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CLINICAL PERSPECTIVE

The Ethics of Clinical Research

Kevin C. Chung, MD, Sandra V. Kotsis, MPH

The purpose of this article is to discuss the ethical concepts involved in the conception,design, execution, analysis, publication, and reporting of clinical research. Although it mightseem burdensome to comply with these ethical necessities, they can assist in the organizationof a well-run clinical trial, if considered at the onset of a study, while also protecting thevaluable human subjects who volunteer for these trials. (J Hand Surg 2011;36A:308–315.Copyright © 2011 by the American Society for Surgery of the Hand. All rights reserved.)

Key words Clinical research, ethics, trial.

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ETHICS THEORY PROVIDES consistency and coher-ence in decision making, so that there is a com-mon framework to approach various problems.1

The American Society for Surgery of the Hand hasrecently created a formal code of ethics and profession-alism.2 This Code does not address ethics related toesearch, but it does encourage hand surgeons to “par-icipate in activities that improve the health and well-eing of individuals and community at large.” Givenhat research—in particular, clinical research—has al-ays been an important focus of the hand surgery

pecialty, as exemplified by innovations in this spe-ialty ranging from microsurgery to implant designs, its relevant to discuss the ethics of conducting clinicalesearch that protects human subjects while also im-roving health outcomes for hand surgery patients.

Despite the ubiquitous consideration of ethics inlinical research, marked by oversight from institutionaleview boards (IRBs), as well as intense scrutiny byederal agencies, studies have shown that surgeons lacknowledge of ethical principles in clinical research.3,4

FromtheSectionofPlasticSurgery,DepartmentofSurgery,UniversityofMichiganHealthSystem,AnnArbor, MI.

Received for publication September 27, 2010; accepted in revised form November 8, 2010.

No benefits in any form have been received or will be received related directly or indirectly to thesubject of this article.

SupportedinpartbyaMidcareer InvestigatorAwardinPatient-OrientedResearch(K24AR053120)from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (to K.C.C.).

Corresponding author: Kevin C. Chung, MD, 1500 E. Medical Center Dr., 2130 Taubman Center,SPC 5340, The University of Michigan Health System, Ann Arbor, MI 48109-0340; e-mail:kecchung@med.umich.edu.

0363-5023/11/36A02-0018$36.00/0

pdoi:10.1016/j.jhsa.2010.11.012

308 � © ASSH � Published by Elsevier, Inc. All rights reserved.

This is not surprising, because residencies and fellow-ships rarely offer formal instruction of the ethical prin-ciples needed to conduct clinical studies. Rutan et alconducted a study of academic surgeons’ knowledge ofFood and Drug Administration and IRB regulations forclinical research.3 In this study, 25% of respondentswere willing to conduct clinical research on subjectswithout the subject’s consent. Of the respondents withprevious or current IRB membership, 24% of themwere willing to conduct their clinical trials withoutproper consent and approvals. Another study showedthat 75% of respondents claimed that the patients intheir study had been aware of the fact that they hadundergone an innovative treatment procedure; however,only 33% specifically mentioned this in the informedconsent form.4

Ethical guidelines are important in clinical researchecause they safeguard patients’ health and privacy.5

Although this should be reason enough to conduct re-search in an ethical manner, other reasons include com-pliance with federal regulations, job security, obtainingresearch funding, and respect from colleagues. Unethi-cal research can undermine public trust, which willincrease litigation and lower confidence in new researchfindings. Not only does unethical research waste timeand money, but it could also lead to increased regula-tions and a slower increase in research funding.6 Theseconcerns were raised by scientists who feared a setbackafter the case of Hwang Woo Suk—the scientist whofraudulently reported to have created human embryonicstem cells by cloning.7

The purpose of this article is to analyze the ethicaloncepts that form the basis for currently accepted

rinciples in the conduct of clinical research.

THE ETHICS OF CLINICAL RESEARCH 309

HISTORYAlthough we might like to think that clinical researchhas the subject’s best interests in mind, several histori-cal incidents tell us otherwise. These incidents haveprompted the development of regulations for clinicalresearch. Human experimentation in the German con-centration camps of World War II led to the NurembergCode in 1948.8 The Nuremberg Code has 10 principlesthat include the need for voluntary consent and statethat research risks should not exceed the benefits.9 In1964, the Declaration of Helsinki was adopted to ad-dress the limitations of the Nuremberg Code. The Dec-laration states that ethical principles must be followedwhen experimentation is combined with clinical care,just as when experimenting on healthy volunteers.8

After discovery of the 40-year-long Tuskegee syphilisstudy, the Belmont Report was published in 1979. TheTuskegee study enrolled nearly 400 economically dis-advantaged African-American men who had syphilis.They were not told that they had syphilis, and they werenot treated for it, even after penicillin became the stan-dard treatment.10 The Belmont Report is often cited for3 basic ethical principles: (1) respect for persons (sub-jects must enter into research voluntarily and with ad-equate information), (2) beneficence (research shouldmaximize benefits and reduce risks), and (3) justice(subjects must be selected fairly for participation inresearch, and the burdens and benefits of researchshould be fairly distributed in society).11 These ethicalprinciples are used by IRBs in the protection of humansubjects. Institutional review boards were created dur-ing this time in direct response to the previous researchabuses and are now regulated by the Office for HumanResearch Protections within the Department of Healthand Human Services.12 Institutional review boardsmust ensure the “meaningful consent” of research sub-jects.8 They perform oversight for human subject re-search that is scientific, ethical, and regulatory.12 Insti-tutions conducting federally funded research must havean IRB,8 and most peer-reviewed journals require astatement for clinical research papers that IRB approvalwas obtained.

PRACTICAL GUIDEEthics need to be considered through all stages of astudy: conception, design, execution, analysis, publica-tion, and reporting. These stages should be part of theconsideration in designing a study that will be consid-ered by an IRB for review. Table 1 provides a guide ofconcepts to remember when planning and conducting

an ethical clinical research study.

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Study conception

The conception of a clinical study begins with aresearch question followed by a hypothesis. “Theprimary question and the primary outcome mea-sure used will determine the design, statisticalpower, and clinical significance of the trial.”13 It ishelpful to think in terms of grant writing: what arethe specific aim, rationale, and hypothesis? Why isthis research necessary, and what is the impact ofthe results? Clinical research must be valuable tobe ethical.9,14 As stated in the Nuremberg Code,the study should “yield fruitful results for the goodof society.”9 Valuable research results in increasedknowledge for society, which justifies putting hu-man subjects at risk.15 Thus, when a study is in theconception phase, the researcher must have a clearidea of what knowledge will be gained through theresearch and how the results could lead to im-proved public health. What are the risks? Everystudy has some risk, no matter how small, and thatrisk must be evaluated against the potential soci-

TABLE 1. Steps to Conducting Ethical ClinicalResearch

Step Things to Remember

Conception Develop a priori research aim,rationale, and hypothesis

Determine availability of studysubjects

Clinical equipoise

Design Develop adequate study design toanswer question

Balance risks and benefitsInclusion and exclusion criteriaConsult with a statisticianDevelop a protocolObtain IRB approvalDevelop informed consent document

Execution Recruit patients using trained researchpersonnel

Submit study amendments to IRB

Analysis Hypothesis-drivenAvoid analyzing during data collectionBe aware of data fabrication and

falsification

Publication Report accurately and promptlySubmit to only 1 journal for

publicationDo not split study outcomes into

multiple publicationsInclude authors based on substantive

contribution

etal gains that the study will provide.

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310 THE ETHICS OF CLINICAL RESEARCH

To determine the feasibility of the study, the re-searcher must have a concrete plan to consider wherepatients will be recruited from and whether enoughpatients will be available for the study. The late LouisLasagna described a study in which only 100 people ofa pool of 8,000 proved eligible.16 This led to “Lasa-gna’s Law,” which states that “Investigators overesti-mate, many fold, the pool of available patients whomeet the inclusion criteria and would be willing toenroll in a particular trial.”17 From 2000 to 2007, 40%of all Cancer Therapy Evaluation Program-sponsoredtrials were unable to achieve their minimum patientrecruitment objectives. More than 8,700 patients wererecruited into these trials before they failed.18 Thus,time, money, and patient resources were wasted, andthe data acquired from the recruited patients were mostlikely of little value. Furthermore, patients’ enrollmentinto a failed study might prevent them from enteringother studies. Patients often volunteer their time toparticipate in clinical research when they might notreceive any direct benefit, only the hope of benefiting amember of society. It is unethical to enroll patients intoa study that might not acquire its recruitment goalbecause of poor planning. As previously stated, subjectsshould not be exposed to harm without a social orscientific benefit.9,14,19,20 One ethical principle beingconsidered here is the avoidance of exploitation.15 Lim-ited research resources (human subjects, as well asmoney) should not be squandered on studies that do notultimately benefit society and that take resources awayfrom other studies.

Clinical equipoise also needs to exist in the concep-tion of a clinical trial that involves randomization. Clin-ical equipoise is the genuine uncertainty that one treat-ment arm is more beneficial than the other.21 Althoughthe researcher might have a hypothesis of one treat-ment being more beneficial, there must be insuff-icient evidence to prove that this is true. In other words,there cannot be a reason to prefer one treatment overanother.22 For example, in the study of silicone meta-carpophalangeal joint arthroplasty (SMPA),23 the au-thors were unsure of the long-term outcomes of thisprocedure. Although prior research indicated a short-term advantage of the SMPA procedure, it was basedon retrospective, uncontrolled studies. Because the reg-ulating IRB would not allow patients to be randomizedto a surgical group, rheumatoid arthritis patients withmetacarpophalangeal joint destruction were given theoption to enroll into the study as a surgical patient (tohave SMPA and be followed up medically) or a non-surgical patient (to be followed up medically only).

Table 2 describes how the SMPA group researchers

JHS �Vol A, F

handled various ethical study issues. If a physician–researcher believes treatment A to be superior to treat-ment B, he or she can perform a prospective cohortstudy involving treatment A only and compare theresults to published reports of treatment B. Thus, thephysician need not compromise what he or she feels isthe best care.

Study design

There are several important considerations of ethics inthe study design. The first is the type of study that willbe used. The researcher must think about the researchaim: Is the purpose to introduce a new intervention or tocompare 2 interventions? Is there already a standardtherapy? One study found that 13.5% of scientists admitto using inadequate or inappropriate study designswithin the 3 previous years.24 Although the random-ized, controlled trial is often considered the gold stan-dard of research, some research, especially surgicalresearch, cannot be conducted as a randomized, con-trolled trial. Surgical procedures are “difficult to stan-dardize, highly operator dependent, and exceedinglycumbersome to control and follow over long periods oftime.”25 Retrospective case studies are the predominantstudy design in surgical research,26 but these studies aresubject to bias and might not provide the level ofevidence necessary for evidence-based medicine. Incertain infrequent hand surgery diseases such as Kien-böck’s disease, in which the condition can take years todevelop, a retrospective cohort study or case controlstudy might be the only study design to provide infer-ence regarding the etiology of a rare disease. Appropri-ate study design must be considered to best answer theresearch question, or time and resources are wasted. Inthe previously mentioned prospective study of SMPAin rheumatoid arthritis patients, the researchers initiallyconsidered a randomized study design to randomlyassign patients to a surgical cohort or to a nonsurgicalcohort. However, they felt that patients have a strongpreference for whether or not to have surgery, andtherefore, few patients would consent to being random-ized. The prospective comparative design still allowsthem to answer their research aims while maintainingpatient autonomy.

In the study design, the researcher must determine abalance in which the benefits outweigh the burdens(beneficence) and the risks are minimized (nonmalefi-cence).5 These principles are introduced in the Nurem-berg Code and the Declaration of Helsinki. Sham sur-gery has been criticized for not minimizing the risk ofharm in the placebo group, whose members are sub-

jected to the risks of anesthesia, infection, and bleeding

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THE ETHICS OF CLINICAL RESEARCH 311

that are present with surgery. However, it is one of thebest study designs to determine the efficacy of an inva-sive surgical procedure. This was proven by the shamsurgery study of arthroscopic knee surgery for osteoar-thritis patients that showed arthroscopic lavage or de-bridement were no better than the placebo (sham pro-cedure).27 Some have argued that it is unethical to usea less risky study design to determine whether a givensurgery works, if that study design is not capable ofanswering the question.28 Similarly, others have arguedthat is unethical to implement a surgical techniquewhen there are insufficient evidence-based results.25

As introduced in the Belmont Report by the principleof justice,11 the researcher must ensure that the subjectpool will not be biased when determining the inclusionand exclusion criteria of the research subjects. Being

TABLE 2. Ethical Issues and Solutions by the SMPA

Ethical Issue

Protection of human subjects Each site’s institu

This study was asagency (Nationseparate from th

Obtaining adequate sample size Patients were recrsites allowed foincome.

Due to difficulty iDSMB grantedstatistician confithe study aims.

Clinical equipoise The investigatorssurgical cohort

Study design Due to an inabilityparticipate in—could have sele

Inclusion and exclusion criteria All patients had athey would be ein the surgical o

Patients with comexcluded from tin terms of patie

Original inclusionolder patients wsurgery due to searly in the stud

Patient recruitment Because some subrecruited by trai

Data analysis A statistician was

Authors Members of the Snot actively invAcknowledgme

Publication Study is registered

too stringent with the eligibility criteria will limit the

JHS �Vol A, F

ability to generalize the research results. Results thatapply to only a select group of people are not beneficialto society. It is also unethical to include patients who donot meet the research criteria or to exclude patients,without reason, who could benefit from the research.Similarly, the researcher must determine the inclusionor exclusion of vulnerable subjects (defined by theDepartment of Health and Human Services as children,pregnant women, human fetuses and neonates, or pris-oners).29 A vulnerable subject is one whose ability toprotect himself or herself is absent or diminished.30 Ifvulnerable subjects are included, the investigator mustspecify what additional safeguards will be provided toprotect them. For example, pregnant women must begiven adequate information about the risks and benefitsto themselves, their pregnancies, and their fetuses.30

roup Researchers23

Solution

l review board (IRB) approved this study.

d a Data and Safety Monitoring Board (DSMB) by the fundingtitutes of Health), which monitors data and adverse eventsB.

from 3 sites: 2 in the United States and 1 in England. The 3eased sample size and patient diversity in terms of race and

aining the original targeted recruitment of 200 subjects, theission to reduce the number of subjects to 150. The studythat the study would still be adequately powered to complete

unsure of the long-term effects of SMPA. Thus, neither thee nonsurgical cohort was favored as the beneficial treatment.

andomize, patients were allowed to choose which cohort tocal or nonsurgical. A limitation was that the nonsurgical cohortbias by older subjects who did not want surgery.

mum degree of hand deformity to participate, meaning thatle for the SMPA procedure no matter whether they chose to besurgical cohort.

conditions who would not be eligible for surgery weretudy, so that the surgical and nonsurgical cohorts were similararacteristics.

ria set upper age limit at 75 years of age to avoid a bias ofad long-standing rheumatoid arthritis and were ineligible for

metacarpophalangeal disease. When this proved to be untruee age limit was increased to 80 years.

were patients of the physician researchers, all patients wereesearch assistants.

lved from the study conception.

Study Group who assisted in conducting the study but werein writing the manuscript were included in the

ction of published papers.

unique identifier NCT00124254 at clinicaltrials.gov.

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Other individuals, such as students, residents, employ-

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312 THE ETHICS OF CLINICAL RESEARCH

ees, patients of the investigator, those with cognitiveimpairment, and those who are economically disadvan-taged are considered special populations because theymight be subject to coercion to participate in a study.30

Again, if included, the investigator will most likelyhave to specify how these individuals will be safe-guarded. For example, a trained research assistant canrecruit patients of the investigator so that the patients donot feel undue influence to participate or feel that theirmedical care will be affected by their participation ortheir refusal to participate.

In designing the study, a statistician can assist indetermining the a priori sample size. A sample size thatis too large will waste money and, as previously men-tioned, it is also unethical to include patients unneces-sarily. A sample size that is too small could lead to alack of statistical power. Lack of statistical power couldlead to a beta error, whereby the null hypothesis—nodifference between treatment groups—is acceptedwhen it is, in fact, not true. A small sample size has alsowasted the time of those conducting and participating inthe research because, most likely, the negative findingswill not be published. The Office of Research Integrityof the Department of Health and Human Services statesthat “research has no value if it is not made public.”31

Because power is based on the primary outcome, onemust be cautious of data that focus on statisticallysignificant secondary outcomes because the primaryoutcome was statistically nonsignificant. Boutron et alfound that, in 72 published parallel-group RCTs withstatistically nonsignificant primary outcomes, half ofthem had some sort of “specific reporting” in theirconclusions to distort the interpretation of their results,such as not acknowledging the statistically nonsignifi-cant findings.32

Most likely, all the issues discussed earlier will becovered when the researcher applies for IRB approval.The IRB will probably require a written protocol of thestudy, as well as a written informed consent form. TheBelmont Report states that informed consent means thatsubjects have been given sufficient information, inves-tigators have ascertained that a subject comprehends theinformation, and the subject consents voluntarily, with-out undue influence or coercion.11 The information inTable 3 must be provided in the consent form to theprospective subject or the subject’s legally authorizedrepresentative in language that is understandable to himor her (medical terminology should be replaced with layterms, and readability should be between 6th and 8thgrade levels33). Foreseeable risks should include therisks of confidentiality breaches, who will see the data,

and how it will be protected (eg, stored in a locked

JHS �Vol A, F

cabinet). The subject must be given ample time todecide whether to participate. Ideally, the subjectshould be taken into a private room to discuss studyparticipation, read over the consent form, and ask anyquestions. If the subject chooses to participate, he or sheshould sign the consent form and be given a copy.

The consent form should clearly describe any ran-domization that will occur. It is difficult for most peopleto understand randomization.34–36 Even after signing aconsent form that tells patients they will be randomized,many people might feel that they are being placed intothe treatment group that has been determined to providethe best medical treatment for them.26 In the previouslyreferenced sham surgery study involving knee arthros-copy,27 consenting patients were required to write thefollowing statement in their chart: “On entering thisstudy, I realize that I may receive only placebo surgery.I further realize that this means that I will not havesurgery on my knee joint. This placebo surgery will notbenefit my knee arthritis.” A predetermined randomiza-tion scheme will ensure that patients are placed into aparticular treatment group truly at random and not byphysician preference, which could bias the study sample.

Sources of research funding and financial interests

TABLE 3. Necessary Information for InformedConsent Document29

1. A statement that the study involves research2. An explanation of the purposes of the research3. The expected duration of the subject’s participation4. A description of the procedures5. Identification of procedures that are experimental6. Foreseeable risks7. Benefits8. A description of alternative treatments9. How confidentiality of records will be maintained

10. Compensation11. Explanation of medical treatments if research-related

injury occurs12. Contact information for researchers or if research-

related injury occurs13. A statement that participation is voluntary, there is no

penalty for refusing to participate, and the subject candiscontinue participation at any time

Additional Elements, as Appropriate:

14. A statement that there might be unforeseeable risks15. Circumstances in which subject’s participation can be

terminated16. Additional costs to the subject17. Consequences if a subject chooses to withdraw18. Statement that new findings related to the subject’s

willingness to participate will be provided19. Approximate number of subjects involved

should also be disclosed to the research subjects in the

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THE ETHICS OF CLINICAL RESEARCH 313

consent form. Most research subjects want to know aboutthe researchers’ financial relationships, even though itmight not affect their decision to enroll into the study.37–38

Study execution

The next phase is execution. During study execution,subject recruitment and consent should ideally be con-ducted by trained research personnel and not by thephysician–researcher. This will avoid patient coercion.Patients with debilitating medical conditions might besusceptible to influence due to their willingness to con-sider any form of treatment.39 They might not under-stand that research is not designed as a form of treat-ment, which can cause them to underestimate risks andemphasize benefits.40 Research personnel must ensurethat the subject is indeed informed when giving in-formed consent. These issues were faced and ideallyhandled for the innovative hand transplantation proce-dure. In this situation, each hand transplant candidatewas asked to name a patient advocate to “assist in theprocessing of technical information, risk-benefit analy-sis, and thoroughness of informed consent.”41 In thisunique situation, a psychiatric interview and psychiatrictesting were also used to ensure that the patient under-stood the benefits and risks and to assess their decision-making capacity.42

The study should be carried out as stated in theprotocol. Amendments in the study design or consentform should be submitted for approval to the IRB.

Data analysis

Data analysis should always be hypothesis driven. Em-ploying a statistician in the study design phase shouldensure that the data are not “fished” for points of inter-est and then analyzed. Furthermore, some researchersmight be eager to analyze the data as they are beingcollected and before the target sample is reached, in thehopes of ending the study early. However, such data“peeks” with multiple statistical testing can greatly in-flate the type 1 error rate (the probability that the nullhypothesis is inappropriately rejected).43 For example,if 100 statistical tests are run on the same data, it isexpected that up to 5 would be statistically significant atp � .05 even if no true differences exist.13

The researcher must avoid any data falsificationand/or fabrication by any member of the research team.One study found that 15.3% of scientists had droppedobservations or data points from analyses “based on agut feeling that they were inaccurate.”24 The conse-quences of data fabrication can be severe and longlasting. In 1981, a panel of scientists was appointed by

the National Institutes of Health to investigate a Har-

JHS �Vol A, F

vard Medical School research fellow who was sus-pected of data falsification. The research fellow wasfound guilty and was barred from receiving federalresearch funds for 10 years. Five of his published pa-pers were retracted, and the research laboratory wasasked to repay $122,371 of National Institutes of Healthfunds provided for the project in which the results werefabricated. The National Institutes of Health recom-mended an inspection of the laboratory to prevent sim-ilar misconduct.44 In dealing with data falsification, thejournal Science has recommended to “red flag” studiesthat claim major breakthroughs in high-visibility fieldsor studies in which authors could gain financially fromthe publication.7

Publication and reporting

When reporting research findings, it is important toreport them accurately and promptly. The ConsolidatedStandards of Reporting Trials (CONSORT) statementis a valuable checklist for accurate reporting of trialresults.45 Prompt reporting allows for the possibleadoption of new surgical techniques or therapies thatcan reduce patient suffering.

Redundant publication is another breach of researchethics. Redundant articles are those that report the samestudy in 2 journals or split a study into 2 or more partsand submit each to separate journals. Redundant articlescan distort the estimate of treatment effects when thesame patient sample is included more than once inmeta-analyses.46 Redundancy can also overemphasizethe importance of the findings.47 Journals often requireauthors to declare that the submitted manuscript has notbeen published or submitted for publication elsewhere.Requiring clinical trials to be registered allows for iden-tification of the primary data source if a researcherattempts to split the results from one study sample intonumerous articles.48

Although authorship is probably not considered bymost to be an ethical concern, authors are responsiblefor the integrity of the research.49 Authors are consid-ered those who have made substantive intellectual con-tributions to a published study,50 but it is difficult todetermine responsibility when there are numerous au-thors for 1 manuscript. One study involving an interna-tional collaboration had 976 authors!51 Many journalsnow require manuscripts with multiple authors to indi-cate the role of each author and to list other contributorsin the acknowledgment section.

Scientific journals have had to amend their reviewpractices to identify and manage scientific misconduct.Editors often rely on the reviewers to alert them to any

submitted paper that exhibits suspicious material. The

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314 THE ETHICS OF CLINICAL RESEARCH

Best Practice Guidelines on Publication Ethics has beenwritten to “offer journal editors a framework for devel-oping and implementing their own publication ethicspolicies and systems.”48 It provides a guide for howeditors can handle various ethics dilemmas in publica-tions, such as fabricated data and plagiarism. Further-more, the International Committee of Medical JournalEditors has developed the “Uniform Requirements forManuscripts Submitted to Biomedical Journals.”50

These requirements include the ethics principles in theconduct and reporting of research.

There are many ethics concepts to remember whenconducting clinical research, from the conception, de-sign, execution, analysis, publication, and reporting of astudy. However, it is possible to obtain valuable out-comes that can guide treatment while also safeguardingthe subjects who are devoting their time and effort toparticipate in research studies. It must not be forgottenthat the subject’s health comes first and foremost andthat he or she is most likely entering the treatmentfacility as a patient to be treated for an illness ratherthan as a research subject. Care must be taken at theonset of a study to ensure that all the phases conform toethics standards.

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