Ethical Considerations in Clinical Trials

Matthew Whalen1,*, Felix Khin-Maung-Gyi1, Ann L. Wambolt2

1Chesapeake Research Review, Inc., 7063 Columbia Gateway Drive, Columbia, MD, USA 2Bristol-Myers Squibb, USA

Copyright © 2004 John Wiley & Sons, Ltd. Qual Assur J 2004; 88, 172–176. DOI: 10.1002/qaj.279

Key Words

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Preface

The authors of this article had the pleasure ofbeing participants on a panel devoted to the arti-cle’s title topic at the 2003 Society of QualityAssurance (SQA) Annual Meeting in Washington,DC, USA. The panel was moderated by Ann L.Wambolt (nee Douglass) of Bristol-Myers Squibb;and also included the insights of Bonnie M. Lee ofUS Food and Drug Administration (FDA).

Ann posed a range of scenarios to the panelfor their consideration. The subjects includedethical issues relating to Phase I research and‘professional subjects’; complications of ‘thera-peutic misconception’ and subjects involved inresearch on life-threatening illnesses; differenttypes of potential conflicts of interest; and com-pensation to subjects, physicians, and studystaff.

Here, rather than attempt to capture what wassaid verbatim in the course of the panel and thesubsequent audience participation, we are pro-viding a summary of the ethical and public policy-related underpinnings for our comments duringthe session. We have chosen to do so more forthose who were unable to attend the session aswell as to provide further perspectives for thosewho participated in the discussion.

The opinions expressed in this article aresolely those of the authors and do not representthe opinions, positions or views of theiremployers.

Ethics in the Context ofClinical Research

Ethics is no longer the privileged domain of a fewacademicians, nor of Institutional ReviewBoards/Ethics Review Committees (IRBs/ERCs)overseeing clinical trials. Ethical considerationsimpacting multiple aspects of the conduct ofresearch are central to clinical research. As aresult, there are ethical dimensions to everyaspect of clinical research:

● from the design of the protocol (and evenearlier) through the dissemination of infor-mation at the conclusion of the trial (andsubsequently);

● from an organization determining strategi-cally what to study to what protocol writers,

*Correspondence to: Matthew D. Whalen, President, ChesapeakeResearch Review, Inc., 7063 Columbia Gateway Drive, Suite 110,Columbia, MD 21046, USA. E-mail: mwhalen@irbinfo.com

Summary

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legal counsel, regulatory affairs professionals,project managers, investigators, studycoordinators and quality assurance profes-sionals, including auditors, monitors, andmanagers, do; and, no less,

● from executive corporate and institutiongovernance to start up biotech/drug/devicestrategic decisions made in the interest ofenhancing shareholder wealth and/or orga-nizational direction.

The two most relevant aspects in this thor-ough-going sense of ethics and clinical researchare:

● Understanding and applying ethical princi-ples (here, we suggest five) in variousaspects of core clinical research processes,thereby assuring good human subject pro-tection as well as good clinical research;and,

● Developing and maintaining a culture ofconscience infusing all clinical researchprocesses as a proactive strategy thatinsures actual application of conscience aswell as fostering a ‘culture of compliance’(with both regulations and institutional pro-cedures); not to mention contributing other-wise to the bottom line in ways such ashigher key person and employee retention,process improvement, and risk managementwhen managers and employees share thisculture.

Five Guiding EthicalPrinciples

In a fundamental way, the success of clinicalresearch activities relies on experience, commonsense, and, we suggest, guiding ethical princi-ples for planning and acting. In clinicalresearch, the enterprise is fortunate to be ableto resort to the three that are also the basis ofUS federal regulations, articulated in TheBelmont Report [1], Respect for Persons (oftensynonymously referred to as Autonomy),Beneficence, and Justice and which also have along history in Western culture. Having regula-

tions founded in ethics is not a luxury manyindustries, or countries, have.

There are two additional guiding principlesthat can also be applied to assist the clinicalresearch leader and professional to deal withtheir ethical challenges. Both emphasize impor-tant aspects of the core three, especially Respectfor Persons and Justice. They are Permissionand Compassion. An additional benefit in evok-ing the latter is that it has particular signifi-cance beyond, as well as within, Westerncultures.

In applying these principles to guide an ethicalanalysis of an issue or situation, it is important toemploy as many as are appropriate. As we con-sider each briefly below, however, we will simplyindicate a ‘lead’ principle as an introductoryillustration.

1. Permission: We begin with the principle ofPermission, it is: ‘Do not do to others that whichthey would not have done unto them, and do forthem that which one has contracted to do’ [2].Permission, here, is really the principle ofinformed decision-making which goes beyondinformed consent. It is contracting – written andverbal – in an ethical, if not legal, sense.

In light of Permission, decision-making isfounded on an arrangement – one might even saypart of the larger social, or public, contract –involving all parties (colleagues as much as, forexample, investigator/coordinator and potentialsubject) in a dynamic give-and-take. Decisionsare made proactively in its light – or reactively, toshore it up when threatened. The more towardthe latter, the greater the potential ethicalconcern.

The ‘therapeutic misconception’ issue isone that lends itself to ethical analysis begin-ning with the Permission principle. One result-ing consideration: How truly informed adecision is one that is made when no otheroptions exist? Equally, how truly informed is adecision when no other options are believed toexist? And, how truly informed is a decisionwhen no other options are presented to a poten-tial subject?

Undue influence is another concern that canbe viewed as an issue of Permission.

Copyright © 2004 John Wiley & Sons, Ltd. Qual Assur J 2004; 88, 172–176.

Ethical Considerations in Clinical Trials 173

2. Beneficence: The principle of Beneficence,‘Do[ing] to others their good’† is inclusive of all‘others’ and multiple ‘good.’ In this construct,Beneficence goes beyond the Hippocratic versionthat stresses physical benefit or lack of harm.‘Good’ expands to embrace the psychological,social, and economic good; and more. Beneficenceis the context from which leadership and ‘execut-ing’ decisions need to be made – motivated by‘self’ and ‘other’ interests.

Contemplating the ‘professional subject’ mov-ing from one Phase I trial to another is particu-larly amenable to invoking the Beneficenceprinciple as a point of departure, consideringboth the impact on the subject and the impact onthe ‘cleanliness’ of the resulting data.

3. Justice: The principle of Justice can be suc-cinctly described as ‘equitable benefits for equi-table risks’. That is, those that experience therisks need to experience the benefits. This princi-ple is particularly useful in considering interna-tional research issues, especially in developingand re-developing countries where drawing ‘real-world’ distinctions between clinical care and clin-ical research are particularly vexing. Matters ofcompensation to study staff and subjects can alsobe scrutinized using this principle.

4. Autonomy or Respect for Persons:Implementing the principle of Autonomy, orRespect for Persons, carries the responsibility fortaking into account the individual as an individ-ual, not simply as a member of a group.

Perhaps in a special way for clinical research,both Justice and Autonomy place an emphasis onthe individual, reminding professionals that one-size decisions do not, frequently, fit all.

These principles may be fruitfully employed inworking through the situation of research thatoffers potential benefit to those who suffer fromthe same disease longer-term, but little or nodirect benefit to the individual subject.

5. Compassion: Finally, Compassion, as aprinciple, is the foundation of the other fourprinciples, and an especially useful one for exam-ining the ethical conduct of research profession-als themselves.

It emphasizes that, fundamentally, ethics is anintersubjective reality, to use a formal term; or,less philosophically-speaking, involving a personengaging, interacting with others where ‘enlight-ened self-interest’ can be achieved throughachieving the interests of others.

Accordingly, for key process determinations,Compassion, like Beneficence, is not only the con-text from which one should make decisions(driven by other as well as self interests) but alsothe context of the decision itself, the dialog orcommunication; as well as the characteristics ofthose same decision-makers themselves as need-ing to demonstrate generosity and humility if act-ing ethically.

One might reach some interesting conclusionsby applying Compassion-based analysis to con-flicts of interest; then reviewing the resultsthrough the Beneficence filter.

A Culture of Conscienceand Moral Courage

Legislation, regulation, and litigation can go onlyso far in ensuring the efficiency and effectivenessof the research side of the healthcare coin – theone that deals with new, different, novel therapies,often for chronic and devastating illnesses.Beneath legislation, regulation, and litigation mustbe the bedrock of moral courage. Beyond legisla-tion, regulation, and litigation must be an atmos-phere that fosters the exercise of moral courage.

Moral courage is required to engage vigorouslyin the debates and discussions needed to makesound decisions in clinical research – embracingexecutives of product development companies,sponsors of research, physician investigators andstudy coordinators, IRB/ERC participants, andthe public at large as consumers of researchresults.

Moral courage is a way of conduct, behavior,and thinking – related to the fundamental fabric

174 M. Whalen et al.

Copyright © 2004 John Wiley & Sons, Ltd. Qual Assur J 2004; 88, 172–176.

†‘Preferred methods of control [over government or institutionalsanctions] include cultivation of an atmosphere of mutual trust …to promote in researchers and in sponsors the capacity for ethicalconduct of research.’ Council for International Organizations ofMedical Sciences (CIOMS), International Ethical Guidelines forBiomedical Research Involving Human Subjects,’ Guideline 2,September 24, 2002. Emphases are authors’.

of being a person – characterized by the five guid-ing principles of Autonomy, Beneficence, Justice,Permission, and Compassion. It is in this sense ofindividuals – professionals in clinical researchthroughout the enterprise – exercising moralcourage that a culture of conscience is establishedand maintained, one that is a critical complementto a culture of compliance.

Importantly, these two cultures have beenidentified as the cornerstones of the activities ofthe Office of Human Research Protections(OHRP) of the U.S. Department of Health andHuman Services (DHHS) as articulated by theOffice’s founding Director, Dr Greg Koski.‡

Moral cowardice – the abject opposite of moralcourage – is the failure to recognize that morallycourageous behavior is a requirement of one’sown profession on a regular and routine basis; asmuch as it is arrogance and greed (the opposite ofgenerosity and humility) prevailing in a givensituation.

It is also abrogating the responsibility to beself-reflective: What is the real outcome of myactions apart from a therapeutic or knowledge-enhancing goal? Or, more essentially, why am I inthis profession and business in the first place?But, having mixed motivation does not automati-cally constitute a failure of moral courage. Whatmotivation prevails may.

Applications, I

Developing and maintaining a culture of con-science may be the most persuasive argument formandating ethics training – as well as GCP train-ing – for all of us involved in clinical research.But this education needs to go beyond an intellec-tual exploration of basic concepts. Again, wereturn to the importance of the emphasis onapplied ethics in our industry.

Fortunately, those involved in the clinicalresearch enterprise are, by and large, intelligent

individuals with more than passing common senseand sensitivity to the needs of patients-turned-subjects. This is a strong foundation for recep-tiveness to ethics training.

However, formal training or continuing educa-tion for healthcare professionals is not noted forbeing inclusive of bedside manners or socialskills, much less moral philosophy. What skillsare developed are, for the most part, from ‘on-the-job training’.

Being exposed to applied ethics, even taking itquite seriously, is not sufficient. Developing one’sability to understand one’s own motives is theinfrastructure on which an appreciation of ethicsneeds to be built. To do so, both psychological andspiritual counseling are useful avenues. Anotheris self-study – reflection on the cognitive andvalue foundations of one’s identity and role.

Training, education, counseling, and self-studyare not the only avenues to development of moralcourage. Having formal structures in place alsocontributes to encouraging a key element of moralcourage, self-reflection.

Human Research Protections Programs(HRPPs) are frequently viewed only from thepoint of view of the administrative paperworkentailed in accreditation and certification. Athorough-going HRPP has in place a system ofcommunications and checks and balances that gobeyond the letter of the regulations and guidanceof federal, or international, authorities. Part ofsuch a system’s very existence is to serve as areminder to consider carefully what one’s role inresearch is and what the implications are.

In addition, HRPPs can contain certain roleswhose primary function is to serve as a con-science, such as an ombuds-like role, to preservethe integrity of the system. These roles can beeffectively distributed, for maximum impact, pro-viding there is clear and routine communicationamong them. They can range from a chiefresearch officer and chief privacy officer to thepresence of bioethicists on various Boards andCommittees overseeing research.

An HRPP function within sponsor andClinical Research Organisations (CRO) can par-allel that being encouraged within healthcareinstitutions and IRBs. In addition, some sponsors

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Ethical Considerations in Clinical Trials 175

‡Dr Koski developed and used the notion of the two culturesthroughout his tenure at OHRP, presenting them orally in publicpresentations at the Association of Clinical Research Professionalsand Drug Information Association national conferences in 2001, forexamples.

are relying more and more on scientific and ethi-cal review panels or outside consultants to pre-view proposed studies.

The danger, of course, is relying on structuresand roles effectively reducing moral courage toStandard Operating Procedures (SOPs); hence,the need for the clinical research professional toassume responsibility for developing skills of eth-ical analysis and self-reflection. Indeed, onemight suggest that a powerful signal indicating theneed for self-correction is when a clinicalresearch professional begins to emphasize theimportance of SOPs before her or his own inten-tions to conduct ethical research studies.

Applications, II: A FinalNote

For at least a century, clinical research has been avictim of its own successes: the publics of theworld expecting miracles (‘magic bullets’ to use anexpression of the popular media of the 1920s)without risks (the specter of ‘guinea pigs’ embla-zoned on the cover of Time magazine).

And lately, for the last decade, clinicalresearch has also been a victim of its own publiclyrecorded failings: arrogance and greed leading totragic miscalculations.

The more ethical principles are consideredand used to develop and drive public under-standing of clinical research, the better thechances for a more thorough-going (meaning real-istic) appreciation for and acceptance of clinicalresearch as a whole.

In dealing with public understanding, there isanother aspect transcending the context of the

clinical research experience itself – that of lawand public policy. Political winds blow as publicconstituencies dictate – or, at least as they areperceived to dictate. Public Policy-makers doindeed have a profound impact on our enterprise– as ‘final authorities’. Important adjuncts arethe judicial branch of government and the legalcommunity who refine policy dictates in courtdecisions.

As we all continue to wrestle with the risks andbenefits of clinical research, two differentapproaches seem to be favored to improve humanresearch protections. ‘Mutual assurance’ (HRPP)systems tend to be favored in the United States;and, in international discussions, ‘an atmosphereof mutual trust’ appears to predominate. (seefootnote†). Regardless, the emphasis is on mutu-ality – whether of the nature of formal documen-tation or of personal and professionalintentionality.

Mutuality, in our view, has deep roots in moralcourage; no less, the Eastern and Western tradi-tions under-girding it. It also emphasizes theshared-ness of clinical research – the sharing ofbenefits, risks, and responsibilities – lest we veeronce more too closely to paternalism or devolveinto anarchy of either competing fiefdoms orabdications of accountability.

References

1. The Belmont Report – Ethical principles and guidelines for the

protection of human subjects of Research. 18 April 1979. avail-

able at http://www.fda.gov/oc/ohrt/irbs/belmont.html

2. Tristram Engelhardt Jr, H. The Foundations of Bioethics (2nd

edn). Oxford University Press. New York, 1996, 123–124.

176 M. Whalen et al.

Copyright © 2004 John Wiley & Sons, Ltd. Qual Assur J 2004; 88, 172–176.