Central Ethical Dilemmas in Research Involving Children

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Central Ethical Dilemmas inResearch Involving ChildrenCarol A. Tauer aa Emeritus Professor of Philosophy , The College ofSt. Catherine , St. Paul, Minnesota, USAPublished online: 08 Sep 2010.

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Central Ethical Dilemmas in Research InvolvingChildren

Carol A. TauerEmeritus Professor of PhilosophyThe College of St. CatherineSt. Paul, Minnesota, USA

We are obligated to protect individual child subjects of research, yet it is alsonecessary to investigate the safety and efficacy of medical treatments that benefitchildren as a class. The federal regulations on research with children have pro-vided ethical guidance since 1983, but divergent interpretations persist. Sincevarying interpretations can lead to confusion and abuses, efforts are underway toclarify the criteria. Clarity is needed to protect individual child subjects fromharm while enabling ethical research to proceed. The “pediatric rule” and the“pediatric exclusivity” incentive are important policy initiatives for promotingsound research on the medical treatment of children.

KEY WORDS: drug testing, federal research regulations, pediatric rule, pediatric ex-clusivity, research ethics, research involving children

I. THE HISTORICAL CONTEXT

In discussing research involving children, we are immediately confrontedwith two concerns that are in ethical tension with each other. On the onehand, children have been described as “therapeutic orphans” because ofthe absence of adequate research on the treatment of children, especiallythe inadequate testing of drugs and biologics used in the treatment ofchildren (Shirkey, 1968; Coté et al., 1996). On the other hand, a series ofabuses in human subjects research, particularly abuses involving per-sons who were unable to give consent to their own participation, has ledsome to believe that such research should generally be avoided (Lederer

Presented at Friends Research Institute’s Conference on Ethics of Research with Children, May5–7, 2002, held in San Francisco, California.

Address correspondence to Carol A. Tauer, Ph.D., Emeritus Professor of Philosophy, The Col-lege of St. Catherine, St. Paul, MN 55105.

and Grodin, 1994).When Congress established the National Commission for the Protec-

tion of Human Subjects in 1974, one of its mandates was to scrutinizeresearch involving children. After hearing testimony from experts whoheld widely differing views, and after extensive debate that was some-times contentious, the National Commission produced a set of criteria togovern research with children (National Commission, 1977). With someadaptations, the Commission’s recommendations regarding children wereenacted into federal regulation in 1983 and have essentially remainedunchanged since then, although regulations governing research on neo-nates of uncertain viability and nonviable neonates were revised in 2001(Code of Federal Regulations, 1983; Code of Federal Regulations, 2001).In 2001, Congress extended the federal regulations on research with chil-dren to apply to research that is regulated as well as funded by the De-partment of Health and Human Services (DHHS), thus including re-search on drugs and medical devices that is regulated by the Food andDrug Administration (Food and Drug Administration, 2001a).

II. AN ETHICAL CHALLENGE

Research involving children continues to present an ethical challenge.On the one hand, we are obligated to protect individual child subjects ofresearch from being harmed or improperly used. On the other hand, thewelfare of all children depends on research to test the safety and effec-tiveness of medical procedures, drugs and biologics, and public healthmeasures. Such research is essential in order to provide benefits and toprevent harms within the population of children as a whole.

In general, we do not allow individual research subjects to assumesignificant risks unless there is also some prospect of benefit to them asindividuals. A purely utilitarian perspective might permit harming a smallnumber of individuals in order to achieve great good for a larger num-ber; however, the principles governing research ethics in the United Statesare explicitly not utilitarian. The level of risk to the individual subjectmust be limited by investigators and IRBs, regardless of the potentialvalue to society (Code of Federal Regulations, 1991; National BioethicsAdvisory Commission, 2001).

In the case of research subjects who are unable to consent to theirown participation, the level of risk must be limited even more carefully.Those who are charged with protecting children may not impose riskson an individual child for the sake of a benefit to other children. Thatstatement, of course, must be qualified; all of life involves risk. More-over, as noted earlier, if no research on children is conducted, then manychildren could be harmed.

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In an effort to balance these important ethical concerns, the NationalCommission developed several risk categories to be used in evaluatingresearch involving children. The Commission’s aim was to protect indi-vidual children who might be subjects in research while at the same timeallowing ethically appropriate research that had the potential to benefitchildren as a class.

A. Minimal Risk

The category of minimal risk is the baseline; it was defined this wayby the National Commission:

The probability and magnitude of physical or psychological harm that isnormally encountered in the daily lives, or in the routine medical or psy-chological examination, of healthy children (National Commission, 1977).

The current definition in the Common Rule is slightly different:

The probability and magnitude of harm or discomfort anticipated in theresearch are not greater in and of themselves than those ordinarily en-countered in daily life or during the performance of routine physical orpsychological examinations or tests (Code of Federal Regulations, 1991).

Research that involves no more than minimal risk to children may beconducted or funded under DHHS sponsorship or regulation (Code ofFederal Regulations, 1983).

This criterion seems to allow a wide range of types of research whileprotecting subjects of research from any significant harms; however,although the regulations have been in force for nearly two decades, dis-agreement persists regarding just what “minimal risk” means. Repeatedsurveys indicate that persons involved in research and pediatrics differas to whether particular procedures are minimal risk procedures; forexample, arterial puncture, gastric intubation, and lumbar puncture(Janofsky and Starfield, 1981; Lascari, 1981; Kopelman, 1989;Kopelman, 2000).

In addition, much ink has been spilled over the proper interpretationof the risks “ordinarily encountered in daily life.” If these risks varyfrom one population of children to another, whose daily lives constitutethe standard? The National Commission specifically identified the popu-lation as that of “healthy children” (although it did not address the issueof children whose daily lives might be more dangerous because of envi-ronmental hazards). The adjective “healthy” disappeared from the defi-nition several years later, when the DHHS issued final regulations onresearch policy (Department of Health and Human Services, 1981). Thepreamble to the regulations states:

Ethical Dilemmas in Research with Children 129

In light of the public comments . . . , HHS has reworded the final regula-tion to reflect its intention that the risks of harm ordinarily encountered indaily life means those risks encountered in the daily lives of the subjectsof the research (DHHS, 1981).

This interpretation has frequently been taken to be authoritative. Itappears to permit fairly risky or potentially harmful research, if the stan-dard is relative to the lives of groups of children who are seriously ill orwho live under dangerous conditions or in situations where they are de-prived of standard medical treatments. The DHHS interpretation, how-ever, was formulated not in the context of research involving children,but in the context of determining what research with adults could beapproved under a system of expedited review (Department of Healthand Human Services, 1981). Moreover, while there were over 500 com-ments on the proposed regulations, only 11 comments addressed the con-cept of “minimal risk,” and a subset of these 11 suggested the changethat was actually made (Department of Health and Human Services,1981).

It is more consistent with the overall rationale of the National Com-mission to interpret the risks “ordinarily encountered in daily life” as therisks that healthy children in moderately safe environments experience.As Loretta Kopelman argues in her careful study of risk:

It is morally unacceptable to locate children in places with increased risksof harm, and then use that increased risk to redefine “minimal risk” or“justify” higher research risks for them. One standard for all preventssingling out people or groups with higher daily risks in order to “excuse”higher research risks as minimal (Kopelman, 2000).

The National Bioethics Advisory Commission’s report on human sub-jects research takes the same position, recommending that the standardfor minimal risk be risks “that are familiar to the general population”rather than risks “encountered by particular persons or groups” (NBAC,2001).

There are ways in which sick children might ethically be treated dif-ferently from healthy children as participants in research, but these spe-cial circumstances are addressed in later sections of the federal regula-tions and should not be incorporated into the concept of “minimal risk.”

B. Risks Justified by Benefits

If the risk to the subject of research is more than minimal, then othercriteria in the regulations may apply. Section 46.405 requires a balanc-ing of the risks and benefits of the research, much as would be done inoffering medical treatment. Research involving children is permissible

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when the risk is justified by the anticipated direct (medical) benefit tothe subjects and when the benefit/risk ratio is at least as favorable as inalternative approaches, including the alternative of not participating inresearch (45 CFR 46, 1983).

C. Minor Increase over Minimal Risk

The National Commission struggled over the issue of whether to al-low sick children to participate in somewhat more risky research if itwas not expected to benefit them personally, but had the potential tobenefit other children who had the same ailment. Vigorous debate led toa compromise criterion that was highly nuanced. According to 46.406,research that involves a “minor increase over minimal risk” is permit-ted, provided that (1) the research procedures are commensurate withthose already inherent in the subjects’ situation; (2) the research is “likelyto yield generalizable knowledge about the subjects’ disorder or condi-tion”; and (3) the anticipated knowledge “is of vital importance for theunderstanding or amelioration of [that] disorder or condition” (45 CFR46, 1983).

Once again, there is little consensus on the application of the conceptof a “minor increase over minimal risk.” Since the baseline concept of“minimal” is not firmly established, it is nearly impossible to identifywith any consistency a “minor increase” over minimal risk.

Furthermore, the appropriate interpretation of “disorder or condition”continues to be hotly debated. The transcripts and final report of theNational Commission are explicit in referring to “a disease process” and“disease states” (National Commission, 1977; Tauer, 1994); however,applications of this criterion by various review boards and IRBs haveextended the notion of “condition” to a wide range of populations, in-cluding children in particular environmental situations and children iden-tified by statistical or predictive measurements as being at increasedrisk.

D. Examples

Disagreements about the interpretation of various concepts in the re-search regulations are not merely speculative or theoretical. When vari-ous IRBs select differing interpretations, they may also reach differentconclusions about the ethical acceptability of the same research proto-col.

Example 1. A randomized controlled trial (RCT) of growth hormonein girls with Turner’s syndrome (Prentice et al., 1989). This multicenter

protocol was approved by a number of IRBs but was rejected by theUniversity of Nebraska IRB. This IRB concluded that the placebo injec-tions (over 200), together with nontreatment of the placebo group withother available options, constituted more than a minor increase overminimal risk and was a risk that was not justified by potential benefit tothe subjects in the placebo group. Hence they could not approve theprotocol.

Example 2. A placebo-controlled RCT of growth hormone in chil-dren with idiopathic short stature (Tauer, 1994). This is an ongoingNIH-sponsored trial that was suspended in 1993 because of objectionsbut resumed after a review committee approved it, despite dissent byone of the committee’s co-chairs. Besides differences of opinion on thelevel of risk, mainly the risk to children in the placebo group, discus-sions of this protocol disagree as to whether short stature is the type of“condition” that 46.406 is intended to apply to. Classifying shortness asa “disorder or condition” seems to be premised on the view that short-ness, per se, is a medical problem or a disabling condition, a view that isdebatable (Tauer, 1994; Tauer, 2000).

Examples 3 and 4. In two other controversial studies, the ethicalassessment depends heavily on one’s interpretation of “the subjects’ con-dition,” as this interpretation determines whether 46.406 applies. An NIH-sponsored study of metabolism and obesity that included both obesechildren and nonobese children of obese parents was approved under46.406 after several reviews and much controversy. Initially the debatefocused on whether the risks to the children in the study were minimalrisk or greater. Later, however, the Office of Human Research Protec-tions (OHRP) accepted the IRB’s analysis that the research satisfied theconditions of 46.406. To make this finding, OHRP and the IRB had toassume that healthy nonobese children with obese parents had a “condi-tion” because they were statistically at increased risk of becoming obesethemselves (NIH, 2000; HSRAC, 2000; OHRP, 2001).

Some discussions of this study have cited an earlier study as a prece-dent. In that study, which involved administration of the drugfenfluramine, children with siblings who had been incarcerated werejudged to suffer from a “condition” because of their increased risk forbecoming delinquent themselves (NIH, 2000; HSRAC, 2000; Shamoo,2002).

Such expansive interpretations of the concept, “the subjects’ condi-tion,” go far beyond what the members of the National Commission hadin mind, as shown by transcripts of meetings and the Commission’s fi-nal report on research with children (Tauer, 1994). Although the inten-tions of that Commission do not necessarily bind all future generations,it is troubling that new interpretations arise without a coherent rationaleto support them. Currently the confusion appears to be increasing rather

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than the reverse; it has become sufficient to encompass an NIH official’sstatement that the term “condition” in 46.406 simply refers to the “con-dition” of being a child (OHRP, 2000; NHRPAC, 2000). Such an inter-pretation renders 46.406 meaningless, as it would allow “minor increaseover minimal risk” research with all children simply by virtue of theirbeing children.

Example 5. The Kennedy Krieger study of methods of lead paintabatement. This study was clearly aimed at benefiting children as a groupand had a public health purpose: To encourage landlords to use a cost-effective method of removing lead-based paint from their properties,thus enabling more urban children to live in safe dwellings. Even thejustices of the Maryland Court of Appeals, who were scathing in theircriticisms of this study, stated that “the general motives of all concerned. . . were, for the most part, proper” (Grimes v. Kennedy Krieger Inst.,2001).

In assessing the level of risk that could be justified for the sake of thisadmirable public health goal, there is disagreement among commenta-tors. Some argue that children who were already living in homes wherelead was a problem were benefited by any level of lead abatement. Hencethe risk they incurred by participating in the study might possibly bejustified by the benefit they received (Nelson, 2001). Other commenta-tors disagree with this assessment (see Kopelman, 2002). The KennedyKrieger Institute maintained that all subject participants benefited fromthe study (Kennedy Krieger Inst., 2001). Not only did the MarylandCourt of Appeals strongly disagree with this claim, but it described theresearch as “nontherapeutic” research that caused risk to all the childreninvolved (Grimes v. Kennedy Krieger Inst., 2001).

III. RESOLVING PROBLEMS

A. The Value of Consensus

Besides disagreeing on the meaning of significant concepts in theregulations on research with children, commentators and IRBs differ asto whether they think this variation is good or bad. The Committee onDrugs of the American Academy of Pediatrics (AAP) accepts “the lackof specificity of the regulations [that] allows for local interpretation anddefinition,” although they infer only that local IRBs “may interpret ordevelop guidelines . . . that are more limiting than the federal regula-tions” (AAP, 1995). In a presentation to the National Human ResearchProtections Advisory Committee (NHRPAC) at its first meeting in De-cember 2000, Duane Alexander, Director of the National Institute ofChild Health and Human Development, maintained that it was the “clear

intent” of the National Commission “that there not be any fixed nationalstandard of what minimal risk was,” and that differences between IRBswere “healthy and to be encouraged” (OHRP, 2000; NHRPAC, 2000).

When local IRBs develop differing interpretations of federal regula-tions, they become laboratories for testing various interpretations, some-what as the states of the United States have been viewed as laboratoriesfor testing a variety of social policies. However, an effective use of such“laboratories” requires that the different practices and their outcomes beshared and evaluated. Currently there are no systematic structures forsharing the practices and interpretations of different local IRBs and forassessing them in comparison with one another.

In addition, a standard that is too fluid can lead to abuses in which alocal IRB picks whatever interpretation will enable it to approve a study,perhaps because the goals seem noble (as in the Kennedy Krieger leadabatement study) or because the investigators are highly respected.Undoubtedly, the application of general principles to particular caseswill always involve the exercise of good judgment; however, that factdoes not exclude seeking a consensus or identifying paradigm cases thatclearly satisfy or do not satisfy a particular standard or criterion in theregulations.

B. Attempts to Clarify Standards

Recently a number of efforts to clarify standards and criteria haveemerged. These projects involve federal agencies and commissions andgo beyond academic discussion in journal articles.

The FDA’s document on “Additional Safeguards for Children in Clini-cal Investigations” gives very specific examples of minimal risk proce-dures: “clean-catch urinalysis, obtaining stool samples, administeringelectroencephalograms, requiring minimal changes in diet or daily rou-tine” (FDA, 2001a). These procedures are unquestionably very low riskand unproblematic. It would have been helpful for the FDA to suggestadditional examples of procedures it regarded as more than minimal risk,thus opening these examples for public comment. The document doesrequest comment on the meaning of a “minor increase over minimalrisk” and on the question of whether IRBs have the expertise to makethis determination (FDA, 2001a).

The Children’s Working Group of the NHRPAC has been chargedwith the task of clarifying significant concepts in the regulations. At thefull committee meeting on April 29, 2002, the Working Group presentedits preliminary report. In this report, the Working Group attempted toclarify the definitions of “minimal risk” and “a minor increase over mini-mal risk.” It also struggled to identify a balanced definition of “disorder

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or condition,” together with other criteria in 45 CFR 46.406, such as thecommensurability of research procedures with those in the subjects’ ac-tual or expected experience. While the transcripts of this meeting arethought-provoking, they indicate that more work is needed to reach anacceptable resolution of important and long-standing controversies inresearch with children (OHRP, 2000; NHRPAC, 2002).*

The National Bioethics Advisory Commission (NBAC) undertook anextensive study of ethical and policy issues in human subjects researchin 2001 (NBAC, 2001). The NBAC report recognized a need for changein the current system, including greater oversight and the inclusion un-der federal research policy of research that is neither federally fundednor federally regulated. With respect to research with children, it recom-mended that children be subsumed into a general category of vulnerablesubjects, within which different types of vulnerability would be recog-nized. In the report’s discussion of the assessment of risks and potentialbenefits, it proposed that “each component of a study should be evalu-ated separately,” and “potential benefits from one component of a studyshould not be used to justify risks posed by a separate component of astudy (p. xvi)”.

The NBAC proposal to eliminate special protections for children as aunique class does not seem to have generated much support. The sepa-rate-component assessment of risks and benefits is logically defensible,but the approach may be too cumbersome for most IRBs to navigate.For one thing, in making treatment decisions, clinicians are accustomedto weighing the risks and benefits of a course of treatment taken as awhole, and to take a different approach to assessing risks and benefits ina research protocol would be difficult.

A little-used provision in the federal research regulations might behelpful in resolving some problems in the interpretation and applicationof the regulations. If a local IRB finds that a protocol does not satisfy46.404-46.406, or is uncertain as to whether it does, then according to46.407, the protocol may be referred to the Secretary of DHHS. Afterconsulting with an expert review panel, the Secretary is to determinewhether the research risks are justifiable because of the study’s potentialfor understanding, preventing, or alleviating “a serious problem affect-ing the health or welfare of children” (45 CFR 46, 1983).

Until recently, this provision had been invoked only two times(Kopelman, 2000). Because of concerns raised over several studies in-volving children, however, IRBs are currently submitting a number of

*Unfortunately, the NHRPAC was in the midst of this work when its charter expired in summer2002 and was not renewed. This unanticipated action by the Bush administration seemed to be partof a broader plan for disbanding and possibly reconstituting scientific advisory committees(Margulies, 2002).

protocols for 46.407 review, resulting in a backlog. Because this situa-tion is new and somewhat unanticipated, it will be necessary to developprocedures for dealing with the requested reviews (Marshall, 2002).

The review process under 46.407, once it is functioning efficiently,may be very useful for handling research proposals that promise greatbenefit to populations of children, but that may impose risks on indi-vidual child subjects. For example, the investigators who designed thelead abatement study had a worthy purpose: to reduce the number ofurban children growing up in homes where lead paint was a hazard. Cana study with the goals of the Kennedy Krieger study be conducted ethi-cally? What would constitute an ethical research protocol? The reviewprocess described in 46.407 may help us answer such questions.

IV. POLICIES TO PROMOTE RESEARCH INVOLVINGCHILDREN

A consensus regarding what research with children is ethically ac-ceptable and what is not acceptable has the immediate purpose of pro-tecting individual child subjects; however, it also helps to ensure thatresearch involving children, when ethically sound, is encouraged ratherthan discouraged.

Consider, for example, the issue of testing drugs for use by children.Because of a history of exclusion in research, children as a whole sufferfrom being given nonvalidated treatments. They are exposed to risksfrom drugs that are not labeled for use in children but that pediatriciansfind useful and even necessary for treating their patients. Underdosingor overdosing may result, adverse effects not seen in adult populationsmay occur, or a potentially helpful drug may not be usable because ofthe lack of pediatric formulations. The younger the children, the moredifficult it is to extrapolate from adult data (Kauffman, 1994; FDA, 1998).

In 1998, the National Institutes of Health took the initiative of requir-ing that children be included in all human subjects research that is con-ducted or supported by NIH “unless there are scientific and ethical rea-sons not to include them” (NIH, 1998).

Also in 1998, the FDA issued its “pediatric rule,” aimed at increasinglabeling for use in children of drugs and biologics that are appropriatefor the treatment of children. A series of attempts by the FDA to encour-age pediatric testing and labeling on a voluntary basis had been largelyunsuccessful. The FDA pediatric rule requires that new drugs and bio-logical products be tested in pediatric as well as adult populations if oneof the following two conditions holds: (1) the product represents a mean-ingful therapeutic benefit over existing treatments for pediatric patientsor (2) it is likely to be used in a substantial number of pediatric patients.

C. A. Tauer136

The FDA may also apply the rule to already marketed products if either(1) or (2) holds and, in addition, the absence of pediatric labeling couldpose significant risks (through “off-label” use in children) (FDA, 1998).

The pediatric rule, while requiring testing of certain drugs for use inchildren, does not require any infringement of ethical standards for re-search with children (Tauer, 1999). As of April 2001, FDA-regulatedresearch involving children must follow the DHHS regulations on re-search with children, as found in Subpart D of 45 CFR 46. In addition,the FDA has published a number of guidances on the proper conduct ofresearch involving children (FDA, 2001a). The pediatric rule itself isvery flexible and allows waivers of pediatric testing under a number ofconditions, including ethical problems in testing a particular product.

Because of the obligation to protect children as subjects, the FDAdoes not allow pediatric studies to begin until the end of phase 2 testingin adults, with the exception of treatments for life-threatening or seriousdiseases that have no other adequate treatments. In this case, pediatrictesting may and should begin at the end of phase 1. Moreover, the FDArule does not necessarily require placebo-controlled pediatric trials inphase 3. A variety of alternatives may be proposed, such as active con-trol studies, placebo against a background of standard therapy, and phar-macokinetic studies (FDA, 1998).

At approximately the same time that the FDA was developing thepediatric rule, Congress enacted a provision to encourage the testing ofdrugs for use in children through “pediatric exclusivity.” First passed in1997 as part of the Best Pharmaceuticals for Children Act, the provisionwas reauthorized in January 2002 with a number of changes (Best Phar-maceuticals, 2002).

Pediatric exclusivity is intended to give manufacturers an incentiveto conduct pediatric studies by offering a reward—a 6-month extensionof the patent that protects exclusive marketing rights. The provision isan incentive, not a requirement. The FDA sends the manufacturer a writtenrequest for pediatric studies that would qualify a drug for the extendedpatent protection, or the manufacturer asks the FDA for such a request.

Pediatric exclusivity has been quite successful as an incentive to pe-diatric testing. As of February 2002, 53 drugs have received exclusivityand have been tested; but only 31 of these now have pediatric labeling,and in some cases it took over a year for labeling to be added (Roberts,2002). It does appear that the incentive of market exclusivity has beenused more often than the mandate in the pediatric rule. These two provi-sions operate in different ways, however, and each of them has its ownusefulness (FDA, 2001b).

Shortly after the pediatric rule was issued, three organizations filed alawsuit alleging that the FDA had exceeded its statutory authority byrequiring pediatric testing. The plaintiffs claimed that it was up to a

manufacturer, not the FDA, to determine uses of a drug for which itwanted approval and labeling (Ass’n of Amer. Physicians and Surgeonset al. v. U.S. Food and Drug Admin., 2001). Because the FDA wasunable to get this case dismissed, in March 2002 it asked for a delay inorder to consider suspending the pediatric testing rule for two years.During this time it would study whether the incentive of market exclu-sivity was sufficient to encourage pediatric testing so that the pediatricrule was not really needed (Lueck, 2002; Connolly, 2002).

I am not competent to evaluate the validity of the legal complaintregarding the FDA’s authority; however, I believe that the plaintiffs’ criti-cisms of the FDA rule based on ethical concerns are not valid (Con-sumer Alert, Inc., 1999; Plummer, 2000; Morrison, 2001). For example,they allege that the rule puts child subjects at risk because it requiresdrugs to be tested on children before they are proven safe in adults (thisstatement is not true). They claim that individual pediatricians will behampered in their “off-label” use of drugs for children if the FDA re-quires pediatric testing and labeling (this claim is not true; a physician isfree to use approved drugs off-label regardless). Plaintiffs further statethat “pediatricians who administer individualized care to patients theyknow, can judge prescription risks and benefits better than Beltway bu-reaucrats” (Plummer, 2000). Not only does this statement express arejection of evidence-based medicine, but years of experience withunderdosing, overdosing, and adverse effects of drug use in pediatricpopulations show that it is an unsupportable statement.

Pediatric exclusivity, if not supplemented by the pediatric rule, hassignificant limitations. It can be used only for drugs that have alreadybeen approved and marketed but that are still under patent. The incen-tive is most effective with manufacturers when it extends market exclu-sivity for drugs that are highly profitable whether or not they are thedrugs for which pediatric testing is most needed.

In contrast, the pediatric rule applies to drugs while they are in theFDA approval process. The rule may also be invoked to require testingof drugs that are no longer under patent, if there are concerns that thesedrugs are causing risks to children, or to subpopulations of children,such as newborns and infants (American Academy of Pediatrics et al.,2002; Waxman, Dingell, and Brown, 2002).

Fortunately, in the words of a New York Times editorial, “The Bushadministration came to its senses [April 19] on the issue of whether drugsshould be tested to ensure that they are safe and effective for children.”On that date, Tommy Thompson announced that the pediatric rule wouldnot be suspended. Instead, the FDA would solicit public comment as tohow the rule could be improved but would keep the current rule in placeuntil any revisions were made (New York Times, 2002; Kaufman andConnolly, 2002).

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A spokesperson for the American Academy of Pediatrics praised theadministration for its change of heart, noting that the AAP had workedvery hard to get the pediatric rule enacted and was very surprised by thethreat of its withdrawal (Kaufman and Connolly, 2002). Currently threesenators are proposing legislation to codify the pediatric rule. This leg-islation would clarify that the FDA has the authority to require pediatrictesting, hence making it impossible for legal challenges to that authorityto be successful (Reuters, 2002).

V. CONCLUSION

Research involving children presents a difficult ethical challenge. Weare obligated to protect individual child subjects of research, yet it isnecessary to conduct research on the safety and efficacy of medical treat-ments and public health measures in order to benefit and protect chil-dren as a class.

In 1977, the National Commission for the Protection of Human Sub-jects recommended ethical standards that permit research for the benefitof child health and welfare, while protecting the subjects of researchfrom harm. While these standards have guided research with childrenfor two decades, their application has been subject to varied interpreta-tions and continuing debate.

Such disagreements have not been merely theoretical but have led towide discrepancies in IRB approval or disapproval of particular researchprotocols. The uncertainty has also led to interpretations that are so broadas to be untenable, particularly regarding the scope of the term “condi-tion” in the regulation allowing an increased research risk in order tostudy “the subjects’ disorder or condition.”

Although some would argue that a variation in interpretation fromone IRB to another is healthy, I maintain that too much flexibility canresult in abuses, confusion, and an ensuing lack of trust in the systemsfor protecting human subjects. In their day-to-day operations, IRBs tendto be guided by what is spelled out in the federal regulations and inter-pretive documents. An IRB will hesitate to deny approval to a researchproposal unless its decision can be supported by reference to an officialor semi-official source. In practice, IRBs need specific guidance, andwith rare exceptions, they have neither the time nor the expertise to de-velop detailed and original arguments for their findings.

Thus it is crucial that federal agencies take steps to clarify the appli-cation of the criteria in the regulations on research with children. Notonly are these regulations particularly complex and somewhat ambigu-ous, but most IRB members are not specialists in pediatric treatment andresearch. Currently, the most promising federal initiative is the study

undertaken by the Children’s Working Group of the National HumanResearch Protections Advisory Committee. This work in progress is ex-plicitly aimed at clarifying the interpretation and strengthening the ap-plication of criteria in the federal regulations on research with children(OHRP, 2002; NHRPAC, 2002). [See footnote on p. 135 of this article.]

Besides serving to protect individual children from risk and harm,such clarification will also enable ethical research with children to pro-ceed and flourish. History and experience show that such research isessential for the health and welfare of children and needs to be encour-aged. The provisions of the FDA’s pediatric rule, which requires thetesting of drugs and biologics for use in children, and the pediatric ex-clusivity incentive in the Best Pharmaceuticals for Children Act, whichrewards manufacturers for pediatric testing, both serve a useful purpose.These public policy initiatives are intended to encourage the testing andvalidation of treatments for use in children while maintaining the high-est standards of ethical scrutiny to protect the child subjects of research.

REFERENCES

American Academy of Pediatrics (AAP) Committee on Drugs (1995). Guidelines forthe ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics95:286–294.

American Academy of Pediatrics, Ambulatory Pediatric Association, American Pediat-ric Society, Association of Medical School Pediatric Department Chairs, ElizabethGlaser Pediatric AIDS Foundation, and Society for Pediatric Research (2002). Letterto Tommy Thompson on the pediatric rule, March 22. Available at http://www.aap.org/advocacy/washing/fda%5Fletter.htm

Ass’n of Amer. Physicians and Surgeons et al. v. U.S. Food & Drug Admin. (2001). No.00-02898 (D.D.C., October 25).

Best Pharmaceuticals for Children Act (2002). 21 U.S.C. s 505A.Code of Federal Regulations, 45 CFR 46:101–124 (1991). Federal policy for the protec-

tion of human subjects. (The Common Rule.) Federal Register 56:28003–28016.Code of Federal Regulations, 45 CFR 46:201–207 (2001). Additional protections for

pregnant women, human fetuses and neonates involved in research. (Subpart B.)Federal Register 66:56778–56780.

Code of Federal Regulations, 45 CFR 46:401–409 (1983). Additional protections forchildren involved as subjects in research. (Subpart D.) Federal Register 48:9816–9820.

Connolly, C. (2002). FDA to suspend a rule on child drug testing. Washington Post,March 19, p. A10.

Consumer Alert, Inc. (1999). FDA’s rule challenged. Consumer Comments, December.Available at http://www.consumeralert.org/pubs/comments/NovDec99/FDA.htm.

Coté, C. J., Kauffman, R. E., Troendle, G. J., and Lambert, G. H. (1996). Is the “therapeu-tic orphan” about to be adopted? Pediatrics 98:118–123.

Department of Health and Human Services (DHHS) (1981). Final regulations amending

C. A. Tauer140

basic HHS policy for the protection of human research subjects. Federal Register46:8366–8391.

Food and Drug Administration (FDA ) (2001a). Additional safeguards for children inclinical investigations of FDA-regulated products: Interim rule. Federal Register66:20589–20600.

Food and Drug Administration (FDA) (2001b). Frequently asked questions on pediatricexclusivity (505A), the pediatric “rule,” and their interaction. Available at http://www.fda.gov/cder/pediatric/faqs.htm

Food and Drug Administration (FDA) (1998). Regulations requiring manufacturers toassess the safety and effectiveness of new drugs and biological products in pediatricpatients: Final rule. Federal Register 63:66631–66672.

Grimes v. Kennedy Krieger Institute (2001). 782 A.2d 807 (Md. 2001).Janofsky, B. A., and Starfield, B. (1981). Assessment of risk in research on children.

Journal of Pediatrics 98:842–846.Kauffman, R. E. (1994). Scientific issues in biomedical research with children. In M. A.

Grodin and L.H. Glantz (eds.), Children as Research Subjects: Science, Ethics, andLaw, pp. 29–45. New York: Oxford University Press.

Kaufman, M., and Connolly, C. (2002). U.S. backs pediatric tests in reversal on drugsafety. Washington Post, April 20, p. A3.

Kennedy Krieger Institute (2001). Lead-based paint study fact sheet. Available athttp://www.hopkinsmedicine.org/press/2001/SEPTEMBER/leadfactsheet.htm

Kopelman, L. M. (2002). Pediatric research regulations under legal scrutiny: Grimesnarrows their interpretation. Journal of Law, Medicine & Ethics 30:39–49.

Kopelman, L. M. (2000). Children as research subjects: A dilemma. Journal of Medi-cine and Philosophy 25:745–764.

Kopelman, L. M. (1989). When is the risk minimal enough for children to be used asresearch subjects? In L. M. Kopelman and J. C. Moskop (eds.) Children and HealthCare: Moral and Social Issues, pp. 89–99. Dordrecht: Kluwer Academic Publishers.

Lascari, A. D. (1981). Risks of research in children. Journal of Pediatrics 98:759–760.Lederer, S. E., and Grodin, M. A. (1994). Historical overview: Pediatric experimenta-

tion. In M. A. Grodin and L. H. Glantz (eds.) Children as Research Subjects: Sci-ence, Ethics, and Law, pp. 3–25. New York: Oxford University Press.

Lueck, S. (2002). FDA to suspend rules for testing drugs on children. Wall Street Jour-nal, March 19, p. B10.

Margulies, J. (2002). Bush administration allows research-protections panel to expire.Chronicle of Higher Education, September 18. Available at http://chronicle.com/daily/2002/09/20020918oln.htm

Marshall, M. F. (2002). As the pendulum swings: New approach to research withchildren. Presentation at Friends Research Institute National Ethics Conference, “Eth-ics of Research with Children,” May 6.

Morrison, R. (2001). FDA’s pediatric rule hurts public health. Competitive EnterpriseInstitute press release, March. Available at http://www.heartland.org/health/mar01/fda.htm

National Bioethics Advisory Commission (2001). Ethical and Policy Issues in ResearchInvolving Human Participants, Vol. I: Report and Recommendations. Bethesda, MD:National Bioethics Advisory Commission.

National Commission for the Protection of Human Subjects of Biomedical and Behav-ioral Research (1977). Report and Recommendations: Research Involving Children.

Washington, DC: Department of Health Education and Welfare (DHEW PublicationNo. (OS) 77-0004).

National Institutes of Health (NIH) (1998). NIH policy and guidelines on the inclusionof children as participants in research involving human subjects, March 6.

National Institutes of Health (NIH), Human Subjects Research Advisory Committee(HSRAC) (2000). Minutes, meeting of November 9. Available at http://ohsr.od.nih.gov/HSRACminutes/110900_HSRAC_minutes.htm

Nelson, R. M. (2001). Nontherapeutic research, minimal risk, and the Kennedy Kriegerlead abatement study. IRB 23, 6:7–11.

New York Times Editorial Staff (2002). Sanity on pediatric drug safety. New York Times,April 23, p. A22.

Office for Human Research Protections (OHRP) (2001). Letter of determination onprotocol number 96-CH-0101, August 15. Available at http://ohrp.osophs.dhhs.gov/detrm_letrs/aug01o.pdf

Office for Human Research Protections (OHRP), National Human Research ProtectionsAdvisory Committee (NHRPAC) (2002). Transcript of meeting of April 29. Avail-able at http://ohrp.osophs.dhhs.gov/nhrpac/mtg04-02/0429NHR.txt

Office for Human Research Protections (OHRP), National Human Research ProtectionsAdvisory Committee (NHRPAC) (2000). Transcript of meeting of December 21.Available at http://ohrp.osophs.dhhs.gov/nhrpac/mtg12-00/1221meet.txt

Plummer, J. (2000). FDA’s pediatric rule restricts access to medicine. Consumers’Research Magazine, May. Available at http://www.consumeralert.org/pubs/research/CRMay00.htm

Prentice, E. D., Antonson, D. L., Jameton, A., Graber, B., and Sears, T. (1989). Canchildren be enrolled in a placebo-controlled randomized clinical trial of syntheticgrowth hormone? IRB 11, 1:6–10.

Reuters (2002). US senators want pediatric test mandate made law. Reuters HealthInformation, April 18. Available at http://www.reutershealth.com/archive/2002/04/18/eline/links/20020418elin030.htm

Roberts, R. (2002). The view from FDA. Presentation at Friends Research InstituteNational Ethics Conference, “Ethics of Research with Children,” May 7.

Shamoo, A. E. (2002). Recent examples of ethically questionable research with chil-dren. Presentation at Friends Research Institute National Ethics Conference, “Ethicsof Research with Children,” May 7.

Shirkey, H. (1968). Editorial comment: Therapeutic orphans. Journal of Pediatrics72:119–120.

Tauer, C. A. (2000). Human enhancement uses of biotechnology, ethics, human growthhormone. In T.J. Murray and M.J. Mehlman (eds.) Encyclopedia of Ethical, Legal,and Policy Issues in Biotechnology, pp. 491–502. New York: John Wiley & Sons.

Tauer, C. A. (1999). Testing drugs in pediatric populations: The FDA mandate. Account-ability in Research 7:37–58.

Tauer, C. A. (1994). The NIH trials of growth hormone for short stature. IRB 16, 3:1–9.Waxman, H. A., Dingell, J. D., and Brown, S. (2002). Letter to the President on suspend-

ing the pediatric rule, March 18. Available at http://www.house.gov/reform/min/pdfs/pdf_recent/pdf.president.pediatric3.18.02.pdf

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