Beyond Informed Consent: The Ethical Design of Pain Research

PAIN MEDICINE

Volume 2

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Number 2

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2001

© Blackwell Science, Inc. 1526-2375/01/$15.00/138 138–146

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Beyond Informed Consent: The Ethical Design of Pain Research

David J. Casarett, MD, MA,* and Jason Karlawish, MD*

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*Philadelphia VA Medical Center, and

†

Division of Geriatrics, Institute on Aging and the Center for Bioethics,

A B S T R A C T

University of Pennsylvania, Philadelphia, Pennsylvania

In the wake of the rapid development of medical research over the past 50 years, investigators, clini-cians, and ethicists have raised numerous concerns about the ethical conduct of research. Perhaps thesingle most important protective mechanism to emerge from the fray has been the requirement of in-formed consent. Certainly it has the longest history. However, even though informed consent has be-come the most widely recognized mechanism of protecting human subjects in research, there are lim-its to what the informed consent process can accomplish. Another, and more far-reaching, way toprotect human subjects involved in research is to ensure that the study design is as consistent as possi-ble with patients’ preferences and goals. That is, pain investigators have a significant opportunity toimprove the ethical rigor of their work by designing a study that offers a subject what is a reasonablebalance of risks and benefits. This article suggests some specific ways in which investigators may de-sign research that is more consistent with patient preferences. We describe several aspects of the eth-ical design of clinical pain research that appear to be important to patients, including the potentialbenefits for subjects, the benefits for future patients, the risks and burdens of research participation,and the voluntariness of a subject’s choice whether to enroll. We conclude by discussing ways inwhich the ethical design of research might make the informed consent process more robust.

Key Words.

Pain; Ethics; Research Ethics; Informed Consent

I

n the wake of the rapid development of medicalresearch over the past 50 years, investigators, cli-

nicians, and ethicists have raised numerous con-cerns about the ethical conduct of research. In gen-eral, the field has assumed this protectionist posturebecause of a series of unfortunate scandals and thepublic outcry that ensued [1–3]. As a result, researchethics has focused primarily on protecting humansubjects from the risks of research.

Perhaps the single most important protectivemechanism to emerge from the fray has been therequirement of informed consent. Certainly it hasthe longest history. The requirement for informedconsent dates back at least to the Nuremberg Code,which articulated the need for voluntary consent asits first principle [4]. This requirement has seenfurther elaboration and specification and has be-come a central part of virtually all regulations and

guidelines governing the conduct of human sub-jects research both in the United States [5,6] (46.116-117) and abroad [7–10]. Indeed, it seems to be truethat scandals in research ethics, when they occur,almost invariably hinge on the adequacy of the in-formed consent process [1–3].

However, even though informed consent has be-come the most widely recognized mechanism ofprotecting human subjects in research, there arelimits to what the informed consent process can ac-complish. In fact, the most thorough review of theliterature to date has demonstrated that across awide variety of settings, informed consent is oftenimperfect [11]. For instance, subjects in researchfrequently fail to understand even basic design fea-tures, the probability of benefit, or even the distinc-tion between research and clinical care [12–15].

The success of efforts to improve the informedconsent process, and particularly subjects’ under-standing of important information about the stud-ies in which they enroll, has been mixed. Althoughsome studies have demonstrated improved under-standing, others have not [16–22]. Therefore, al-

Reprint requests to:

David Casarett, MD, MA, University ofPennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104.Tel: (215) 898-2583; Fax: (215) 573-8684; E-mail: [email protected].

Beyond Informed Consent

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though these sorts of interventions offer an impor-tant opportunity to protect subjects who are involvedin research, informed consent should not be thesole mechanism of protection.

Another, and more far-reaching, way to protecthuman subjects involved in research is to ensurethat the study design is as consistent as possiblewith patients’ preferences and goals. That is, paininvestigators have a significant opportunity to im-prove the ethical rigor of their work by designing astudy that offers a subject what is a reasonable bal-ance of risks and benefits. By doing so, investigatorscan lift some of the burden under which the in-formed consent process labors.

Here we suggest specific ways in which investiga-tors may design research that is more consistent withpatient preferences. These observations are drawnfrom the results of an interview study conducted on40 patients with chronic pain who were seen at anacademic anesthesia pain clinic [23]. Subjects werepresented with five brief (four to five sentences) vi-gnettes describing hypothetical pain studies. Foreach, subjects were asked to think of risks and bene-fits the study might have for them. Subjects werethen asked to describe features of the study thatwould make them more or less likely to want to par-ticipate. The methods used and a full account of thestudy’s results have been published [23].

Here we discuss the implications of these resultsfor pain researchers. Specifically, these interviewssuggest several ways in which pain researchers maydesign studies that are more consistent with patients’preferences. In this article, we describe several as-pects of the ethical design of clinical pain researchthat appear to be important to patients, includingthe potential benefits for subjects, the benefits for fu-ture patients, the risks and burdens of research par-ticipation, and the voluntariness of a subject’s choicewhether to enroll. Finally, we conclude by discussingways in which the ethical design of research mightmake the informed consent process more robust.

Benefits to Subjects

One way in which investigators can enhance theethical design of a pain study is to maximize thebenefits that it will offer to subjects. Broadly, thesebenefits can be considered under two categories:benefits to subjects during the study and benefitsfrom the data that are collected.

Benefits to Subjects During the Study

Investigators may have several opportunities to max-imize potential benefits of research to the subjects

who participate. These opportunities extend fromthe initial stages of study design to study completion.Perhaps the first opportunity that investigators haveto maximize potential benefits, at least in an inter-ventional study, is in their choice of an intervention.Ideally, a new intervention to be studied should havea reasonable chance of success. More importantly, ifit is to offer subjects a significant potential benefit,an intervention should offer the possibility of ameaningful improvement over other interventionsthat are available to subjects outside the study.

For instance, an exercise program that is expectedto reduce chronic pain [24] would only offer poten-tial benefits if it is qualitatively or quantitatively dif-ferent from the exercise programs that constitute theusual standard of care. Similarly, a trial to evaluatethe effectiveness of a medication would offer poten-tial benefits to subjects only if there were reason tobelieve that it offered greater effectiveness, a betterpharmacokinetic profile, or fewer side effects thanmedications that are currently available. For instance,a comparison of two medications that are commer-cially available, such as topical fentanyl and sustained-release morphine, would not offer subjects any po-tential benefit, although the study’s result could offerconsiderable clinical value [25]. It is quite possiblethat one of the medications or interventions beingevaluated will prove to be superior to the other. Forexample, one treatment arm might show better effi-cacy or a more favorable side-effect profile. Never-theless, if the superior medication was available off-protocol and subjects in the trial would have hadaccess to it in the course of their usual clinical care,they cannot be said to have benefited from their ex-posure to that medication in the trial.

This is an admittedly narrow definition of benefit.It is possible that some investigators and institutionalreview boards take a more liberal position and wouldclassify a study as beneficial if the intervention to beevaluated has the potential to be effective. Seen fromthis perspective, a trial comparing a sustained-releaseopioid preparation to placebo would offer potentialbenefits to subjects [26] because those subjects whoare assigned to the active treatment arm might expe-rience pain relief. Although intuitively appealing, thisargument is misleading. From the subject’s perspec-tive, if the active medication, or an equivalent treat-ment, were available off-protocol, then participationin the study would offer no incremental benefitscompared with what is available as standard of care.

Of course, these benefits are never certain. Ifthey were, a randomized trial would not be ethi-cally acceptable. That is, a legitimate argument forthe uncertainty that justifies a clinical trial, or equi-

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poise, could not be made [27]. However, investiga-tors generally design studies of interventions forwhich there is at least some evidence of effective-ness. Therefore, even though these potential bene-fits are not certain, they are more or less likely, andthis assessment of likelihood should be consideredin the design of pain research.

Even if the intervention of interest offers poten-tial benefits that are significant when comparedwith standard treatment, whether or not a study of-fers potential benefits is influenced to a large de-gree by the study’s design. For instance, if a studyto evaluate the effectiveness of a new medicationinvolves a placebo arm, any potential benefits of themedication are diluted or adjusted downward. Forexample, a long-acting medication might offer sub-jects the chance of a modest decrease in need forbreakthrough dosing [26]. However, if this medica-tion is evaluated in a randomized, placebo-con-trolled, parallel design trial, a subject’s realistic ex-pectations of benefit are cut, roughly, in half.

The potential benefits of a study can be enhancedby choosing an active control design rather than aplacebo [25,28]. On the other hand, if a placebo isused, a study’s potential benefits can also be im-proved by altering the standard 1:1 randomizationscheme in a placebo-controlled trial in a way thatincreases subjects’ chances of receiving an activeagent [29]. The potential benefits of a placebo-con-trolled trial can also be enhanced by using a cross-over design, so that all subjects are offered potentialbenefits, if the medication’s pharmacokinetic profilemakes it possible to avoid carryover effects.

All these manipulations come with a cost. For in-stance, a departure from the standard 1:1 random-ization scheme will demand a larger sample size andgreater study costs. Nevertheless, when such changesare feasible they should be considered.

Benefits From Data Collected During a Study

Although the opportunities to enhance potentialbenefits described above apply largely to studies in-volving interventions, another opportunity appliesequally well, if not better, to descriptive research. Acommon ethical issue in the design of pain-relatedresearch, and particularly descriptive research, isthe possibility that data gathered may contribute toa subject’s care. For instance, data gathered duringan ostensibly descriptive study may identify severepain [30–33], dissatisfaction with pain management[34–38], or related clinical problems like depressionin certain populations in which pain is common[30,39]. In anticipation of instances like these, in-vestigators have the opportunity to design standard

operating procedures that help to ensure that valu-able clinical information, such as the presence ofunrecognized and untreated pain or concurrent dis-orders like depression, [40] are made available to thesubject and his or her clinicians. This is arguably anethical obligation of all symptom-oriented research[41]. However, even if these procedures are not re-quired, they still offer a significant opportunity forinvestigators to enhance the potential benefits ofpain research.

Benefits to Others

Another ethical aspect of a study’s design that de-serves mention is its benefits for future patients. Al-though these benefits to others are not benefits inthe same sense as those that were described above,they are, nonetheless, an important aspect of anyethical study. Benefit to others can be described ontwo levels, validity and value.

Validity

First, all studies must be valid. That is, they must usetechniques of design and data analysis that peer re-viewers can agree are appropriate. In addition, allstudies must be designed to produce knowledge thatis generalizable. Indeed, generalizability is the cor-nerstone of the Common Rule’s definition of re-search: “a systematic investigation, including researchdevelopment, testing, and evaluation, designed to de-velop or contribute to generalizable knowledge” [6](46.102.d). These requirements collectively describea study’s validity [42]. Validity is a threshold require-ment for all research, because it is unethical to exposehuman subjects to risks in studies that peer reviewersagree cannot adequately answer a research question[43]. Therefore, at a minimum, investigators routinelyconsider a study’s validity.

Value

Above this threshold of validity, studies may offermore or less importance, or “value.” Broadly, valuecan be defined as the likelihood that a study’s resultswill improve the health and well-being of future pa-tients [44]. Like validity, value is an important mea-sure of a study design’s scientific quality, but it isalso a measure of its ethical quality. Value is an es-sential aspect of a study’s ethical design because acentral goal of research is to produce knowledgethat will ultimately be “important” [6] (46.111.92)[10], “fruitful” [4], or “valuable” [45]. In fact, onereason that subjects participate in clinical research isto produce knowledge that will benefit others [1].Because subjects are willing to accept risks and bur-


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dens of research at least in part to benefit others, in-vestigators have accepted an ethical responsibility tomaximize the probability that a study will be able todo so. Therefore, in addition to widely accepted sci-entific arguments for valuable research, there arecompelling ethical arguments as well.

Space does not permit a comprehensive over-view of ways in which a study’s value can be as-sessed and improved. Indeed, such a discussionmoves quickly beyond ethics and into the technicallanguage of clinical trial design. Nevertheless, twoquestions deserve brief attention: how value is de-scribed and how value can be measured.

Immediate versus potential value.

A descriptionof value has been elusive, and perhaps the most ac-curate statement might be that one knows it whenone sees it. However, this terse formulation offerslittle guidance to investigators. Instead, a rough de-scription of a study’s value might reasonably be es-tablished based on two questions. First, one mightask whether a study has the potential to improvethe health and well-being of patients who are not inthe study. A study may achieve this goal if its resultswill be immediately applicable to improve health,in which case it might be said to have “immediatevalue.” Another study may produce knowledge thatadvances understanding of the pathophysiology ofpain, without an immediate application to painmanagement. Such a study might be said to have“potential value.”

Value to future patients, populations, and re-search subjects.

The second aspect of value has todo with the identity of future patients who maybenefit from the study’s results. These patients fallinto three categories: future patients, the popula-tion from which the research subjects are selected,and the subjects themselves.

The broadest group for whom value can be as-sessed is that of unidentified future patients. If astudy is to offer potential clinical value to the futurepatients, its results must be generalizable. Thismeans that the sample of subjects in the study mustbe representative. Furthermore, it must be de-signed to answer a question about which there isgenuine uncertainty.

A second group for whom investigators can as-sess a study’s value is the population from whichthe subjects in the study were selected. Thus, animportant test of the value of a medication study tobe carried out in a clinic would be whether patientsin that population would have the resources to ob-tain the medication under study, if it becomes clini-cally available. If they would not, then the study

may offer value to future patients, if the medicationis promising, but it would not offer value to thispopulation because they will not have access to themedication.

This assessment of value is important becauseinvestigators may have numerous opportunities toenhance a study’s value to a population, for in-stance, by matching a study medication’s character-istics (e.g., cost) to the population from which astudy’s subjects will be recruited. For both inter-ventional and descriptive research, investigatorscan also include in a study’s design (and budget) adissemination phase in which the study’s results aremade available to the population. Depending onthe study question, this might include in-servicesfor clinicians, patient education materials, or both.

A third group for whom investigators can assessa study’s value is the subjects themselves. Thesesorts of poststudy benefits are not usually includedin assessments of a study’s balance of risks and ben-efits, but they may nonetheless be significant. Forinstance, subjects in pain research can benefit aftera study’s completion if they learn from the study’saggregate results. This might be the case if a studycomparing two medications found that one resultedin fewer side effects overall [25]. Subjects in thestudy would benefit from these data because thisknowledge should allow them to make a more in-formed choice among available medications. Sub-jects might also benefit from results that are spe-cific to them. For instance, if a subject receives twomedications in a blinded crossover trial and prefersone to the other, he or she would be better able tochoose between these medications in future clinicalsituations, armed with the results of a blinded com-parison of the two [46–48].

Finally, investigators can help to ensure that sub-jects have continued access to medications that arestudied. If medications are not available, either due tohigh cost or because the medication has not yet re-ceived regulatory approval, subjects will not benefit(immediately) from the study’s results. Thus, by ar-ranging reduced rate programs or open-label exten-sion phases, investigators can increase a study’s po-tential benefits for subjects by helping to ensure thatsubjects will benefit from the study’s results.

Minimizing Risks and Burdens

Investigators can also enhance a study’s ethicalsoundness by taking steps to minimize a study’srisks and burdens. Although the distinction be-tween risks and burdens is not always clear, a roughheuristic is useful. In general, a risk can be consid-

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ered as the probability of an adverse medical eventor outcome. Thus, risks might include side effectsof medication, bruising during phlebotomy, or in-creased pain during the study. The term “burden”can be used to describe those unpleasant features ofparticipation in a study that are more certain andbetter thought of as inconveniences. Thus, addi-tional clinic visits, time spent filling out question-naires, or time spent waiting in clinic might be de-scribed as burdens.

Identifying Risks and Burdens

Attention to the ethical design of pain research andto the minimization of research risks and burdensrequires a clear agreement about how they shouldbe defined. The criteria by which study risks andburdens are identified and evaluated uses the con-cept of incremental or “demarcated” risks createdby a study [49]. The application of this standard tointerventional pain research would mean, for in-stance, that investigators designing a trial to com-pare the effectiveness of two opioids for cancer pain[25] do not need to go to great lengths to justify therisks of the opioids being evaluated, if subjects inthe trial would have received similar medications,with similar risks, off-protocol. Of course, the risksof any medication in a clinical trial should be dis-closed in the informed consent process [6] (46.116–117). Nevertheless, investigators are not under theobligation to minimize or justify these risks as theywould be if, for instance, the same medicationswere being given to patients with mild pain whowould not receive opioids as part of standard care.

Minimizing Risks

Most risks of pain research are neither hidden nordifficult to evaluate. Indeed, in many studies therisks of research are fixed, in a sense, by the re-search question. Thus, if the question to be an-swered has to do with the effectiveness of a short-acting medication relative to placebo, the risks ofincreased pain due to the placebo are set. There-fore, decisions made very early in the design pro-cess, like the decision to compare a medication witha placebo or the choice of one or more medicationsto study, have a profound influence on the sorts ofrisks that subjects will eventually be asked to take.For this reason, investigators can have the mostprofound effect on a study’s risks by consideringthem early in the design process.

Even within the frame provided by these initialdecisions, investigators can take steps to amelioratethe risks created by a particular design. For in-stance, in a placebo-controlled study, investigators

can ensure that subjects have adequate access tobreakthrough medications. This may in turn alter atrial’s end points. For instance, the free use ofbreakthrough dosing in a trial suggests the possibleinclusion of these doses as a study end point eitherdirectly [50,51] or as part of a composite end point[26,52].

It is worth noting that the use of a sham controlarm presents special challenges for ethical design.For instance, when research uses a sham control itmay sometimes be difficult to justify the additionalrisks and discomfort created if some of the subjectswho undergo these procedures will receive no ac-tive treatment [53]. One solution is to conductthese studies in a setting in which the procedure it-self (whether sham or real) poses few if any addi-tional, or “incremental,” risks above and beyondusual care. For instance, investigators might inserta sham epidural catheter that would then be usedfor postoperative analgesia [54].

When this is not possible, investigators maychoose a crossover design, in which subjects are as-signed to receive either the sham or the real proce-dure, followed by the other. This design does notdecrease the incremental risks of the sham proce-dure. However, it does ensure that all subjects whobear the risks of the sham procedure also have ac-cess to the real procedure’s potential benefits. Thiscrossover sham design has been used in other set-tings [55] and might be appropriate for pain re-search when the risks or discomforts of the shamprocedure are substantial.

Minimizing Burdens

For the most part, opportunities to minimize bur-dens are also readily apparent. For instance, itseems reasonable wherever possible to minimizesurveys, interviews, and additional study visits. Al-though these burdens all seem to be important toprospective research subjects [23], they are all bur-dens that investigators routinely consider carefullyin designing studies.

However, there may be other needs and con-cerns that may be unique to, or more common in,pain patients. For instance, although it is intuitivelyobvious that all research subjects would like toavoid the added time commitment and inconve-nience of travel to and from additional appoint-ment, this concern may be especially important topatients with chronic pain, for whom long periodsof time spent sitting in a car can exacerbate painfulconditions. Similarly, patients may view surveysand questionnaires not only as time consuming butalso as a source of increased pain. Therefore, inves-


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tigators who conduct pain research may have anadded reason to minimize the burdens of extra vis-its and data collection procedures. Moreover, in-vestigators have opportunities to enhance the ethi-cal design of pain studies by relying on telephonedata collection strategies whenever possible.

Another set of burdens that investigators may beless likely to consider are those burdens that a studycreates for friends and family members. Althoughmost burdens of research participation are borne bythe subject, the requirements of time, travel, andperhaps time off from work create burdens for others.Pain patients may be very sensitive to these burdens,and for some burdens to others can be influential inthe decision whether or not to enroll in a study. Bybuilding flexibility into a study design (e.g., use ofbrief telephone interviews, multiple options fortiming of clinic visits), investigators may reduce theburdens of research participation on others.

Protecting Voluntariness

Another way investigators can enhance the ethicalsoundness of a study’s design is to examine ways inwhich subjects’ voluntary participation can be pro-tected. In general terms, a choice is voluntary if it ismade without significant controlling influences[56,57]. At first glance, assurances of voluntarinessappear to be an issue of informed consent, and infact for the most part they are. However, a study’sdesign and plan for subject selection and recruit-ment may have as great an influence on subjects’freedom to refuse research participation as does theinformed consent process.

If a subject’s participation in research is to betruly voluntary, in addition to the absence of influ-ence in the consent process, two features of astudy’s design are relevant. First, a prospective sub-ject’s choice must be made with full knowledge ofavailable alternatives [6] (46.116–117). Second, hisor her choice must be made with the understandingthat he or she can withdraw at any time [6](46.116–117). Each of these creates opportunitiesto ensure voluntariness at the level of a study’s de-sign, which are discussed below.

Reasonable Alternatives to Participation

First, investigators can make sure that a study re-cruits subjects from an environment with excellentstandards of pain management. If patients in oneclinic or inpatient setting generally receive excel-lent pain treatment, they will be best able to make afree and uncoerced choice about research participa-tion. If, however, patients do not have access to a

bare minimum of treatment options and expertise,they may view research participation more favor-ably, out of desperation.

One solution, albeit a somewhat draconian one,would be to require that clinical pain research isconducted only in settings in which patients haveaccess to a full range of services, treatment, and ex-pertise. Although this requirement would reducethe potential for research participation out of des-peration, it would effectively limit research to asmall number of advanced centers. Another optionmight be to include a lead-in phase when clinicalpain research is conducted in settings where thestandard of care is poor [41]. A lead-in phase allowsan opportunity to optimize pain management be-fore recruitment. This strategy not only has ethicalvalue but scientific value as well because it providesa uniform baseline before randomization.

Opportunities to Withdraw

Investigators can also enhance the ethics of astudy’s design by ensuring that subjects are able towithdraw at any time. Although a subject’s abilityto withdraw should be a fundamental aspect of anyethical research, there may be unique barriers towithdrawal from pain research. For instance, sub-jects who withdraw from clinical pain research thatinvolves one or more medications will usually needaccess to a different medication upon withdrawal.This problem may be straightforward in manycases but can be very challenging if the investiga-tional medication is an opioid. The subject mustget a new prescription and get it filled. Most stateshave created considerable barriers to opioid pre-scribing, including triplicate prescriptions, whichmay make it very difficult for a subject to obtain anew prescription and get it filled in a timely man-ner. If a subject has his or her medication available,the process may be easier. Nevertheless, consider-able challenges of calculating an equianalgesic doseremain. For both of these reasons, investigators canenhance the ethical design of pain research by de-veloping mechanisms to ensure that subjects whodrop out continue to receive adequate pain treat-ment with as little interruption as possible.

Conclusion: Implications of Study Design for Informed Consent

This article began with the position that attentionto informed consent is not adequate to ensure theethical conduct of pain research. Certainly consentis essential, but it should not be the sole ethicalconcern of investigators. It is worth noting that at-

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tention to the ethical design of pain research, insome of the ways described above, may also im-prove the informed consent process. That is, theinformed consent process will be more effectiveand more likely to yield a decision that is consistentwith a subject’s true preferences if adequate atten-tion is given to a study’s design.

This is because the quality of informed consentis only as good as the design of the study in whichsubjects are being asked to participate. Informedconsent is, ultimately, designed to ensure that achoice to participate in research is autonomous.That is, effective and ethically sound informed con-sent should ensure that the risks and benefits of re-search participation are consistent with a subject’svalues and preferences. This will be relatively easyto achieve if research fits well with what subjectswant and expect. However, it may be very difficultif a proposed study deviates widely from those de-sires and expectations.

As an example, imagine that most patients whoenroll in clinical pain research expect some im-provement in their pain control. Although this po-sition is not necessarily valid in all cases, qualitativedata support it in pain research [23]. In addition,other studies from a variety of very different set-tings have found that the hope of direct benefit isimportant to most people who enroll in research[58,59]. Next, consider a study that offers no directbenefits. In clinical pain research, this might in-clude survey studies [31,38,60] or perhaps pharma-cokinetic studies of medications [61,62].

When a subject who expects to benefit from re-search is asked to participate in a study that offersno benefit, it is likely that the subject will see bene-fit where none exists. That is, this discrepancy be-tween expectations and design increases the likeli-hood that the subject’s decision to participate willnot be consistent with his or her true preferences.Phrased somewhat differently, this discrepancymeans that when expectations and study design di-verge, the informed consent process must take onadditional burdens to ensure that subjects who con-sent to participate in nonbeneficial research trulyunderstand that they will not benefit.

For these reasons, the ethics of a study’s designand the quality of informed consent for that studyare intimately related. Not only can investigatorsimprove the ethics of pain research through atten-tion to research design, they can also make the in-formed consent process for those studies moresmooth. This offers a substantial opportunity forinvestigators. As investigators in pain research andother fields strive to improve informed consent

through a variety of mechanisms, they have at theirdisposal another important but underused avenue.By modifying a study’s design in small but measur-able ways, investigators can enhance its acceptabil-ity to prospective subjects. In doing so, investiga-tors can take some of the burden off the informedconsent process, allowing the process to focus in-stead on study features that are more consistentwith subjects’ expectations.

Acknowledgments

Doctor Casarett is a recipient of a Research Career De-velopment Award from the Department of Veterans Af-fairs and receives funding from the VistaCare Founda-tion, the Greenwall Foundation, and the CommonwealthFund. Doctor Karlawish is funded by a Paul Beeson Phy-sician Scholarship, and NIA K01 AG-00931.

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Beyond Informed Consent: The Ethical Design of Pain Research