5
Raising Awareness of Regulatory, Legal, and Ethical Issues

Every year, information necessary for the proper use of drugs and biologics in infants and children is lacking for more than half of newly approved drugs and biologics that are likely to be used by children. This is often because children are not sufficiently included in research studies. Pediatric clinical trials involve many logistical challenges as well as legal and regulatory considerations. For instance, a special consideration is informed consent and whether parental consent, the assent of the child, or both are required.

The U.S. Food and Drug Administration's (FDA's) new Pediatric Rule makes it more likely that children will receive improved treatment, because physicians will have more complete information on how drugs affect children and the appropriate doses for each age group (FDA, 1998e). The rule also allows FDA to require industry to test already marketed products in studies with pediatric populations in certain compelling circumstances, such as when a drug is commonly prescribed for use in children but when the absence of adequate testing and labeling could pose significant risks. The intent of this session is to examine the many interrelated legal and regulatory issues, as well as the interrelated social and ethical concerns, in the evaluation of the effects of drugs and biologics on pediatric populations.



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Rational Therapeutics for Infants and Children: Workshop Summary 5 Raising Awareness of Regulatory, Legal, and Ethical Issues Every year, information necessary for the proper use of drugs and biologics in infants and children is lacking for more than half of newly approved drugs and biologics that are likely to be used by children. This is often because children are not sufficiently included in research studies. Pediatric clinical trials involve many logistical challenges as well as legal and regulatory considerations. For instance, a special consideration is informed consent and whether parental consent, the assent of the child, or both are required. The U.S. Food and Drug Administration's (FDA's) new Pediatric Rule makes it more likely that children will receive improved treatment, because physicians will have more complete information on how drugs affect children and the appropriate doses for each age group (FDA, 1998e). The rule also allows FDA to require industry to test already marketed products in studies with pediatric populations in certain compelling circumstances, such as when a drug is commonly prescribed for use in children but when the absence of adequate testing and labeling could pose significant risks. The intent of this session is to examine the many interrelated legal and regulatory issues, as well as the interrelated social and ethical concerns, in the evaluation of the effects of drugs and biologics on pediatric populations.

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Rational Therapeutics for Infants and Children: Workshop Summary FDA PERSPECTIVE ON NEW REGULATIONS Presented by Dianne Murphy, M.D. Associate Director for Pediatrics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration In 1994, FDA provided a new regulatory approach to encourage studies with pediatric populations to develop information on the proper use of a product being prescribed for the pediatric population. With that regulatory approach, where appropriate, FDA could conclude that the course of the disease and the effects of a drug, both beneficial and adverse, were sufficiently similar in the pediatric and adult populations to permit extrapolation of efficacy in adults to efficacy in children. In such a situation, there would be no need to again prove efficacy in the pediatric population. Unfortunately, the rule did not achieve its intended objectives. Seventy-seven percent of the labeling changes proposed by drug companies in response to this rule did not result in improved labeling for children. To improve on that record, two additional legislative and regulatory tools are now available: (1) Section III of the 1997 Food and Drug Administration Modernization Act (FDAMA; PL 105–115), which provides 6 months of additional marketing exclusivity, and (2) the 1998 Pediatric Rule which requires studies in the pediatric population unless such studies are waived or deferred. Under FDAMA, which is voluntary, the studies to be submitted by the sponsor must be responsive to a written request issued by FDA. The way in which this actually works is that the sponsor first submits a proposal of what studies it thinks will be necessary. FDA's written request in response to that proposal is based on its assessment of what studies are needed to produce a health benefit in the pediatric population. Having a sponsor submit a proposal first allows FDA to determine the level of interest in and commitment to pursuing studies for a particular moiety. Because the additional exclusivity will attach to the ''active moiety," the sponsor may need to provide the results of studies for all products with that moiety if those products are being used in pediatrics but are not appropriately labeled for such use. As of May 1999, of the 15 technical divisions in the FDA's Center for Drug Evaluation and Research, all but two had received proposals. As of May 23, 1999, there were 133 proposals and FDA had issued 83 written requests asking for 155 studies. Fifty-five of these studies were efficacy and safety studies, 55 were pharmacokinetic studies, and the remaining were pharmacokinetic or pharmacodynamic, safety only, or "other" types of studies. "Other" includes prophylaxis studies and studies of the actual use of over-the-counter products. During this period 14 studies were proposed for the neonatal population and 24 studies were proposed for the population less than 2 years old. Physiologic and functional childhood changes and development often occur across the arbitrary

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Rational Therapeutics for Infants and Children: Workshop Summary age groups defined in the 1994 regulation. Most of the requested studies reflect these fundamental realities and include subjects in a number of age ranges. FDA realizes the need for flexibility in this area and is basing requests on the needs of science and is not constrained by age groups. Because FDAMA is voluntary and does not include biologics, old antibiotics, or products without remaining patents or exclusivity, the Pediatric Rule was published in December 1998. Compliance with the Pediatric Rule is not voluntary. Under the Pediatric Rule, applications for new drug approvals must include results of studies with the pediatric population unless FDA has waived or deferred these studies. FDA has, however, stated that it will not delay approval of a product for adults if the result of studies in the pediatric population are not ready. The driving principle behind the Pediatric Rule has been the generation of information with respect to: (a) those drugs that will provide meaningful therapeutic benefit (defined as a significant improvement in the treatment, diagnosis, or prevention of a disease); and (b) drugs for which there is a need for additional therapeutic options. These study requirements may be waived if the drug does not meet the criteria for meaningful therapeutic benefit and substantial use. Alternatively, these studies may be deferred if additional safety and effectiveness information is needed from the adult usage or if the product is ready for approval for adult use. The sponsor must, however, have a plan for such studies and must have obtained a deferral that states when the results of the studies are to be submitted. In summary, under the Pediatric Rule, at the time of approval, a new drug application must include studies in the pediatric population, a waiver for such studies, or an agreement on the deferral of pediatric studies. FDA must report to the U.S. Congress on the impact of FDAMA's Pediatric Exclusivity by legislation by January 2001. In addition to determining the economic impact of the program and any suggestions for modification, the agency will focus on the types of studies that have been useful in providing needed information, endpoints that have been studied and proven to be useful, and the pharmacokinetic or pharmacodynamic approaches that can be used to decrease the need for efficacy studies in certain diseases. ROLES OF INSTITUTIONAL REVIEW BOARDS AND DATA-MONITORING COMMITTEES IN CLINICAL TRIALS Presented by Susan S. Ellenberg, Ph.D. Division of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration Data-monitoring committees (DMCs) and institutional review boards (IRBs) serve different but complementary roles in clinical trials. The major re-

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Rational Therapeutics for Infants and Children: Workshop Summary sponsibility of the IRB is to ensure that all research conducted in the institution for which it is responsible is appropriate and safe for the projected study population. Its review focuses on the initial design and study protocol, although IRBs do receive information about serious adverse effects in real time during the trial and are required to perform regular rereview of studies with whatever updated information is available to the study sponsor. The responsibility of the DMC, in contrast, focuses on the interim data accumulated as the trial progresses. An independent DMC will not necessarily be established for every clinical trial, but when one exists it is usually the only trial component that has access to the unblinded interim data. Thus, a DMC has primary responsibility for detailed consideration of the interim data and for recommending any changes (including early termination) in the study protocol. An IRB generally does not have either the time or the requisite expertise to perform such intensive interim reviews. A DMC may be defined as a group of experts that reviews the ongoing conduct of a clinical thai to ensure continuing patient safety as well as the validity and scientific merit of the trial. These committees are also frequently referred to as data and safety monitoring boards, or by other similar designations. DMCs were first established as components of trials sponsored by the National Institutes of Health starting in the 1960s. In recent years, their use has expanded among federally sponsored trials and especially industry-sponsored trials. Monitoring of ongoing clinical trials is important. Monitoring is needed to ensure that any unexpected safety concern is identified as rapidly as possible. Monitoring is also important to detect and correct problems in thai conduct, such as lagging accrual, unacceptably high ineligibility rates, lack of compliance with the study protocol, and excessive numbers of dropouts. Finally, monitoring allows for the possibility of early termination of the trial when the results are either so strongly positive or negative that the likelihood is small that the conclusions would change if the trial were to continue to its planned conclusion. Typically, DMC members are physicians specializing in the disease being studied and biostatisticians with experience in the design and analysis of clinical trials. Frequently, DMCs will include a bioethicist, particularly when the trial is addressing a major public health issue or when the thai raises difficult ethical issues. Some trials will require other types of expertise for adequate monitoring—for example, basic science, pharmacology, epidemiology, and law. In some cases a patient advocate or community representative will be appointed as a committee member. A variety of models have been proposed for DMC operations, and many different models are in use (Ellenberg et al., 1993). There is variation in the sizes of committees, the frequency and type (in-person or conference call) of meetings, attendance or participation of individuals other than committee members at meetings, formats for presentation of data to the DMC, and many other aspects of DMC operations. Although some differences may be explained by differences in the types of trials (highly complex trials addressing multiple

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Rational Therapeutics for Infants and Children: Workshop Summary questions may, for example, require a larger DMC than simpler studies with a single focus), other differences have been controversial (Fleming and DeMets, 1993; Meinert, 1998). Although all clinical trials require monitoring, all trials do not necessarily need a formal DMC. DMCs are most important when the treatments address a major outcome—for example, in trials of potentially lifesaving treatments. In such trials, an unanticipated safety issue or a large treatment effect that appears early in the trial may raise ethical concerns about continuing the trial as designed. It is optimal when those scientists making judgments as to whether the interim data are strong enough to support reliable conclusions do not have financial, intellectual, or other ties to the study outcome that could inappropriately influence these judgments. "Independent" DMCs include no representatives from the industry sponsor, the study investigators, or others with some vested interest (either financial or intellectual) in the outcome of the study. Independent committees help ensure the objectivity of decision making, as described above. In addition, they reduce the chance that the conduct of the study will be affected by the awareness of the interim data. For example, a study investigator with knowledge that the data are even slightly trending toward the superiority of one of the study treatments may cease to enter patients in the study, may begin entering only certain types of patients in the study, or may encourage or facilitate patient noncompliance and dropout (Green et al., 1987). Despite their importance in clinical trials, DMCs have received little attention in the regulatory arena. Independent DMCs are not required for any trials except for the very limited subset of trials performed in emergency situations in which informed consent is waived (21 CFR [Code of Federal Regulations] 50.24). The purpose and operations of DMCs are briefly discussed in guidance documents on good clinical practices and on statistical principles for clinical trials (FDA, 1997a; 1998). Both of these documents emerged from the International Conference on Harmonization, a collaboration of industry and regulatory authorities in the United States, Europe, and Japan to optimize and standardize drug development practices and policies internationally. DMCs have monitored many trials with pediatric populations in areas such as AIDS, cancer, and other serious diseases. In principle, there are no reasons why DMCs for pediatric studies would operate any differently from DMCs for adult studies except for the types of expertise that would be needed on the committee. The fact that ethical concerns may, on average, be more intense for trials with pediatric populations because children are a "vulnerable population" who cannot provide full informed consent for their treatment suggests, however, that DMCs may be particularly valuable for many trials with pediatric populations.

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Rational Therapeutics for Infants and Children: Workshop Summary ETHICS OF DRUG AND BIOLOGIC RESEARCH IN INFANTS AND CHILDREN* Presented by Robert M. Nelson, M.D., Ph.D. Associate Professor of Pediatrics and Bioethics, Medical College of Wisconsin An individual child may benefit from participation in research in a variety of ways, including access to new therapeutic interventions or from close individual monitoring (Nelson, 1998). Although an alternative to participating in research is to receive the currently available treatment, the assumption that these treatments are safer and more effective than interventions under investigation may not be justified. In fact, most drugs used to treat children have never been tested formally, making off-label use of medications the de facto standard of care in pediatrics. It follows that inadequate information may expose children to unexpected adverse reactions or to suboptimal treatment. In addition, the lack of a pediatric formulation of a drug may deny a child access to an important therapeutic advance or expose a child to a drug in homemade, poorly absorbed preparations. In other words, if children have not been sufficiently included in research, adequate information may be lacking to guide the pediatric use of a medication. Thus, any particular child may be exposed to greater risk and deprived of potential benefit compared with the risk and benefit for an adult, given the same medication, an unfair difference based solely on age. This situation may be due to regulatory impediments, economic disincentives, or reluctance to require studies with pediatric populations unless the primary use of a drug will be by children. Also, the logistics of performing research with pediatric populations may be more difficult given, for example, the lower incidence of a disease in children, the complexity of the developmental changes that may be taking place in children, and the limited market for the recapture of the costs of drug development. The American Academy of Pediatrics (AAP) Committee on Drugs (1995) argues that drug researchers have an ethical obligation to conduct drug (and biologics) research with children: There is a moral imperative to formally study drugs in children so that they can enjoy equal access to existing as well as new therapeutic agents. . . . The AAP believes it is unethical to deny children appropriate access to existing and new therapeutic agents. It is the combined responsibility of the pediatric community, pharmaceutical industry, and regulatory agencies to conduct the necessary studies; it is the responsibility of the general public to support the necessary research in order to assure that all children have access to important medications and receive optimal drug therapy. (pp. 287, 294) *    Portions of the text were adapted from Nelson (1998).

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Rational Therapeutics for Infants and Children: Workshop Summary This claim rests on two assertions: Given the widespread "off-label" use of drugs and biologics by pediatricians, children are being harmed (either by the presence of adverse events or by absence of therapeutic effect) by the lack of basic safety and efficacy data concerning the pediatric use of a drug or biologic. This "harm" can be reduced or eliminated through properly designed and conducted clinical studies of a drug or biologic with children as participants. Although this claim is widely shared, it is difficult to estimate the exact nature and extent of the harms suffered by children in the absence of such information. Four issues are important in considering the ethics of drug and biologics research with infants and children: (1) anchoring studies to "minimal risk," (2) current regulations guiding clinical research, (3) placebo-controlled trials, and (4) respecting a child's assent or dissent concerning participation in research. Anchoring Studies to "Minimal Risk" The dominant interpretation of the requirements of justice in research has been to protect so-called "vulnerable" populations from exposure to an inappropriate share of risk in the absence of certain benefit. One way to protect against the involuntary assumption of research risk is the requirement for obtaining voluntary and informed consent, a requirement that excludes persons who are incapable of providing informed consent (e.g., children and mentally disabled people) or who, if capable, may not be in a position to provide voluntary consent (e.g., prisoners). Although perhaps reasonable for adults, such a consent requirement would preclude all research with children who are not legally or developmentally capable of providing voluntary and informed consent. The inability of children to provide consent has led to restrictions based on the stratification of research proposals according to risk. The conceptual cornerstone of current research policy, the Belmont Report (National Commission, 1979), interprets the principles of respect for persons, beneficence, and justice as requiring the protection of children through limitation of the risk to which a child may be exposed regardless of parental permission. The concept of "minimal risk" serves to anchor allowable risk to the risk encountered in the normal course of a child's everyday life. The challenge to enhance justice in regard to pediatric research is to broaden the participation of children who are not capable of consent while at the same time minimizing any exposure to risk that may not be balanced by an appropriate benefit for that particular child, or for children with the condition being studied.

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Rational Therapeutics for Infants and Children: Workshop Summary Current Regulations Guiding Clinical Research Both investigators and institutional review boards familiar with clinical trials with children should assist in ensuring the use of practices (FDA, 1998b) that safeguard the child participant (American Academy of Pediatrics Committee on Drugs, 1995). Particular attention needs to be directed to the International Conference on Harmonization (ICH) guidance on good clinical practice, which contains a section (Section 4) on nontherapeutic trials with children (FDA, 1996). Population pharmacokinetic approaches may mitigate several of the problems associated with conducting pharmacokinetic studies with pediatric populations (FDA, 1998c). All research involving human subjects conducted, supported, or otherwise subject to regulation by any federal department or agency is subject to the U.S. Department of Health and Human Services (DHHS) Policy for Protection of Human Research Subjects (45 CFR 46). The issues of consent and assent for pediatric patients enrolled in clinical trials are discussed in this DHHS regulation. If the study is performed under a U.S. investigational new drug application (IND), the informed consent (21 CFR 50) and IRB (21 CFR 56) regulations apply. If the study is not performed under a U.S. IND but the data are submitted as part of a new drug application, a biologics license application, or a product license application, the standards of the country in which the study is performed or the Declaration of Helsinki standards, whichever provides greater protection for the subjects of the study, must be met (21 CFR 312.120). Placebo-Controlled Trials Randomized controlled trials (whether they are against placebo or active treatment) may be necessary to be able to infer that an intervention (drug, biologic, or device) is effective for the selected population under the conditions of the study. The research imperative, to the extent that it privileges the knowledge gained from randomized controlled trials over clinical knowledge gained in the practice of medicine, may do a disservice to physicians and patients. However, the uncritical and anecdotal application of medical technology based on "biologic plausibility" or the uncontrolled "case series" experience of a group of physicians is also problematic. FDA focuses the urgency or moral requirement to do research with the notion of "meaningful therapeutic benefit" (FDA, 1998c). Yet, how is "meaningful therapeutic benefit" to be determined? If no drug or biologic is approved for use by children with the indicated condition or disease (and no drug or biologic is, thus, labeled for this indication), a new entity will by default have a "meaningful

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Rational Therapeutics for Infants and Children: Workshop Summary therapeutic benefit" regardless of the efficacy of other "off-label"* treatments. The possibility of an "off-label" use of a drug that provides a ''meaningful therapeutic benefit" appears to be disallowed in the absence of published data that establish the safety and effectiveness of that medication. Thus, the restricted comparison with labeled products in determining "meaningful therapeutic benefit" may undervalue "off-label" clinical knowledge and reinforce the apparent need for a placebo-controlled trial regardless of the medical standard of care. Placebo-controlled trials are controversial, especially those with children. The argument about placebos centers on two general issues: (1) scientific necessity, and (2) ethical appropriateness. The question, then, is how this placebo controversy translates into the pediatric setting. When is a placebo control justified in research with children? This question can be addressed in two steps: (1) If efficacy has been established in adults, what further information is necessary to establish efficacy in children? (2) If it is necessary to establish efficacy in children in the absence of applicable data from adults, is a placebo-controlled trial necessary and justified (that is, ethical)? First, FDA allows for the possibility that the safety and effectiveness of an intervention for the pediatric population can be established on the basis of data for adults and appropriate pharmacokinetic data. Second, FDA acknowledges that a placebo-controlled trial may not be necessary. However, this admission is of limited value in getting away from the initial use of placebo controls. According to the FDA, only when there is an established effective treatment will it be unnecessary to perform further placebo-controlled trials. The crux of the problem lies in the determination of efficacy. In the absence of an adequate and well-controlled study published in the medical literature, it is highly doubtful that FDA would accept a current "offlabel" pediatric use of a biologic or drug as effective (absent pharmacokinetic data and study with adults establishing effectiveness). The results of an active control equivalence trial, no matter how well designed, would not be accepted as evidence if neither of the treatments being compared had been studied against a placebo. How, then, might an IRB evaluate design of the research that involves children and that includes a placebo-control arm? One specific issue in the IRB review of "placebo-controlled" trials is the analysis of benefit. Approval under Section 405 requires the "prospect of direct benefit." If the inclusion of a placebo-controlled arm is interpreted as not offering the prospect of direct benefit, the protocol can be approved only under Section 404 (if the research involves no greater than minimal risk) or Section 406 (if the research involves only a minor increase over minimal risk). Since research considered under Section 405 is not indexed to minimal risk but must simply be commensurate with the *    Off-label means the clinical use of a drug or device for an indication, using a dosage form or a dose regimen, for a patient population or other drug or device use parameter which is not mentioned in the approved label.

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Rational Therapeutics for Infants and Children: Workshop Summary available alternatives, the determination of whether a protocol does or does not offer the prospect of direct benefit directly impacts on the allowable level of risk exposure (DHHS, 1983, 1991b). The controversy over the placebo-controlled trial of human growth hormone illustrates the important difference between what has been called a "prerandomization" analysis of benefit and a "postrandomization" analysis of benefit. In effect, for an IRB to decide that the placebo-control arm of a randomized trial does not have the prospect of direct benefit is to "prejudge precisely the information the research is designed to discover" (Williams, 1996). The issue, then, is not the inclusion of a placebo arm but whether an effective treatment is being denied to those who are randomized to the placebo arm. If the medical standard of care involved an otherwise nonvalidated treatment but was nevertheless believed to be effective by the involved physicians (and other IRB consultants), an IRB would likely deny approval of the study on the basis of the potential of harm to the children in the placebo-control arm from being denied the standard "effective" treatment. Further justification would likely be needed (beyond the fact that the current standard treatment had never been evaluated against a placebo) to make the case that an IRB should approve the protocol. Consent, Assent, and Determination of Risk The Report and Recommendations on Research Involving Children of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (the National Commission) was published in 1977 and is the foundation for the 1983 federal regulations known as Subpart D of Title 45, Code of Federal Regulations, Part 46 (DHHS, 1991a). In addition, the National Commission also issued the Belmont Report on the basis of the ethical principles and general guidelines that ground the more specific rules governing research with human subjects. The Belmont Report identified three principles: (1) respect for the rights of the individual (on the basis of respect for persons), (2) the obligation to protect the individual from undue risk (beneficence), and (3) fairness in the distribution of the burdens and benefits of research (justice). Subpart D, based on the National Commission's Report on Research Involving Children (National Commission, 1977), incorporates these added protections on the basis of a risk classification anchored to the concept of minimal risk. The concept of "minimal risk" was meant to serve as a limit to parental authority to enroll a child in "nontherapeutic" research. The National Commission recognized that parents make day-to-day decisions that concern their children's medical treatment, and such decisions are based on a balancing of risks and benefits. The National Commission applies this discretionary authority of the parent to "therapeutic" research regardless of the absolute level of risk, provided that the risk is justified by the anticipated benefit

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Rational Therapeutics for Infants and Children: Workshop Summary to the child and that the relation of the anticipated benefit and risk is at least as favorable as those of the available alternative approaches. In fact, IRBs are explicitly advised to "evaluate [therapeutic] research protocols . . . in the same way that comparable decisions are made in clinical practice" (National Commission, 1977). Thus, for research that may directly benefit a child, the acceptability of risk is left to the discretion of the parent, provided that an IRB believes that the risks and benefits of the research project are comparable to those of the other available options, a condition that has been referred to as "clinical equipoise" (Freedman, 1987). Under such circumstances, the assent of the child or the permission of the parent is sufficient for participation in the research. The National Commission then extends the scope of parental authority into research that offers no benefit to the child by comparing the child's research experiences with those that are normally encountered apart from being a research subject. Parents have the responsibility and authority "to choose activities and to define a manner of life for their children." The National Commission asserts that "many of the experiences which parents generally allow to their children are somewhat risky and cannot be said, without forcing the case, to involve particular benefits." Consequently, "when risks entailed in research are equivalent to normal risks of childhood, parents may properly permit these risks" (National Commission, 1977). The National Commission assumes that parental discretion properly operates to balance the risks and benefits of everyday life. Nevertheless, the question of whether the risks and benefits of participating in research are similar to that of a child's nonresearch experiences is not left up to the sole discretion of a child's parents, apart from the limited situation in which the child may directly benefit from the research. With a definition of "minimal risk," the National Commission seeks to create a research environment that resembles this everyday context and thus to specify the limits of parental authority in permitting a child to participate in nonbeneficial research. "Minimal risk" is defined as "the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical or psychological examination, of healthy children" (National Commission, 1979). Thus, the definition of "minimal risk" specifies the conditions under which parents may appropriately allow a child to participate in any activity, whether in the context of research or in the course of daily life. In effect, the scope of parental authority is extended to cover a child's participation in nonbeneficial research if the risks are reasonably commensurate with those of the child's nonresearch life. In doing so, the National Commission set up two further problems: first, should the risk that a child is exposed to vary depending on the child's particular life experience? and, second, does a parent have the authority to expose a child to any increased risk when there is no hope for benefit for that particular child? The National Commission introduced the concept of "minimal risk" in an attempt to provide a boundary condition that serves to limit parental discretion

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Rational Therapeutics for Infants and Children: Workshop Summary to permit a child's participation in research. In effect, before allowing a parent to permit a child's participation in research, an IRB was to determine the extent to which the research presented a range of risks and benefits commensurate with that child's situation. The federal regulations define "minimal risk" as "the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests" (45 CFR 46.102(I)). This definition omits the phrase "of healthy children" that is found in the National Commission's report, creating an ambiguity that the risks of research may be indexed to the "ordinary" experiences of sick children rather than those of healthy children. The National Commission suggested four perspectives that need to be considered in estimating the allowable risk: common sense, the investigators' experiences, any statistical information, and, finally, the situation of the proposed subjects. The last perspective also raises the possibility that allowable risk will be indexed to the actual risks experienced by a particular child and does not indicate whether the risks should be evaluated from an adult's perspective or from a child's perspective. The National Commission's decision to permit nonbeneficial research involving greater than minimal risk if the research investigated a child's "disorder or condition" presented the most controversy. The majority argument in favor of allowing children to participate in nonbeneficial research that presents greater than minimal risk was largely pragmatic. The National Commission noted that "parental authority routinely covers a child's participation in many activities [such as skiing and contact sports] in which risk is more than minimal, and yet benefit is questionable." They were also "impressed by reported examples of diagnostic, therapeutic and preventive measures that might well have been derived from research involving risk that, while minor, would be considered more than minimal" (National Commission, 1977). In effect, given the potential benefit to others, the National Commission thought that it was reasonable to allow a parent to permit a child to participate in nonbeneficial research that presented more than a minimal risk. Nevertheless, the National Commission was unwilling to extend this parental authority beyond what was called a "minor increase" over minimal risk. Paul Ramsey was a prominent critic of the National Commission's decision to allow a parent to enroll a child in nonbeneficial research that presented even a minor increase over minimal risk. According to Ramsey, for a parent to allow a child to undergo any risk for the sake of another person was "a violation of the nature and meaning of the responsibilities of parenthood" (Ramsey, 1970). For a parent to permit such non-beneficial research, "a need or interest on the part of the child-subjects must be discovered if substituted consent has moral warrant. Without that, or without sufficiently competent supplementary consent on the part of the subject accepting the risk, the responsibility of parenthood would be flawed or deflected from its primary role" (Ramsey, 1978). Ramsey later picks up on the suggestion of William Bartholome that participation in research can be

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Rational Therapeutics for Infants and Children: Workshop Summary "an opportunity for moral growth" (Ramsey, 1978). Thus, a parent may choose to permit a child to participate in non-beneficial research yet remain faithful to the responsibility of parenthood out of a concern for a child's "moral education" (Bartholome, 1977). The National Commission, in the context of discussing the justification for allowing a child to participate in nontherapeutic research, makes little of the importance of the child's assent apart from the more general requirement for obtaining a child's assent or a parent's permission. Absent the child's assent, the parent would likely be judged as having overstepped the appropriate limits of parental authority. In addition, the stipulation that the research experience be commensurate with a child's actual or routine experience was meant not to increase the risk that the child may justifiably be exposed but to assist children who can assent to make knowledgeable decisions. This suggests that allowable risks are those that the child-subject would judge to be no more than a "minor increase over minimal risk." The federal regulations, based on the National Commission's report, require both parental permission and child assent except under some clearly defined limits. Assent is defined as the child's "affirmative agreement to participate in research" (45 CFR 46.402(b)). Parental permission and child assent thus function in the pediatric setting as the practical application of the principle of respect for persons, a principle that, in research with competent adult subjects, establishes the requirement for voluntary and informed consent. In the context of research with adults, the requirement for voluntary and informed consent may overprotect certain classes of human subjects, such as those who are unable to provide informed consent yet who may benefit from a research intervention. In the context of research with pediatric subjects, the requirement for assent does not run the risk of overprotection in the therapeutic context as the child's assent may be waived. However, the regulations assume that parental permission (with or without a child's assent) is an insufficient protection against inappropriate research risks. Even when participation in research may directly benefit the child, the IRB is given the responsibility to restrict the available choices to only those research projects that present risks and benefits commensurate with the child's nonresearch alternatives. Finally, nonbeneficial research is restricted to projects presenting no more than minimal risk unless the research may result in important information pertinent to a child's disease or condition, effectively restricting any research involving greater than minimal risk to sick or afflicted children. Rather than serving as a moral benefit to the child, can a child's assent function as a self-protection mechanism and allow the relaxation of the minimal risk restrictions in pediatric research? It is difficult to arrive at an answer to this question given the absence of agreement on what "assent means." Box 5-1 provides various meanings of the word "assent."

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Rational Therapeutics for Infants and Children: Workshop Summary BOX 5-1 Definitions of "Assent" Definition from the Code of Federal Regulations "Assent . . . means a child's affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent." 45 CFR 46.402(b) Comment: As opposed to the extensive guidance on the general requirements for informed consent found in 45 CFR 46.116, there is little discussion of the meaning of assent apart from the brief definition found in Section 46.402(b). Definition from the National Commission Know that procedures will be performed. Choose freely to undergo those procedures. Communicate this choice unambiguously. Be aware of the option to withdraw. National Commission, as quoted in Bartholome (1996, p. 356) Comment: This set of recommendations was never incorporated into federal regulations. One of the issues in the discussion of a child's ability to assent or consent to research participation is the developing capacity of the child to reason" about participation in research. An emphasis On the ability to reason suggests that a child may not consent to research participation until the age of 9 (Leikin, 1993; Weithorn and Campbell, 1982), or when a child is mature enough, for example, to be a "babysitter" (Koren et al., 1993). Note that the above elements of assent as initially discussed by the National Commission do not imply or depend upon a child's ability to reason about the purpose of the research, nor to consider the various risks and benefits of research participation. Definition from Bartholome Help the child achieve a developmentally appropriate awareness of his/her condition; disclose the nature of the proposed intervention and child's likely experience; assess the child's understanding and any (coercive) factors influencing the child; and solicit the child's unwillingness to accept the proposed intervention. Bartholome (1996, pp. 360–361 )

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Rational Therapeutics for Infants and Children: Workshop Summary Comment: Note that nothing in these four elements of assent requires a sophisticated ability to reason or a sophisticated understanding of the risks and benefits of participation in the research or of the alternatives to participation. As Bartholome points out, the only right that is assumed by the concept of assent is the right to say "no." If a child is capable of reasoning about research participation based on a knowledge of risks and benefits, Bartholome prefers to use the term "consent" (apart from its legal use) to distinguish this level of understanding from "assent." LEGAL AND REGULATORY CONSIDERATIONS FOR THE CONDUCT OF CLINICAL TRIALS WITH PEDIATRIC POPULATIONS Presented by Michael Labson, J.D. Covington & Burling, Washington, D. C. In general, the legal system is supportive of research with pediatric populations and provides a great deal of flexibility for such research to be conducted. Nonetheless, the legal system influences research with pediatric populations in two ways: first, by establishing regulatory protections and controls and, second, by providing incentives and requirements to conduct research. The same general protections that exist for the protection of all human subjects exist for pediatric research subjects, the hallmarks of which are informed consent and IRB review. There are special considerations for informed consent, related to whether to require parental consent, the assent of the child, or both. There are added protections due to the special vulnerability of pediatric patients and special protections for certain subpopulations, like children who are under the care of the state. Sources for these requirements are the federal policy (45 CFR 46), FDA regulations, some state law, the tort system and the courts, and other nonlegal or extralegal sources, such as professional guidelines. Subpart D of 45 CFR 46 applies to all DHHS-funded research or research conducted by signatories to the so-called Common Rule. Research is reviewed according to its place under one of four categories: (1) not greater than minimal risk, (2) greater than minimal risk but prospect of direct benefit to the individual subjects, (3) greater than minimal risk and no prospect of direct benefit, but likely to yield generalizable knowledge, and (4) "other." The first category, research of not greater than minimal risk, requires the assent of the child, when the child is capable. The regulations do not define what a child is but, rather, defer to state law to dictate the age of majority. The determi-

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Rational Therapeutics for Infants and Children: Workshop Summary nation of capability to assent is determined by criteria established by the local IRB; thus, there is a lot of flexibility. Parental permission for a child's participation in research is also required to be given by one parent or by a legal guardian. For the second category, greater than minimal risk but prospect of direct benefit, the child's assent (where capable) and parental consent are required, as is IRB review. In addition, the risk must be justified by the anticipated benefit to the subject. For the third category, no direct benefit but likely to yield generalizable knowledge, the same basic requirements for the previous categories apply but consent or permission of one parent is not sufficient. If there are two parents, the permission of both needs to be obtained. There are added requirements that there be only a minor increase over minimal risk and that the research presents experiences reasonably commensurate with the subject's actual medical experience. The research also must be likely to yield generalizable knowledge of vital importance for the subject's disease or condition. For research that does not fit into the first three categories, assent of the child, when capable, is required, as is the consent of both parents or legal guardian. In addition, a special requirement holds: a public determination by DHHS that requires expert consultation and public comment to determine that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem that affects children, and that the research will be conducted in accordance with sound ethical principles. As these federal rules illustrate, broad standards exist, but the legal system does not impose specific constraints on research. That task is undertaken by IRBs. These federal regulations do not preempt state laws. Some states have special requirements that address research with pediatric populations. California's laws might be the broadest, basically prohibiting the use of experimental drugs unless it is related to the health of a subject or obtaining information about the subject's condition. Michigan has a prohibition against nontherapeutic research involving neonates, fetuses, or embryos if it jeopardizes life or health. Illinois has a restriction on the use of purely experimental drugs for minors who are under the care of the state unless use of such a drug is the best chance to save the child's life or treat a serious disease. The tort system operates against this background. The primary legal theories that are relevant are nonconsensual trespass on the body (battery), and negligence, which can apply even with appropriate informed consent if the responsible researchers or entities are deemed to be exposing their patients to undue risk in violation of the duty to care that they owe to their patients. There is little case law in this area. In addition to these regulatory protections and controls on pediatric research, the law creates incentives and requirements to perform research. FDAMA (PL 105–115) contains provisions that establish economic incentives for conducting studies with pediatric populations with drugs for which exclusiv-

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Rational Therapeutics for Infants and Children: Workshop Summary ity or patent protection is available under the Drug Price Competition and Patent Term Restoration Act (PL 98–417) and the Orphan Drug Act (PL 97–414). These provisions extend by 6 months any existing exclusivity or patent protection for a drug for which FDA has requested studies with a pediatric population and the manufacturer has conducted such studies in accordance with the requirements of FDAMA. This exclusivity will be particularly important in encouraging companies to study formulations and dosing for study patients. Manufacturers are eligible for exclusivity under FDAMA when they submit the results of a study to FDA in response to FDA's written request for such a study. The study results are not required to provide useful information on use by pediatric patients (e.g., the results may be inconclusive), and the sponsor is not required to obtain approval for the addition of the information gained in the study to the drug's label. In addition to the incentives of FDAMA for studies with pediatric populations, FDA has promulgated a regulation mandating that manufacturers conduct studies of certain products with pediatric populations. The rule establishes a presumption that all new drugs and biologics will be studied in pediatric patients, but allows manufacturers to obtain a waiver of the requirement if the product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients and is not likely to be used by a substantial number of pediatric patients. The rule also provides that FDA will require studies of already marketed drugs under "compelling circumstances." As described in FDA's earlier 1994 rule on labeling for pediatric patient use, the gathering of adequate data to establish safety and effectiveness for pediatric populations may not require controlled clinical trials with pediatric patients. When the course of the disease and the product's effects are similar in adults and pediatric patients, FDA may conclude that safety and effectiveness for pediatric patients can be supported by effectiveness data for adults together with additional data, such as dosing, pharmacokinetic, and safety data for pediatric patients. The new rule does not necessarily require separate studies with pediatric patients. In appropriate cases, adequate data may be gathered by including pediatric patients as well as adults in the original studies conducted on the product. The mandatory study rule requires studies with pediatric populations for new and marketed drugs and biologics, effective April 1, 1999, with data by December 2000, unless a deferral is granted. Studies must cover each age group for which the studies would be likely to produce a meaningful therapeutic benefit or for which the product is used by a substantial number of pediatric patients. This includes the stipulation that companies may be required to develop a new formulation. The rule also requires that sponsors submit postmarketing reports. One of the controversial legal issues presented by the mandatory rule is whether FDA has the authority to require studies when a sponsor is not coming forward and proposing the studies or when a sponsor is not proposing the

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Rational Therapeutics for Infants and Children: Workshop Summary placement of indications on its labeling for pediatric patients. No legal challenge has been brought to the rule. However, it is possible that in individual cases a company might challenge FDA's authority to require pediatric studies. Although it is too early to draw definitive conclusions about FDA's current research initiative for pediatric populations, it holds great promise to improve drug labeling for pediatric patients. The incentives in FDAMA in particular provide a powerful engine to drive research initiatives for pediatric populations and place them on a par with competing research demands. INTERNATIONAL DEVELOPMENT OF DRUGS FOR PEDIATRIC PATIENTS: AN INDUSTRY PERSPECTIVE Stephen P. Spielberg, M.D., Ph.D. Vice President, Pediatric Drug Development, Janssen Research Foundation The International Conference on Harmonization (ICH) is a tripartite effort to harmonize the process of drug development in the United States, Europe, and Japan. There is also representation from Canada and from European countries that are not members of the European Union. In terms of regulations for pediatric populations, its goal is the international availability of standardized, validated formulations for use by pediatric populations and of drug evaluation standards that permit the use and the regulatory acceptability of similar protocols internationally. An example of why this is needed is provided by the differences between Canada and the United States on two types of sweeteners. On the basis of analyses with identical data, saccharin was approved for use in the United States and cyclamates were banned, but in Canada saccharin was banned and cyclamates were approved. This means that if a U.S. product is sweetened with saccharin, it cannot be sold in Canada. Another pressing concern is that many of the children live in places where refrigeration is not available. Thus, if medicines are stable only under refrigerated conditions, those medicines are not going to be usable by most of the children in the world. A third concern had to do with the generalizability of the data derived from clinical trials conducted in one country in terms of application in other countries. There is a need for pediatric investigators to have the ability to work together, on an international scale, by using the same validated formulations, with defined bioavailability and stability, and by studying medications under similar protocols. Application of pediatric pharmaceuticals on a global scale necessitates the acceptability of formulations and requires that the data generated from such international trials for labeling purposes be internationally accepted.

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Rational Therapeutics for Infants and Children: Workshop Summary As one of its first tasks, the ICH pediatric working group reviewed current international regulatory documents on development of drugs for children to identify areas of consensus and disagreement and to try to negotiate a document that would be acceptable to all participants. The working group was able to reach consensus, signing off on a ''Step 2" document (ICH E-11: Investigation of Medicinal Products in the Pediatric Population) in October 1999. The document will now go through a 6-month comment period in the United States, the European Union, and Japan; on the basis of input, a final document to be adopted by ICH will then be prepared. The general principles set forth in the document reaffirm that safe and effective pharmacotherapy in children requires studies with children; indeed, not to do such studies places children at greater risk from therapeutic misadventures with nonvalidated treatments. The ethical imperative to obtain needed information in clinical studies must be balanced against the ethical imperative to protect each child in such studies. The document discusses several critical issues in development of drugs for pediatric populations: timing of initiation of studies with pediatric populations in the process of overall drug development; development of pediatric formulations, types of studies (pharmacokinetic, pharmacokinetic-pharmacodynamic, efficacy, safety), and the age categories of the patients to be studied. In addition, there is a section on special ethical considerations in studies with pediatric populations, including the role and composition of IRBs, recruitment of subjects, parental consent (permission) and assent of the child, and approaches to minimizing risk and distress and maximizing the benefit for children in studies. In the latter context, there is discussion about the nature of investigative sites where children should be studied, the training and expertise of personnel, and assurance that being a patient in a clinical study is made as positive an experience for the child as possible. Regulatory and legislative initiatives in the United States have had a major impact on development of drugs for pediatric populations. The 1997 FDAMA included provisions for an incentive to industry in the form of a 6-month extension of marketing exclusivity for performance of pediatric studies. Since its inception, more than 100 drugs not previously labeled for use by children are now being evaluated. The 1998 FDA Pediatric Rule contains additional provisions to ensure that medicines that are important for children and that will be used by pediatricians will have appropriate information on their safe and effective use. With the increase in investigative activity that has occurred, it is the hope that ICH E-11 can provide a framework for international cooperation on clinical investigations with pediatric populations for the benefit of all the world's children.

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Rational Therapeutics for Infants and Children: Workshop Summary PANEL DISCUSSION Many new agents are in the pharmaceutical development pipeline. Because of changes in federal regulations and in response to incentives, it is likely that many of these agents will be studied for use in children. This changing environment, although promising, raises issues and concerns in several areas. The Need for Trained Research Personnel A skilled cadre of pediatric clinical pharmacologists will be required to achieve the goals established by new regulatory policies. With the new FDA rule (Pediatric Rule), every drug coming through the pipeline will require appropriate evaluation for use by pediatric populations. That is going to necessitate a new generation of pediatric clinical pharmacologists. Academic health centers will have to provide incentives and rewards for those investigators who conduct research with pediatric populations in multicenter studies. Improved Study Design Single-dose studies with children deserve additional considerations from both ethical and scientific perspectives. They raise concerns about the likelihood of benefit to a particular child or patient population, yet in some cases they might be the only way to obtain valuable clinical data. The need for and value of phase I trials with single-dose studies remain controversial because of the risk that a clinical trial could be started with the wrong dose. The drug then could erroneously be deemed ineffective or the entire trial may need to be repeated with a larger cohort of patients with a new dose. Errors made in past studies with pediatric populations have largely resulted from the fact that trials were started before adequate pharmacokinetic studies had been conducted. Such errors are hazardous and expose more children to risk than do concentrated, smaller studies. Although study size should always be kept to a minimum, statistics, biochemistry, and pharmacology should dictate study size. Obtaining the needed enrollment in pediatric studies can be daunting, as the pool of available patients can be small. Good models are provided by the Pediatric Oncology Group and the National Institute of Child Health and Human Development neonatal network, which provides linkages among neonatologists to conduct studies with larger numbers of patients. In 1991 the Institute of Medicine Forum on Drug Development recommended that National Institutes of Health establish a means of solving the problem of the historic lack of information about drug development for infants and children. As a consequence, the National Institute of Child Health and Human Development established a pediatric pharmacology research network. The net-

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Rational Therapeutics for Infants and Children: Workshop Summary work encompasses many of the leading pediatric clinical pharmacologists at universities and children's hospitals in the United States. Thus, it can draw on the data from the more than 200,000 in patient and 2 million pediatric outpatient visits each year. Role of Insurance and Managed Care Organizations In some areas of the United States, health insurance providers report spending more on pharmaceutical coverage than in patient hospital services. In trying to address the rapidly growing cost of prescription pharmaceuticals, some insurers and managed care organizations have begun to develop more restrictive formularies, basically applying tiered payments to offer incentives for the purchase of preferred pharmaceuticals. Thus, insurers have an interest in encouraging safe and efficient clinical testing of drugs for use by the pediatric population. One way of building on the incentives already being supplied through FDAMA would be to encourage the use of pharmaceuticals that have received guidance and labeling instructions for administration to pediatric patients. Some have suggested that third party payers should perhaps stop paying for either off-label or innovative interventions unless they are used as part of a well designed, controlled, and adequate study. Other providers have established policies that do not deny payment to any patient participating in any phase I through IV clinical trials. In New Jersey, for example, insurance and managed care organizations have agreed not to exclude patients from coverage for health care needed because of participation in certain phases of clinical trials. Standard contracts often exclude patients from coverage when they participate in clinical trials. Legal Concerns Legal questions remain: What will the effect of the mandatory study rule be, particularly for marketed products? Will the FDAMA incentive be renewed after its initial impact is evaluated? International Issues Although the ethics of research with children will always differ among cultures and nations, the fundamental principles of how such research should be done can be developed. In any event, ethical issues should be openly discussed. The World Medical Association and the American Medical Association have established a task force to receive and review input on the Helsinki Declaration in an effort to achieve some standardization of basic ethical principles for research with humans.