material transfer and data use agreements, physical security measures, and applicable legal protections (e.g., the Genetic Information Non-Discrimination Act, Certificates of Confidentiality)

Benefits A statement of any benefits that may accrue from research participation, which in most cases will be societal rather than direct health benefits to participants

Costs/payments A description of any costs to the participant or the participant’s insurance, as well as any payments to compensate participants (e.g., for their time, travel, inconvenience)

Commercialization A statement that the research could result in a commercial product such as a test or drug, and whether participants will share in any profits

Research results A statement concerning what kind of individual research results and/or incidental findings (if any) participants will be offered and under what circumstances, as well as a statement concerning access to aggregate results

Discontinuing participation

A statement that participants can withdraw at any time without penalty, including any limitations on that right (e.g., that samples/data already distributed for research cannot be called back)

Contacts An explanation of whom participants should contact in the event of questions or concerns

purpose of the research, limitations to confidentiality protec-tions, that their DNA would be stored as part of the research, that the research involved some risks, and whether they would receive individual genetic results. In one of the two studies, par-ticipants also misunderstood duration of participation, contact information for questions or concerns, the ability to withdraw, researcher access to medical records, use of identifying informa-tion, and alternatives to participation (McCarty et al., 2007).

Such findings are not unique to biobanking. In a survey of adult cancer patients who had recently enrolled in a clinical trial

(Joffe et al., 2001), the majority of respondents were satisfied with the informed consent process and most considered themselves to be well-informed. Even so, nearly three-quarters did not recognize that the research involved nonstandard treatment, approximately two-thirds did not realize the unproven nature of the treatment nor the potential for incremental risk from participation, and approximately one-fourth did not know that the primary purpose was to benefit future patients, nor that direct medical benefit to self was uncertain. Similar results have been found in other stud-ies (Bergenmar et al., 2008; Jefford et al., 2010).

410 CHAPTER 35 n Informed Consent

Consent forms themselves are one factor contributing to comprehension problems. Systematic assessments have shown that the average length of consent forms is steadily increasing (Albala et al., 2010; Beardsley et al., 2007; Breese et al., 2004; LoVerde et al., 1989; Sharp, 2004), and that few are written at less than a 10th grade reading level (Beardsley et al., 2007; Breese et al., 2004; Grossman et al., 1994; LoVerde et al., 1989; Paasche-Orlow et al., 2003; Sharp, 2004; Silverman et al., 2001; White et al., 1996). For example, in one study of 27 clinical tri-als across four hospitals in Australia (Beardsley et al., 2007):

l Average consent form length was 8 pages (range: 5–12). [At one of the hospitals, further investigation showed that the page count increased dramatically from a median of 7 pages (range: 3–9) in 2000 to 11 pages (range: 7–21) in 2005.]

l Average consent form reading level was grade 11, despite English being the second language for approximately 10% of patients and about 15% having nine or fewer years of education.

l Scores on a standardized measure of consent understand-ing were significantly higher for trials in which form length was 7 pages or fewer, and significantly lower for trials in which form reading level was grade 11 or higher.

Not surprisingly, there have been continuing calls for consent documents to be simplified (Association of American Medical Colleges, 2007; National Cancer Institute, 1998, 2007), as well as efforts to develop simplified model forms (Beskow et al., 2010a, b; Koyfman et al., 2009; Salvaterra et al., 2008). In general, this can be accomplished by improv-ing readability, improving formatting, and reducing length (Ridpath et al., 2009; US Department of Health and Human Services, 2009) (see Recommended Resources).

In addition to improving consent forms, many other strat-egies have been developed to improve participant under-standing, including multimedia interventions, extended consent discussions, test/feedback approaches, and the use of trained consent educators (Cohn and Larson, 2007; Flory and Emanuel, 2004). Unfortunately, none of these have con-sistently demonstrated success in improving comprehension (Cohn and Larson, 2007; Flory and Emanuel, 2004). However, studies conducted to date have been hampered by issues such as small sample size and questionably valid study design, as well as uncertainties concerning how “comprehension” was defined and measured (Cohn and Larson, 2007; Flory and Emanuel, 2004). There is a significant need for the develop-ment and rigorous assessment of interventions that effectively and efficiently promote comprehension.

SPECIAL CONSIDERATIONS

Clinically Derived BiospecimensWhen biospecimens have been collected and used to meet a clinical need, remaining portions of the samples are often

retained for research, quality control, and/or teaching pur-poses, based on a brief disclosure within a consent-to-treat form. There are ethical concerns about the adequacy of this consent, and about factors in clinical settings that may not be conducive to careful consideration of future research use of surplus tissue. These include patients’ stress and anxiety about upcoming medical procedures, as well as the competing demands of medical decision making (NBAC, 1999). Such con-cerns led NBAC (1999) to recommend:

l When consent for research use of human biospecimens is required, it should be obtained separately from consent for clinical procedures.

l The person who obtains consent in clinical settings should make clear to potential subjects that refusal to consent to the research use of biospecimens would in no way affect the quality of their clinical care.

These recommendations are bolstered by studies dem-onstrating that when they are asked more directly about research use of their surplus tissue, patients are not only bet-ter informed, but few decline. For example, Hamilton and col-leagues (2007) conducted a study of consent approaches to research using surplus tissue. Only 30% of patients who con-sented through a check box embedded in a consent-to-treat form knew that the consent they had given had to do with research use of their tissue, and 65% had no recollection of having given consent. In contrast, among patients who signed a separate, one-page consent form about surplus tissue, approximately 70% knew that the consent they had given had to do with research use of their tissue, and only 7% had no recollection of having given consent.

Another study (Vermeulen et al., 2009) reported similar results when patients were actively informed about research using surplus tissue through brief verbal explanation together with either an information leaflet that asked for written con-sent or a leaflet that provided an opportunity to opt out. These intervention groups were compared to a control group where the information was contained within a general hos-pital leaflet that included opt-out information. Overall, 99% of patients agreed to research with their leftover tissue. However, the majority of patients in the intervention groups stated they felt well-informed, in contrast to the control group where 73% did not remember having read the information about tissue research in the general hospital leaflet and only 27% said they felt well-informed.

In both of these studies, patients expressed a desire to know the basic information that their tissue would be used, but did not feel a need to know too much about it (Hamilton et al., 2007; Vermeulen et al., 2009). Collectively, these find-ings substantiate that actively informing patients – for exam-ple, through concise verbal and written communication that is separate from consent-to-treat information – does not unduly hinder research and is an important way to promote com-prehension and demonstrate value and respect for patients’ opinions.

Special Considerations n 411

With regard to opt-in versus opt-out approaches: When informed consent is required, US federal regulations necessi-tate, with limited exceptions, that research subjects’ affirmative agreement to participate be documented in a written consent form (45 CFR §46.117). When informed consent is not a regula-tory requirement, but an indication of patients’ agreement or non-agreement to the research use of their tissue is sought as an ethical matter, an opt-out approach may be permissible and could result in higher participation rates compared to an opt-in approach (Junghans et al., 2005). Regardless of approach, providing an opportunity for patients to make a meaningful expression of their wishes is paramount (Williams et al., 2007).

The timing of consent processes for research use of clini-cally derived specimens is another important ethical con-sideration. When biospecimens are collected specifically for research purposes (see Research Biopsies, below) or when the procedure for obtaining biospecimens is changed to meet a research need (e.g., collecting extra tissue beyond what is needed for clinical purposes), informed consent is required and it must be obtained prior to the collection of the biospeci-men (National Cancer Institute, 2007).

Otherwise, when specimens are collected for a clinical purpose via an unaltered procedure, separating consent for research use of residual tissue from consent to treatment as described above allows the possibility of obtaining research consent either before or after the clinical procedure. Concerns about obtaining research consent during the pre-operative period include the patient’s mental state, scheduling sufficient time during this busy period, and the possibility of troubling the patient for consent if it turns out that no suitable resid-ual material is available (Hewitt et al., 2009). Concerns about obtaining consent during the post-operative period include the possibility that patients will be preoccupied with subse-quent medical care considerations or have impaired judg-ment due to anesthetic or pain medications, and that careful controls must be in place to ensure that samples are not used until appropriate consent is obtained (Hewitt et al., 2009).

Because there are legitimate arguments on both sides, the National Cancer Institute has recommended that for biospeci-mens collected during the course of medical care, the timing of consent to use biospecimens for research purposes should not be imposed rigidly but instead should be informed by consid-erations such as those outlined above (National Cancer Institute, 2007). Members of the International Society for Biological and Environmental Repositories similarly concluded that there should be a window of time for the completion of the consent process, with defined limits but spanning both the preoperative and post-operative periods (Hewitt et al., 2009). As this group stated:

Whatever the timing of the consent, its validity depends on the integrity and skill of the individual obtaining the consent, and whether they make an honest and reliable assessment of the patient’s current state of mind.

International Society for Biological and Environmental Repositories

Research BiopsiesIn contrast to clinical biopsies, where tissue samples are obtained for purposes directly related to the patient’s care, a research biopsy is a procedure through which tissue is collected for research purposes only, with no proven role in the patient’s clinical management (Peppercorn et al., 2010). Research biopsies may be used in studies seeking to determine whether an intended target is modulated by the investigational agent and to identify prognos-tic and predictive biomarkers that could guide personalized clinical decision making (Brown et al., 2008; Cannistra, 2007; Peppercorn et al., 2010). Because of the need to assess the presence and baseline activity of the target, as well as changes that occur with therapy, such research typically requires serial biopsies before, during, and/or after treatment (Brown et al., 2008; Peppercorn et al., 2010). In some cases, research biopsies may also be used to determine eligibility for a trial of a targeted therapy.

Performing research biopsies raises ethical concerns when patients are asked to undergo a procedure that involves some risk (including the possibility of rare, life-threatening complica-tions) but little or no possibility of direct benefit (Brown et al., 2008; Peppercorn et al., 2010). Although it is permissible to expose participants to risks with no chance of personal benefit – provided that the risks are minimized and are justified by the value of the knowledge to be gained (Joffe and Miller, 2008) – the ethics of doing so hinge on the patient’s ability to give voluntary and meaningful informed consent (Helft and Daugherty, 2006).

A significant challenge to achieving this goal is patients’ well-established tendency toward therapeutic misconception. “Therapeutic misconception” refers to a failure to understand that research participation advances ends other than the participant’s own care (Kimmelman, 2007). With regard to research biopsies specifically, one survey revealed that many patients believed that having such biopsies might influence their care and health, despite an explicit statement in the survey that research biopsies are experimental and done solely for research purposes (Agulnik et al., 2006). This finding was interpreted as a clear indication of patients’ persistent hope for therapeutic benefit that cannot be met in most of these kinds of studies (Agulnik et al., 2006).

Therefore, in addition to making certain that studies involving research biopsies are well-designed and that biopsies will be obtained in ways that minimize risks, it is imperative that significant effort be made to ensure that prospective par-ticipants are adequately informed of the risks, rationale, and requirements of the research (Peppercorn et al., 2010). Specific suggestions include:

l Clearly informing patients that the biopsies are for research purposes only, and of the associated risks (Brown et al., 2008; Peppercorn et al., 2010)

l Distinguishing between the investigational agent and the biopsies, e.g., by using a separate consent form for the research biopsy, using a provider other than the researcher to obtain consent, or offering modest financial compensation to reinforce the fact that these procedures are not intended for participants’ medical benefit (Brown et al., 2008)

412 CHAPTER 35 n Informed Consent

l Informing patients of alternatives to participation, and of their ability to discontinue participation before the biopsy, if they choose (Peppercorn et al., 2010)

l Implementing measures to promote comprehension and to assess the patient’s understanding before accepting consent (Brown et al., 2008).

CONCLUSIONSInformed consent is a process, not a form, and should involve ongoing, interactive dialog between research staff

and prospective participants (Institute of Medicine, 2002; NBAC, 2001). Genomic research presents challenges for tra-ditional models of informed consent, and provides oppor-tunities for new models of consent and communication (Beskow et al., 2010a; Mascalzoni et al., 2008). The focus of any consent process should be on informing and protecting research participants, through disclosure and discussion of rel-evant information, meaningful efforts to promote participants’ understanding, and by ensuring that decisions to participate, or to continue participating, are always made voluntarily.

REFERENCES

Agulnik, M., Oza, A.M., Pond, G.R., Siu, L.L., 2006. Impact and percep-tions of mandatory tumor biopsies for correlative studies in clini-cal trials of novel anticancer agents. J Clin Oncol 24, 4801–4807.

Albala, I., Doyle, M., Appelbaum, P.S., 2010. The evolution of consent forms for research: A quarter century of changes. IRB 32, 7–11.

Association of American Medical Colleges, 2007. Univeral use of short and readable informed consent documents: How do we get there? <https://www.aamc.org/download/75282/data/hdicklermtg-sumrpt53007.pdf>.

Beardsley, E., Jefford, M., Mileshkin, L., 2007. Longer consent forms for clinical trials compromise patient understanding: So why are they lengthening? J Clin Oncol 25, e13–14.

Bergenmar, M., Molin, C., Wilking, N., Brandberg, Y., 2008. Knowledge and understanding among cancer patients consenting to partici-pate in clinical trials. Eur J Cancer 44, 2627–2633.

Beskow, L.M., Dean, E., 2008. Informed consent for biorepositories: Assessing prospective participants’ understanding and opinions. Cancer Epidemiol Biomarkers Prev 17, 1440–1451.

Beskow, L.M., Friedman, J.Y., Hardy, N.C., Lin, L., Weinfurt, K.P., 2010a. Developing a simplified consent form for biobanking. PLoS One 5, e13302.

Beskow, L.M., Friedman, J.Y., Hardy, N.C., Lin, L., Weinfurt, K.P., 2010b. Simplifying informed consent for biorepositories: Stakeholder perspectives. Genet Med 12, 567–572.

Botkin, J., 2001. Protecting the privacy of family members in survey and pedigree research. JAMA 285, 207–211.

Breese, P., Burman, W., Rietmeijer, C., Lezotte, D., 2004. The Health Insurance Portability and Accountability Act and the informed consent process. Ann Intern Med 141, 897–898.

Brown, A.P., Wendler, D.S., Camphausen, K.A., Miller, F.G., Citrin, D., 2008. Performing nondiagnostic research biopsies in irradiated tissue: A review of scientific, clinical, and ethical considerations. J Clin Oncol 26, 3987–3994.

Brunelli, C.A., Zwelling, L.A., 2001. Protecting the privacy of fam-ily members in research. JAMA 285, 1961. author reply 1962–1963.

Cannistra, S.A., 2007. Performance of biopsies in clinical research. J Clin Oncol 25, 1454–1455.

Capron, A.M., Mauron, A., Elger, B.S., Boggio, A., Ganguli-Mitra, A., Biller-Andorno, N., 2009. Ethical norms and the international governance of genetic databases and biobanks: Findings from an international study. Kennedy Inst Ethics J 19, 101–124.

Cohn, E., Larson, E., 2007. Improving participant comprehension in the informed consent process. J Nurs Scholarsh 39, 273–280.

Deschenes, M., Cardinal, G., Knoppers, B.M., Glass, K.C., 2001. Human genetic research, DNA banking and consent: A question of ‘form’? Clin Genet 59, 221–239.

Deschenes, M., Sallee, C., 2005. Accountability in population biobank-ing: Comparative approaches. J Law Med Ethics 33, 40–53.

Elger, B.S., Caplan, A.L., 2006. Consent and anonymization in research involving biobanks: Differing terms and norms present serious barriers to an international framework. EMBO Rep 7, 661–666.

Flory, J., Emanuel, E., 2004. Interventions to improve research par-ticipants’ understanding in informed consent for research: A sys-tematic review. JAMA 292, 1593–1601.

Fullerton, S.M., Anderson, N.R., Guzauskas, G., Freeman, D., Fryer-Edwards, K., 2010. Meeting the governance challenges of next-generation biorepository research. Sci Transl Med 2, 15cm3.

Grossman, S.A., Piantadosi, S., Covahey, C., 1994. Are informed consent forms that describe clinical oncology research protocols readable by most patients and their families? J Clin Oncol 12, 2211–2215.

Hamilton, S., Hepper, J., Hanby, A., Hewison, J., 2007. Consent gained from patients after breast surgery for the use of surplus tissue in research: An exploration. J Med Ethics 33, 229–233.

Helft, P.R., Daugherty, C.K., 2006. Are we taking without giving in return? The ethics of research-related biopsies and the benefits of clinical trial participation. J Clin Oncol 24, 4793–4795.

Hewitt, R., Watson, P.H., Dhir, R., et al., 2009. Timing of consent for the research use of surgically removed tissue: Is postoperative consenting acceptable? Cancer 115, 4–9.

Institute of Medicine, 2002. Responsible Research: A Systems Approach to Protecting Research Participants. National Academies Press, Washington, DC.

Jefford, M., Mileshkin, L., Matthews, J., et al., 2010. Satisfaction with the decision to participate in cancer clinical trials is high, but understanding is a problem. Support Care Cancer 19, 371–379.

Joffe, S., Miller, F.G., 2008. Bench to bedside: Mapping the moral ter-rain of clinical research. Hastings Cent Rep 38, 30–42.

Joffe, S., Cook, E.F., Cleary, P.D., Clark, J.W., Weeks, J.C., 2001. Quality of informed consent in cancer clinical trials: A cross-sectional survey. Lancet 358, 1772–1777.

Junghans, C., Feder, G., Hemingway, H., Timmis, A., Jones, M., 2005. Recruiting patients to medical research: Double blind randomised trial of “opt-in” versus “opt-out” strategies. BMJ 331, 940.

References n 413

Kimmelman, J., 2007. The therapeutic misconception at 25: Treatment, research, and confusion. Hastings Cent Rep 37, 36–42.

Knoppers, B.M., 2005. Biobanking: International norms. J Law Med Ethics 33, 7–14.

Koyfman, S.A., Mccabe, M.S., Emanuel, E.J., Grady, C., 2009. A con-sent form template for phase I oncology trials. IRB 31, 1–8.

Loverde, M.E., Prochazka, A.V., Byyny, R.L., 1989. Research consent forms: Continued unreadability and increasing length. J Gen Intern Med 4, 410–412.

Malin, B., Karp, D., Scheuermann, R.H., 2010. Technical and policy approaches to balancing patient privacy and data sharing in clin-ical and translational research. J Investig Med 58, 11–18.

Mascalzoni, D., Hicks, A., Pramstaller, P., Wjst, M., 2008. Informed consent in the genomics era. PLoS Med 5, e192.

Maschke, K.J., 2005. Navigating an ethical patchwork – human gene banks. Nat Biotechnol 23, 539–545.

Maschke, K.J., 2006. Alternative consent approaches for biobank research. Lancet Oncol 7, 193–194.

McCarty, C.A., Nair, A., Austin, D.M., Giampietro, P.F., 2007. Informed consent and subject motivation to participate in a large, popu-lation-based genomics study: The Marshfield Clinic Personalized Medicine Research Project. Community Genet 10, 2–9.

Mcguire, A.L., Beskow, L.M., 2010. Informed consent in genomics and genetic research. Annu Rev Genomics Hum Genet 11, 361–381.

National Cancer Institute, 1998. Simplification of informed consent documents. <http://www.cancer.gov/clinicaltrials/understanding/ simplification-of-informed-consent-docs>.

National Cancer Institute, 2011. Best practices for biospecimen resources. <http://biospecimens.cancer.gov/bestpractices/2011-NCIBestPrac tices.pdf>.

National Cancer Institute, 2007. Office of biorepositories and bio-specimen research. Custodianship and ownership issues in biospecimen research. <http://biospecimens.cancer.gov/global/pdfs/CaOSumm.pdf>.

NBAC, 1999. Research Involving Human Biological Materials: Ethical Issues and Policy Guidance, vol. 1. US Government Printing Office, Rockville, MD.

NBAC, 2001. Ethical and Policy Issues in Research Involving Human Participants, vol. 1. US Government Printing Office, Rockville, MD.

O’Brien, S.J., 2009. Stewardship of human biospecimens, DNA, gen-otype, and clinical data in the GWAS era. Annu Rev Genomics Hum Genet 10, 193–209.

Ormond, K.E., Cirino, A.L., Helenowski, I.B., Chisholm, R.L., Wolf, W.A., 2009. Assessing the understanding of biobank participants. Am J Med Genet A 149A, 188–198.

Paasche-Orlow, M.K., Taylor, H.A., Brancati, F.L., 2003. Readability standards for informed-consent forms as compared with actual readability. N Engl J Med 348, 721–726.

Peppercorn, J., Shapira, I., Collyar, D., et al., 2010. Ethics of mandatory research biopsy for correlative end points within clinical trials in oncology. J Clin Oncol 28, 2635–2640.

Reilly, P.R., Boshar, M.F., Holtzman, S.H., 1997. Ethical issues in genetic research: Disclosure and informed consent. Nat Genet 15, 16–20.

Ridpath, J.R., Greene, S.M., Wiese, C.J., 2009. PRISM Readability Toolkit. Group Health Research Institute, Seattle, <http://www.grouphealthresearch.org/capabilities/readability/readability_home.html>.

Rothstein, M.A., 2005. Expanding the ethical analysis of biobanks. J Law Med Ethics 33, 89–101.

Salvaterra, E., Lecchi, L., Giovanelli, S., et al., 2008. Banking together. A unified model of informed consent for biobanking. EMBO Rep 9, 307–313.

Sharp, S.M., 2004. Consent documents for oncology trials: Does any-body read these things? Am J Clin Oncol 27, 570–575.

Silverman, H., Hull, S.C., Sugarman, J., 2001. Variability among insti-tutional review boards’ decisions within the context of a multi-center trial. Crit Care Med 29, 235–241.

Swede, H., Stone, C.L., Norwood, A.R., 2007. National population-based biobanks for genetic research. Genet Med 9, 141–149.

US Department of Energy, 2007. Human subjects protection resource book. <http://humansubjects.energy.gov/doe-resources/files/HumSubjProtect-ResourceBook.pdf>.

US Department of Health and Human Services, 2008. Office for human research protections. Guidance on research involving coded private information or biological specimens. <http://www.hhs.gov/ohrp/policy/cdebiol.html>.

US Department of Health and Human Services, 2009. Agency for healthcare research and quality informed consent and authori-zation toolkit for minimal risk research. <http://www.ahrq.gov/fund/informedconsent/>.

Vermeulen, E., Schmidt, M.K., Aaronson, N.K., et al., 2009. A trial of consent procedures for future research with clinically derived biological samples. Br J Cancer 101, 1505–1512.

Wallace, S., Lazor, S., Knoppers, B.M., 2009. Consent and population genomics: The creation of generic tools. IRB 31, 15–20.

White, L.J., Jones, J.S., Felton, C.W., Pool, L.C., 1996. Informed con-sent for medical research: Common discrepancies and readabil-ity. Acad Emerg Med 3, 745–750.

Williams, B., Irvine, L., McGinnis, A.R., McMurdo, M.E., Crombie, I.K., 2007. When “no” might not quite mean “no”; the importance of informed and meaningful non-consent: Results from a survey of individuals refusing participation in a health-related research project. BMC Health Serv Res 7, 59.

Yassin, R., Lockhart, N., Gonzalez Del Riego, M., et al., 2010. Custodianship as an ethical framework for biospecimen-based research. Cancer Epidemiol Biomarkers Prev 19, 1012–1015.

RECOMMENDED RESOURCES

Consent Disclosures and Model LanguageNational Human Genome Research Institute: Informed Consent for

Genomics Researchhttp://www.genome.gov/27026588

Electronic Medical Records and Genomics (eMERGE) Network, Consent and Community Consultation Workgroup, Informed Consent Task Force: Model Consent Language

http://www.genome.gov/Pages/PolicyEthics/InformedConsent/eMERGEModelLanguage2009-12-15.pdf

P3G Observatory, Ethics, Governance, and Public Engagement: Model Consent Form

http://www.p3gobservatory.org/repository/ethics.htm

414 CHAPTER 35 n Informed Consent

Tools to Improve Consent FormsGroup Health Research Institute. Program for Readability in Science

and Medicine (PRISM) Readability Toolkithttp://www.grouphealthresearch.org/capabilities/readability/readability_home.html

National Cancer Institute, Clear and Simple: Developing Effective Print Materials for Low-Literate Readers

http://www.cancer.gov/cancertopics/cancerlibrary/clear-and- simple

US Department of Health and Human Services, Agency for Healthcare Research and Quality: AHRQ Informed Consent and Authorization Toolkit for Minimal Risk Research

http://www.ahrq.gov/fund/informedconsent/