LEDA at Harvard Law
School LEDA at Harvard Law
School
Researching and Regulating
Prescription of
Psychotropic Drugs in Adolescents
Anne B. Claiborne [*]
How can we distinguish public health from medicine? While medicine focuses on the treatment and cure of individual patients, public health aims to understand and ameliorate the causes of disease and disability in a population. In addition, whereas the physician-patient relationship is at the center of medicine, public health involves interactions and relationships among many professionals and members of the community as well as agencies of government in the development, implementation, and assessment of interventions. [1]
The Food and Drug Administration (FDA) occupies a prominent place in the pantheon of public health-oriented agencies of the United States government, seated within the Department of Health and Human Services and maintaining crucially tight regulatory control over, among many other things, the safety of our food supply and the safety and efficacy of our drug supply. Indeed, it is well established that the primary purpose of the Food, Drug, and Cosmetic Act of 1938[2] – FDAs enabling statute – is to “protect the public health.”[3] This paper explores the current widespread prescription of psychotropic drugs in adolescents – and the comparatively low levels of existing and ongoing research investigating their safety, efficacy, and appropriateness – to question whether the policies and procedures that FDA promulgates and follows actually conform to the basic principles of “public health.”
The maintenance of the public’s health through a comprehensive system of public health law and regulation necessarily comprises elements that stand in tension with one another. Many public health practitioners derive from the population focus of public health basic holistic principles of health promotion and disease prevention that emphasize and rely on education and other voluntaristic measures to induce positive health outcomes for a given population. However, public health also contains components of control: when some members of a population engage in behaviors or otherwise present situations that threaten the health of others in the community, government regulatory actors step in with coercive measures designed to eliminate any preventable threat. The law more typically acts to facilitate this second aspect of public health. Thus, Larry Gostin has defined public health law as:
[T]he study of the legal powers and duties of the state to assure the conditions for people to be healthy (e.g., to identify, prevent, and ameliorate risks to health in the population) and the limitations on the power of the state to constrain the autonomy, privacy, liberty, proprietary, or other legally protected interests of individuals for the protection or promotion of community health. [4]
Federal government agencies – as makers and enforcers of such public health law – such as FDA typically find themselves acting exactly according to Gostin’s formula: they tune their health regulatory actions finely so that they do not overstep constitutional bounds – and cultural norms – of autonomy and liberty.[5] Yet they consistently act to constrain individual and commercial actions on the rationale that such constraints are needed to protect the public’s health.[6] By contrast, local community health departments and other local public health actors often undertake positive measures to improve the health of the population they serve; these measures might entail an increase in access to community information, a health education-based program, or a community drive to clean up a neighborhood. Such local public health initiatives aim to empower, rather than to limit, individuals within a community. Both types of government action – encouragement of community volunteerism and empowerment as well as protective regulation and coercion – are needed. However, in fulfillment of its obligation to regulate, one government entity should do its best not to undermine another agency’s fulfillment of the health promotion function.[7] This paper explores whether and to what extent FDA, in fulfillment of its “public health” mandate to ensure the safety and efficacy of psychotropic drugs for use in the general population,[8] has in fact facilitated – or in some other way contributed to – a broad societal violation of the health of one of its most defenseless populations – adolescents – and in so doing, undermined important health promotion strategies.
The widespread prescription of antidepressants and stimulants in adolescents is the subject of considerable debate.[9] Some argue that the drugs are lifesavers, improving functioning and allowing youths to remain integrated in society in ways that they never could prior to obtaining pharmacological treatment. Others argue that the trends of increasing prescription amount to no more than the massive drugging of a vulnerable population in order to keep it under control – in short, that as a society we are engaging in a systemic “pathologization” of teenagers because we do not want to expend the resources to improve their functioning in more holistic ways.
This paper takes neither position. Instead, it argues that in the absence of good data, we will never know the answer to the questions whether, how, and when psychotropic medications should be prescribed for adolescents. In short, we know we are missing data about long-term safety, efficacy, and appropriateness of the drugs that are prescribed to adolescents for these conditions. The current regulatory system – in which drugs may be approved for a general population and then prescribed by individual physicians (working in partnership with both pharmaceutical companies and parents – who can be highly encouraging and demanding, respectively) for unapproved uses, such as in pediatric populations – may be placing adolescents, who are not usually legally positioned to be their own health care decision makers, at risk.
FDA exclusively monitors drugs for their safety and efficacy,[10] leaving determinations of their appropriateness to private actors – namely, physicians. This paper asks whether, by limiting itself to this function, FDA has effectively not encouraged the dedication of enough research and social resources to underlying socio-cultural – and biological – issues with respect to adolescent mental health and psychiatric disorders. The paper concludes that although FDA’s drug regulation function requires only what it currently does, strategies can and should be employed to improve social information to supplement current knowledge and practices regarding psychotropic drug prescription in adolescents. For regulation of drugs used to treat adolescent depression, the paper recommends that the current strategy laid out in the Best Pharmaceuticals for Children Act of 2002[11] (BPCA) be pursued aggressively to gain further information about antidepressants’ safety and efficacy in adolescents; it further discusses ways that the incentive policy could be amended to encourage studies investigating their relative appropriateness. For regulation of stimulants used to treat adolescent Attention Deficit Hyperactivity Disorder (ADHD), the paper recommends a shift to a more public health-oriented conception of the disease, so that more decision makers are seated at the table than simply FDA, the pharmaceutical companies, and physicians. Multi-disciplinary school-based studies should be conducted in schools, gathering the input of teachers, friends and family and collecting information on the socio-cultural environment in which adolescents operate. FDA can adapt its traditional role to this new model by requiring that the results of such independent sociological studies be made broadly available, either on the label or in supplemental drug information sheets.
II. Adolescence – situating the socio-cultural and bio-physical context .
Adolescents occupy a quintessentially awkward stage of development: although it is tempting to categorize them in relation to other, more clearly defined developmental groups, it is important to remember that in actuality they are not simply big children [12] nor are they small adults. [13] Indeed, adolescence is a unique developmental stage characterized by extraordinarily fast physical and cognitive growth[14] and accompanying risk-taking behavior, assertion of autonomy, and dissociation from family in favor of peers and alternative role models. [15] It is therefore by no means clear that the physiological processes studied in either adults or pediatric populations to determine the safety and efficacy of any new drugs can be safely or accurately extrapolated to adolescents. And given the large number of ill-understood but salient differences in the psychology of adolescents as compared to both adults and children, and among adolescents themselves, it is even less obvious that diagnostic tools for psychological conditions and determinations of psychotropic drug dosage in adolescent populations can be imported from an understanding of a particular disease or condition in either an adult or a pediatric population.
A. Social Perspectives on ADHD and Depression in Adolescents
Much has been said in the media and policy arenas regarding the increase in prescription of psychotropic medications to children over the course of the 1990s [19] expressing a collective socio-cultural ambivalence to the topic of child and adolescent use of psychotropic medications. These mixed feelings probably stem partially from the fact that pronounced forces of stigma and feelings of fear permeate the general social understanding of psychiatric disorders. Applying these social concerns to the adolescent population generates an even greater sense of confusion: we do not know whether to nurture our adolescents or hold them responsible for their actions, whether to rehabilitate or punish, whether to push them toward independence or sweep them back into the protective fold. So when an adolescent presents with psychiatric symptoms, it is natural to question whether those symptoms are a sign of normal developmental malaise or a symptom of trouble to come; it is desirable to question whether to treat with medication or allow the situation to run its course. There is no universal answer to these questions because there is no set formula to define the maturation process; this probably explains as well the scientific confusion in the search for an adequate diagnostic protocol for many adolescent psychiatric conditions. Indeed, the process of psychological development and identity formation naturally includes risk-taking behavior: teenagers push at the boundaries of their behavioral “comfort zones” to determine where to draw the lines for themselves. [20] Every individual matures at a different pace, and perhaps even more unsettling, people end up at different points, with some more capable of abstract cognitive reasoning, for example, than others.
Yet for some subset of the population, psychiatric disorders are a real and present threat to their continued normal functioning and development. Attention Deficit Hyperactivity Disorder (ADHD) has been extensively studied in pediatric populations, but is little understood in adolescents. [21] Despite the uncertainties, recent epidemiological studies document a sharp increase in the prescription of psychotropic drugs – primarily stimulants such as Ritalin (generic: methylphenidate) – for ADHD in adolescents. [22] One possible reason for this prescription increase is the longitudinal use of such drugs for adolescents who were diagnosed with ADHD as young children and have simply never discontinued usage of the drugs. [23]
Likewise, there has been an increase among adolescents in the prescription of medications usually used to treat affective disorders such as depression, indicating that such disorders are being diagnosed at increasingly young ages. [24] Mood disorders and other psychiatric illness – when they occur at all – usually arise in adolescence and often stay with a person through adulthood. [25] Presumably, something about the process of growing into adulthood engages both biological and social processes that could trigger or result in the expression of mental illness for some people.[26] Moreover, studies have found that people with depression experience longer delays in getting help the younger they are at its initial onset, indicating that pediatric populations are especially vulnerable to going untreated for depression.[27] Yet commonly prescribed drugs such as Prozac (generic: fluoxetine hydrochloride) have not been extensively tested for their safety and efficacy in pediatric populations, [28] while studies of other drugs (such as tricyclic antidepressants) have had conflicting outcomes regarding efficacy in children and adolescents.[29]
Thus, adolescents are positioned awkwardly just outside of the age range of the intended recipient population for the prescription of the most common psychotropic drugs in use: for ADHD, adolescents are too “old” (specifically, they are older than the young children who have traditionally been the target population for medication for ADHD), and for depression, they are too “young” (specifically, they are increasingly being diagnosed with onset of depressive disorders that previously were primarily diagnosed in adults).
Little is known about how to diagnose these psychiatric conditions in adolescents nor about how to treat them once diagnosed.[30] Indeed, there is considerable debate regarding whether the increased prescription of psychotropic medications in adolescents is due to their success in treating the disease or is attributable to an over-eagerness to treat children with medication rather than provide them with social support and other services. [31] One study investigating stimulant prescription patterns from a community perspective found that fewer than half of those children whose parents expressed a desire that they receive school services for their ADHD actually received them, while “when parents believe that a child requires medication, it is readily available, regardless of whether the child meets full [diagnostic] criteria for ADHD.” [32] Indeed, the very involvement of parties other than the adolescent patient and the diagnosing physician – such as parents and teachers – has been identified as potentially confusing and problematic for making a definitive diagnosis.[33] And there is no basis to assume that the prescribed drugs are the most appropriate – or even a safe – treatment; [34] indeed, there is even some reason to be concerned at the outset about the effectiveness of the diagnostic techniques in use for both disorders. [35]
B. The Current Regulatory Framework for Antidepressants and Stimulants: A Brief Overview
The practice of “unapproved use prescribing” was authorized by FDA with a rulemaking in 1972, which stated that “the physician may, as part of the practice of medicine, lawfully prescribe a different dosage for his patient, or may otherwise vary the conditions of use from those approved in the package insert, without informing or obtaining the approval of the Food and Drug Administration.” [36] This practice is also known as “off-label prescription,” and it serves to remove regulatory barriers to the prescription and use of medications: One such barrier is the lack of specific research, often due to constraints of time, for a particular population or for a particular disease; another barrier occurs when a pharmaceutical company does not desire to conduct such research or go through the approval process for a particular population or disease when it does not view the investment as worthwhile because the intended population is small.[37] In the case of the former, it may only be a matter of time before appropriate studies are conducted. In the case of the latter, research may never be conducted in the absence of regulatory requirements; populations who regularly do not offer pharmaceutical companies a good return on their investment have thus been dubbed “therapeutic orphans.”[38] A recent review of the Physicians’ Desk Reference found that more than 70% of medications approved by FDA have “either no existing dosing information for pediatric patients or explicit statements that the safety and efficacy in children have not been determined.”[39]
Over the course of the 1990s, both FDA and Congress, recognizing the problem of the “therapeutic orphan,” instituted a series of measures intended to increase the amount of pediatric research performed regarding safety and efficacy of drugs commonly used in children and adolescents. [40] First, in 1994 FDA issued a rule, called the “Pediatric Use Labeling Rule,” requiring drug manufacturers affirmatively to disclose on a drug’s label if studies had not been conducted in children for that drug.[41] Next, in 1997, FDA issued another rule, called the “Pediatric Testing Rule,” authorizing FDA to require certain drug manufacturers to conduct research in children for drug labeling purposes. [42] At virtually the same time, Congress enacted the FDA Modernization Act of 1997 (FDAMA),[43] which established market incentives to encourage drug companies to conduct pediatric testing, but did not authorize FDA to require those studies. In January of 2002, the incentives from the FDAMA were reauthorized by Congress under the Best Pharmaceuticals for Children Act (BPCA),[44] while in October of 2002, a federal district court judge in the District of Columbia invalidated the Pediatric Testing Rule.[45]
The problem of the “therapeutic orphan,” per se – meaning the problem of having available safety and efficacy data – is less pronounced for adolescents using psychotropic drugs. Ritalin has long been approved for use in pediatric populations, although it is not approved for use in children under age six, which is a significant portion of the ADHD population.[46] Prozac was recently approved for use in children and adolescents ages seven to seventeen.[47] However, there is still no information on the safety of the long-term use of either drug in children and adolescents, and there are a shortage of data investigating relative appropriateness of the various treatment routes – comparing particular drugs to each other and comparing the use of drugs in general to other treatment techniques such as psychosocial services and biofeedback.[48] Moreover, even the safety of drugs already approved is under question: Prozac has been shown possibly to stunt growth in adolescents,[49] and the addictive nature of Ritalin has been noted. [50]
The use of antidepressants in adolescents must be handled delicately; providers should make careful and well-considered diagnostic and treatment decisions, and parents and teachers should closely monitor adolescents in treatment to ensure continued healthy development and appropriate social support and medical follow-up. Yet ultimately the use of antidepressants in adolescents does not present fundamentally unique concerns among adolescent populations (as compared with adult populations), as does the use of stimulants in adolescent ADHD patients (as compared with child populations). In this Part, I argue that the regulation of antidepressants for the adolescent market can safely be – and in fact should be – encouraged in much the way that is currently being undertaken through the scheme laid out in the BPCA; I call this the “treatment-oriented model” of regulation. I then turn to the more complex problems of developing drugs for, and determining how they should be used in, adolescent populations for the treatment of ADHD. After describing several salient concerns with the diagnosis of ADHD and the prescription of stimulants to treat the disorder in adolescents, I argue that FDA should act to facilitate a more holistic, public health-focused strategy for the acquisition of knowledge about ADHD and I note a few basic elements of that proposed strategy; I call this the “community-oriented model” of regulation.
A. Depression: A Treatment-Oriented Approach
1. Application of the Treatment Model to Antidepressant Drug Regulation .
Although the adolescent patient and her family certainly participate in the decision to initiate treatment with antidepressant medication, such courses of treatment, and the medications prescribed, are subject to the almost-exclusive control of primary care providers, [51] and are thus more accurately characterized as falling within a professional “treatment model” of drug prescription, rather than a more holistic “community model.” For example, the adolescent’s relationships with others, such as teachers, coaches, and peers, while usually offering to the prescribing practitioner an additional perspective on the youth’s mental health for diagnostic purposes (for example, if she increasingly shuns her friends or begins skipping sports practices), do not usually serve as active diagnostic participants, as they so often do for ADHD, in which, for example, teachers regularly provide assessments and referrals for diagnosis, and diagnosing physicians spend little time actually examining children before prescribing stimulants.[52]
Moreover, the diagnosis of, and subsequent treatment for, depression fall aptly into the treatment-oriented model because, notwithstanding a sharp difference in developmental stage, the adolescent experience of depression does not necessarily deviate in significant ways from the adult experience of the disease. For example, there is some indication that many adolescents suffering from depression severe enough to warrant treatment with psychotropic medications are simply contending with their first bout of what they will experience as a chronic disease;[53] chronic depression often materializes around the time of the onset of puberty. [54] Some support for this contention can be found in utilization patterns of psychotropic drugs: trends for treatment with antidepressants in older adolescents are similar to those found in adults. [55] In this way, the depressed adolescent patient may more closely resemble an adult patient than a child patient.
If we assume either that the adolescent patient obtains the legal power to act as an adult in her medical decision making or that she has a parent or guardian providing consent and supervising the therapeutic process, it can be presumed that, absent special circumstances, her interests are adequately represented in her relationship with her provider with respect to her drug treatment plan. Community interventions or other public-focused programs are not necessary to mediate the decision between provider and patient (or patient’s guardian) to attempt treatment with antidepressants, because this is a classic, private professional relationship protected by state consent laws. Thus, in the area of medical attention for depression, the progression from diagnosis, treatment decision, and follow-up therapy might be conceptualized as following the traditional model of diagnosis and drug delivery.
This treatment model as applied to drug research and development primarily revolves around two main categories of actors: the pharmaceutical company and health care providers (with medical researchers in some sense uncomfortably straddling the two market niches). Professional health care providers are considered to be the best-positioned market players to make determinations about the safety, efficacy, and appropriateness of a particular course of treatment, and pharmaceutical researchers are considered to be the best-positioned market players to deliver the tools and material to make those decisions. Traditional FDA strategies in the regulation of drug development are primarily directed toward the first of those two major market players – pharmaceutical companies. FDA does not regulate the way that physicians use drugs once they are approved.[56] In this way, FDA has adopted a targeted regulation strategy that strikes a balance of regulating the safety and efficacy of the drugs produced, and then regulating the way information about safety and efficacy is transmitted to those with the decision making power regarding their prescription. Yet if FDA regulates medical professional behavior only indirectly by controlling physician access to drugs, it does not at all regulate – indeed, hardly considers at all – other actors in the system: patients, friends, colleagues, and health education entities.[57]
To the extent that antidepressant drug development and utilization patterns more closely follow this traditional model (in that they are initiated by pharmaceutical companies and mediated by medical providers), traditional FDA regulation strategies that focus on pharmaceutical companies should be appropriate to increase and improve research on use of antidepressants in adolescents.
2. The Best Pharmaceuticals for Children Act of 2002 as a Treatment-Oriented Approach
The most obvious way to conceptualize the Best Pharmaceuticals for Children Act of 2002 (BPCA) [58] is as a market incentive program – a “carrot,” if you will – designed to elicit child-oriented studies in drugs that FDA identifies “may produce health benefits in [the pediatric] population.”[59] In fact, that very market model itself – predicated as it is on the respective two-dimensional relationships between pharmaceutical companies and medical professionals, and between medical professionals and patients – meshes inextricably with the treatment-oriented model described in the previous section. The antidepressant drug market – modeled on the treatment orientation – should, by extension, therefore be responsive to the recently developed market incentive model advanced by the BPCA.[60] Because most antidepressants are still on-patent, they should respond admirably to the incentive of the six-month market exclusivity offered by BPCA.[61]
For those antidepressants that are off-patent already, pediatric comparative studies conducted by companies still holding exclusivity rights to newer drugs can offer helpful information about those drugs’ safety and relative efficacy in pediatric populations.[62] Indeed, the use of comparative studies presents the encouraging opportunity to gain good information about the effect of drugs on children while addressing one of the primary ethical concerns about conducting research in children: the use of placebo studies or untreated observation groups. Not treating all studied adolescents as part of an experimental group when conducting research can sometimes present a greater than justifiable risk for those children, especially when the efficacy of one drug treatment plan has already been established. [63]
Indeed, information from comparative and sociological studies evaluating the appropriateness – and not just the safety and efficacy – of various antidepressant drug regimens for use in adolescents could be so valuable that Congress or FDA should consider implementing even greater incentives for companies that undertake such studies. There are two options: First, FDA could simply define the studies it requests of drug companies as requiring comparative drug studies, and it could add parameters that include a sociological component to the research questions. In order to receive the grant of six months’ additional exclusivity, a company would be required to conduct the type of studies that FDA has requested. A second incentive could be for Congress to offer a cumulative additional six months of exclusivity, beyond those six months already granted for drugs on which are conducted general pediatric studies. The first strategy has the advantage of greater regulatory control: if companies do not produce the precise type of study requested, they simply do not receive the exclusivity. There should be few, if any, administrative costs of monitoring companies to ensure their compliance with the request because FDA already must approve study plans and ensure that they were followed under the current system. Moreover, it should be less difficult to implement, as FDA can issue case-by-case requests of companies and thus effectively change policy without having to consult with Congress, which for political reasons might be reluctant to enact a provision adopting the second strategy, which would allow for a full year of additional market exclusivity for those companies that conduct the specified studies.
A major drawback to the first strategy proposed above is that it may strain the regulatory role of FDA and its relationships with the companies conducting research. To determine whether and the extent to which FDA should exercise such directive power over pharmaceutical companies conducting pediatric research, it is instructive to analogize this proposal to the case of the recently-struck-down “Pediatric Testing Rule,”[64] which was promulgated by FDA in 1998 as a response to the problem of lack of pediatric studies in drugs being used in pediatric populations. The strategy of the Pediatric Testing Rule was one of coercive regulatory control rather than one of the market incentives adopted by Congress virtually simultaneously (in the FDAMA): FDA asserted that it had the power to require that companies conduct pediatric tests for designated drugs or to label those drugs as “misbranded,” subject almost entirely to FDA discretion.[65] When several parties claimed FDA did not have statutory authority to require that studies be conducted, a District of Columbia district court judge agreed. In Association of American Physicians and Surgeons, Inc. v. FDA ,[66] decided in October, 2002, the trial judge found that FDA could not situate any requirement that pediatric indications be placed on the labels of drugs within the labeling provisions of the FDCA,[67] nor within the misbranding provisions of the same act,[68] as pharmaceutical companies are free to label their drugs for whatever use they determine.[69]
Although the trial judge focused primarily on an interpretation of the Administrative Procedure Act and precedent regarding proper agency action to reach his decision, it seems that the underlying principle at stake in the case goes back to the principles of public health regulation articulated earlier in this paper. There is at least some indication that FDA may have technically had the authority to issue the Pediatric Testing Rule, as even the trial court judge acknowledged, when he conceded that the labeling requirement of 21 U.S.C. § 321(n), which “defines labeling as misleading if it ‘fails to reveal facts ... material with respect to consequences which may result’ from the use of the product as labeled or ‘from use of the article ... under such conditions of use as are customary and usual’.... speak[s] to some of the matters at issue here.” [70] The judge, though, refused to allow the authority of the rule making to rest on that one section, despite the strong administrative law principle of deference to FDA authority.[71] In fact, he looked instead to Congress’s passage of the BPCA, seeking to construe whether it operates in conflict with the Pediatric Testing Rule; if so, the Rule could be inferred as not having been authorized by Congress.[72] Where he found ambiguity in the Congressional legislative history, he presumed a conflict between the agency rule making and the statute, despite the Chevron [73] rule, which seems to dictate to the contrary. In this way, though the schemes could arguably be seen as being complementary to each other,[74] the judge presumed that Congress was a better public health decision maker than FDA; in effect he found that FDA violated its public health function by not following through on its obligation to seek the least intrusive solution first.[75] As the district court found, “Congress adopted an incentive scheme while the FDA adopted a command and control approach.”[76]
It is here that we arrive at a tension in the conduct of public health by a federal agency: the question whether a relatively unaccountable, but expert, agency is better-suited to make public health policy decisions or whether Congress, an accountable and therefore arguably more responsive body, can better assess and codify public health policy to address needs at the community level. The practice of public health calls for a balance between these often-competing functional principles: broad information-gathering and representation, as offered by Congress, and scientific expertise and detail-orientation, as offered by public health agencies. It would seem that the more responsive and flexible body should provide the tie-breaking advantage – in this case, Congress. In practice – and especially given the current “new federalism” in the Supreme Court’s jurisprudence[77] – yet a third type of actor – local community health policy boards, or, more specifically, Institutional Review Boards of local research institutions – offer the most distinct advantages of flexibility, accountability, and expertise.
From the picture drawn here of FDA’s notable shortcomings at enacting a more public health, community-oriented regulatory approach, it appears that FDA’s most appropriate and effective regulatory role is as a relatively two-dimensional, top-down (but not overly controlling) entity located, where it traditionally has been situated, at the nexus between drug development and labeling, regulating drug companies and indirectly exerting influence over medical professionals. In Part IVB, I will briefly propose a different model of community-oriented regulation and make tentative suggestions regarding how it can be implemented in the area of ADHD drug development, but for the remainder of this Part IVA I will briefly discuss application of the traditional regulatory model to the area of psychotropic drug research in adolescent populations, suggesting that this ethical, scientific and regulatory model can effectively and appropriately be followed to encourage the antidepressant drug research that is so badly needed.
3. How psychotropic drug research should be accomplished in adolescents .
Since the advent of our regulated drug market, drugs have not regularly been studied in pediatric populations.[78] Children are considered legally incompetent to consent to studies[79] and there are thus ethical and logistical problems with obtaining valid consent for such studies. Additionally, children develop rapidly and therefore may be more vulnerable to long-term harmful effects from studies gone wrong. Finally, as discussed above, there are very few drugs whose labeling and marketing in pediatric populations would offer sufficient financial incentives to justify the expense of conducting pediatric trials.
Studies investigating the safety and effectiveness of antidepressants in adults yield at least some relevant information, in at least some cases, that can be (and regularly is) extrapolated to adolescent patients.[80] Thus, it is ethical, and indeed preferable, at least to initiate studies in adults before shifting to studies of adolescents (and younger children).[81] Yet although it might be reasonable to use adult research studies to extrapolate appropriate doses for adolescent use of antidepressants,[82] at least at first before adequate pediatric studies have been conducted, for reasons discussed earlier in this paper, it is important that these drugs, which are used regularly and frequently in adolescent populations, be assessed for safety, dosage, and long-term effect in this rapidly developing group of patients. Additionally, studies investigating the appropriateness of drugs relative to each other and relative to other treatment methods should be encouraged.
FDA can regulate these studies using its usual techniques, although two special modifications are in order: First, FDA and Congress should consider implementing some incentives for companies to conduct comparative and sociological research assessing the use of antidepressants specifically in adolescent populations. Second, FDA must coordinate with DHHS to fine-tune current ethical guidance for human subject research in adolescent populations to take into account the unique concerns with that group. The previous section addressed the first of these strategies,[83] while this section addresses the second of these strategies.
A threshold determination when adolescents participate in research studying psychotropic drugs is whether adolescents are pediatric subjects – “children” – as defined by the regulations governing researched conducted or supported by the Department of Health and Human Services,[84] or whether they are treated like adults for the purposes of consent to research and further IRB monitoring of the research. Subpart D, as this section of the Human Subjects protections is known, specifies that adolescents are “children” for the purpose of receiving special protection in research if they “have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted.”[85]
Thus, researchers must determine whether in the applicable jurisdiction – usually the state in which the research takes place – adolescent consent alone is sufficient to obtain treatment with psychotropic drugs. The law regarding minor consent to medical care varies greatly from state to state, and also varies depending on the particular medical condition involved and on factors such as the minor’s living condition or legal status. [86] This patchwork of jurisdictional consent-to-treatment law, which in turn begets a fragmented set of laws governing the designation of adolescents as “children” for the purposes of research, presents the possibility that adolescent research protections could differ markedly depending on the state in which the research takes place. In order to mitigate potential confusion, investigators of large, multi-state-based research trials would probably prefer uniform procedures; thus, if a study includes children from any one state that provides that an adolescent may not consent to receive psychotropic medication, researchers would presumably institute pediatric protective measures for all of their adolescent subjects, which would include parental consent and involvement in the research.[87] This strategy would certainly be in line with that of the many states that explicitly provide that minors may not consent to receive psychotropic drugs without parental consent.[88]
When psychotropic drug trials involve adolescents who would be considered “children” for the purposes of human subject protection, a determination of the applicable regulatory protections is made according to a graded risk assessment scale delineated in Subpart D, which assesses the prospect of risk as weighed against the possibility of direct benefit to the child.[89] The greater the risk to the child, and the less likely that there is a specific benefit for the child, the more stringent the requirements about the prospect of the research yielding generalizable knowledge and the familiarity of the protocols.[90] Psychotropic drug trials in adolescents involving experimental protocols would almost certainly fit into either the second or the third category of analysis: they offer greater than minimal risk and whether they offer direct benefit to the subject depends on whether there is a possibility that a subject might receive a placebo.
Thus, the less risky the research, and the less likely that the confidentiality and privacy of the children subjects is at stake, the more likely Institutional Review Boards are to allow a waiver of parental consent.[91] For example, IRBs are much more comfortable allowing anonymous surveys, in which no identifying information is collected, to be conducted without parents’ knowledge. Much has been said about adolescent needs for confidentiality in health care, particularly confidentiality protections from their parents.[92] Indeed, a guarantee of confidentiality is often cited as a major concern with respect to access to adolescent health care services. Thus, a protocol that purports to protect adolescents’ confidentiality by involving their parents seems a little ironic. Still, as many jurisdictions have recognized, the decision to undertake treatment with psychotropic medications, while certainly involving a sensitive subject that deserves the utmost respect and privacy, should involve the parents of the adolescent patient. And even more compellingly, research into safety and efficacy, and also into long-term safety and appropriateness, should involve parents. [93] Thus, despite adolescents’ very real concerns for confidentiality and the sensitive nature of mental health concerns, as well as their relative maturity compared to younger children, research guidelines should continue to require parental involvement in studies of psychotropic drugs. Parents provide a necessary support for their adolescent children and can help to mediate many of the inevitable struggles that their children will face due to their mental health challenges.
In sum, the current guidelines issued by FDA and DHHS governing research in children allow ample guidance for researchers to conduct rigorous yet ethical research on antidepressants in adolescents. Parents should continue to be involved in the research and their consent should be required in all but the most extreme cases.[94] This top-down regulatory approach, allowing considerable discretion from local institutional review boards, is consistent with FDA’s public health mandate and does not conflict with other health promotion efforts, because adolescent interests can be represented adequately in the treatment model for depression.
B. ADHD: A Community-Oriented Approach
On first glance from a regulatory perspective, it may appear that there is no problem with the current marketing and use of stimulants such as methylphenidate to treat ADHD. After all, the drugs are approved in children age six or older,[95] and the use of stimulants continues to be studied thoroughly. Still, “there are no well-designed, long-term studies employing [stimulant and psychosocial] treatments beyond 14 months nor is there information on long-term outcomes of drug therapy on educational and occupational achievements, involvement with police, or other areas of social functioning.”[96] And there is agreement in the scientific literature that up to 80% of diagnosed hyperactive children continue to display symptoms of the disorder throughout adolescence, and as many as 65% of those children persist with symptoms into adulthood.[97] Thus, though stimulants have not been studied for long-term safety and efficacy, they are increasingly being relied upon by older adolescents and adults, populations that account for a large proportion of the huge increases in their use over the last decade.[98] Additionally, the use of stimulants in such widespread fashion in the United States has been subject to heated criticism due to the huge numbers of youths receiving diagnoses of ADHD, especially when such diagnostic techniques are so subjectively based. There is a sense, then, that parents and teachers increasingly enlist the help of stimulants as either performance enhancers or obedience inducers for teenagers that they want to control.[99]
1. Problems in Diagnosing Adolescents with ADHD
Adolescents are a particularly vulnerable population for the purposes of assessment for psychological conditions because their developmentally normal risk-taking behavior[100] can all-too-often be construed as maladaptive or unhealthy. As families increasingly suffer from the stresses of two parents working in a demanding job market, and as the media focus on the bad behavior of teenagers continues, the temptation to treat youths’ psycho-social problems with a “magic pill” intensifies.
Indeed, there are disturbing indications that socio-cultural factors play a significant role in driving psychiatric diagnoses for adolescents, particularly ADHD. First, scientists and clinicians have not developed valid clinical criteria for diagnosis of ADHD.[101] For example, there is much debate in the literature about whether to conceptualize ADHD as a “categorical” or a “dimensional” disorder, [102] meaning whether children and adolescents who are determined to have ADHD are different in kind or degree from other “normal” children. Moreover, “[a]ll formal diagnostic criteria for ADHD were designed for diagnosing young children and have not been adjusted for older children and adults.”[103] Second, there are differences in diagnostic practices and outcomes between school-based and medical practice-based services, and among different kinds of physicians.[104]
Third, there is also the strong possibility that gender and race operate as factors in diagnosis (and subsequent treatment) of disorders such as ADHD. According to the Congressional Testimony regarding abuse of methylphenidate given by Terrance Woodworth, who is Deputy Director of the Office of Diversion Control at the Drug Enforcement Administration, “boys are four times more likely to receive a diagnosis of ADHD and be prescribed stimulant medication.” [105] And others have detected a recent upswing in the number of girls being diagnosed with ADHD, indicating a cultural shift in diagnosis that has little to do with biology.[106] Racial disparities in the prescription of psychotropic drugs have also been measured. In one study, African-American children were “less likely to receive stimulants and antidepressants despite a lack of evidence supporting racial differences in the prevalence of ADHD or childhood depression.”[107]
Fourth, international comparative prescription practices of methylphenidate also point to differences in cultural perception of ADHD: “According to the United Nations, the U.S. produces and consumes about 85 percent of the world’s production of methylphenidate.”[108] Indeed, even differences among United States communities (and closely related communities) have been found, reflecting the very real possibility of some sort of snowball effect in a community: once a critical mass of children get the diagnosis and treatment, others follow. For instance, one study that attempted to measure stimulant prescription patterns for ADHD found sharp differences in rates of reported ADHD across several of the studied communities. It attributed these differences to reporting rates, postulating the existence of “different cultural thresholds to what constitutes acceptable versus deviant behaviors.”[109]
Fifth, differences in the prescription of all psychotropic drugs (not just stimulants) have been detected between populations enrolled in an HMO and populations of children covered by Medicaid. The possibility that much of this difference is attributable to underlying psychological and health differences in the populations is quite likely.[110] Yet differences in treatment plans independent of underlying diagnosis and health status have been found based on health plan coverage. A recent study of the utilization of antidepressants and psychiatric services compared two state Medicaid programs and found that in one population, 58% of antidepressant-treated youths were receiving psychiatric services (as opposed to simply general primary care services), while in the other population, only 28% of antidepressant-treated youths were receiving psychiatric services. The authors attributed this difference, not to underlying differences in the patient population, but to the variation in availability of specialty psychiatric providers between the two plans. This suggests that treatment – and probably underlying diagnosis – patterns vary considerably depending on health care access and utilization factors such as health care coverage and financing determinations. [111] Moreover, a study comparing insured and uninsured children found that the use of prescribed psychotropic medications among children without health insurance was far below that of children with health insurance coverage.[112]
2. Problems in Treating Adolescents with Stimulants
Even if the diagnostic technique is successful at identifying children truly in need of attention and treatment for either ADHD or depression, there is no consensus on whether psychotropic medications are currently prescribed too little, too much, or in the right amounts. Recent evidence suggests that ADHD may be undertreated, with one study finding that as few as one in eight children diagnosed with ADHD received treatment with medications.[113] The same study, however, also found that half of the children who were prescribed stimulants did not actually meet the diagnostic criteria for ADHD.[114] Moreover, some researchers, following the “continuum” model of the condition, contend that “under some circumstances and for some children, specific ADHD behaviors and traits might constitute adaptive behaviors that can also be maladaptive in other settings.”[115] In these cases, even if a diagnosis is made according to standardized and well-established criteria, it might nevertheless counsel against treatment, because it might be considered sensible not to treat symptoms that are deemed to be adaptive to a particular social environment. Indeed, prescribing medication may inhibit the youth’s capacity to develop independent, effective coping mechanisms in the face of such conditions.[116]
Much uncertainty and conflict abounds about the risks of harmful biological effects from the prescription of psychotropic drugs in adolescents; most of the concern centers around methylphenidate, which is a stimulant classified by the DEA in Schedule II for its highly addictive qualities, its abuse potential, and its similarity to cocaine and methamphetamines. [117] The popular media are replete with stories of teenagers trading Ritalin and of teachers raiding medicine cabinets at schools to feed their speed addictions.[118] However, a recent General Accounting Office study, commissioned by Congress to address concerns about Ritalin abuse in schools, found little cause for concern about Ritalin dealing or abuse in schools.[119] Although most researchers agree that ADHD children experience later problems with substance abuse,[120] studies attempting to measure whether children treated for ADHD with stimulants are more likely than those who are not treated with stimulants to experience later problems with substance abuse have produced conflicting results. [121]
Treatment decisions become even more problematic in the large numbers of adolescents who have comorbid conditions, meaning they have both a diagnosis of depression and of ADHD. Some assert that “depression can be a by-product of wrestling with ADHD”;[122] although there are other indications that the two conditions may simply co-occur due to genetic or environmental factors.[123] Regardless of the causes of the comorbidity, many adolescents receive the diagnosis and are treated with both stimulants and antidepressants.[124] Without further study, there is no way to tell whether the combination of, for example, stimulants and antidepressants, is safe or effective in children and adolescents. [125]
Thus, as is the case with antidepressants, there is an information gap between what we know about the safety and efficacy of stimulants[126] and what we know about their cultural appropriateness. However, in contrast to the case with antidepressants, those who represent adolescent interests, such as parents and teachers, simultaneously possess more power to make treatment determinations (as they are frequently the primary diagnostic actors) and are subject to greater socio-cultural incentives to medicate. Because stimulants are off-patent, and because they are already approved for children down to age six, pharmaceutical companies and academic researchers have few incentives to conduct further research investigating stimulants’ cultural appropriateness. The next section will briefly note various ways that community-based initiatives can seek to fill this information gap, and it will note how those strategies are consistent with a more holistic concept of conducting “public health” activities.
3. School-Based Initiatives – Research and Treatment
Since the early 1990s, it has increasingly been recognized that a great deal of public health and health care delivery targeted at adolescents can be successfully conducted in their schools.[127] School-based health centers (SBHCs) have sprung up across the country; they typically comprise community-school partnerships and deliver primary care, preventive care, and various types of public health services such as peer health education and violence counseling.[128] The structure and philosophy of SBHCs is such that, working as a network, they could successfully accomplish many public health tasks, as described by Larry Gostin:
[Public health’s] features include an emphasis on the promotion of health and the prevention of disease and disability; the collection and use of epidemiological data, population surveillance, and other forms of empirical quantitative assessment; a recognition of the multidimensional nature of the determinants of health; and a focus on the complex interactions of many factors – biological, behavioral, social, and environmental – in developing effective interventions.[129]
SBHCs could conduct such public health surveillance, and the adolescent-focused health care providers that work in them could be expected to offer a more holistic and sympathetic representational model for adolescents in conducting that research.[130] Indeed, the kind of research that SBHCs could conduct organically in the school environment, which is the cultural backdrop against which the ADHD phenomenon is held in stark relief, is not replicable in the research labs at hospitals and academic medical centers. Answers to the sorts of pressing questions that are currently being asked about ADHD could readily be answered; as one group of researchers noted:
[S]tudies of community-based samples of U.S. children are needed that demonstrate exactly how many children within given communities suffer from ADHD, and among these afflicted children, what types of services (medication, school-based services, or psychotherapeutic treatments) they do (or do not) receive. Do some children receive ADHD treatments (such as psychostimulants) who do not meet criteria for ADHD, and if so, how widespread is this phenomenon?[131]
It has equally been recognized that SBHCs represent an excellent model for delivery of ADHD-related services. Because teachers so frequently act as the method of assessment for ADHD, they could provide referrals to ADHD specialty services in school clinics. Teenagers could receive on-site assessment, diagnosis, and follow up care, and the involvement of their parents could easily be enlisted.[132] As the scientists writing the NIH Consensus statement concluded: “School-based clinics with a team approach that includes parents, teachers, school psychologists, and other mental health specialists may be a means to remove these barriers [of problems and inconsistency in diagnosis, assessment, treatment, followup, and monitoring of adverse effect of therapy] and improve access to assessment and treatment.”[133]
4. FDA’s Role
FDA, as regulator and enforcer of well-delineated safety and efficacy guidelines, would not play a direct role in conducting or requiring the conducting of such school-based studies. It can, however, be responsive to – and encouraging of – the type of holistic information that can be gathered from such studies. One strategy that FDA could employ relates to the BPCA: when FDA commissions pediatric studies for indications of new ADHD drugs, it can specify that it be conducted by researchers working in school-based settings. A second strategy is related to existing labeling: FDA could ask that more specific “appropriateness” data, where it is available, be included on pediatric labels. Yet a third strategy would probably require Congress’s help: FDA could increase the labeling requirements of ADHD drugs to require companies to submit certain appropriateness data for either the label or a supplemental information sheet.
In sum, as opposed to the case with antidepressants, in the case of the prescription of stimulants in adolescents for ADHD, adolescents may need greater protection from social forces that would most likely err on the side of overprescribing stimulants. FDA should recognize this need for regulatory protection as a mechanism for encouraging community-based health promotion activities.
The Food and Drug Administration is a scientifically oriented law enforcement agency . Our mission is to provide consumer protection through judicious enforcement of the various laws which have been entrusted to our administration.
FDA Compliance Philosophy[134]
The BPCA market incentives approach is not “coercive” in the sense that it does not allow FDA to require pharmaceutical companies to conduct pediatric studies or risk being labeled “misbranded.” It certainly fits squarely within FDA’s “public health” mission to enforce laws regarding drug safety and efficacy entrusted to FDA. This is FDA’s primary role, as only one public health agency among hundreds of other public health actors: other agencies, Congress, and state and local public health actors. Yet FDA should pay attention to some of the consequences of its two-dimensional treatment-oriented approach for the performance of public health in the area of approval and prescription of psychotropic drugs in adolescents. In the case of the prescription of antidepressants for depression, FDA can implement, through existing market-based pathways, strategies to encourage studies investigating the relative appropriateness and long-term efficacy and safety of antidepressants in adolescents. Moreover, where necessary, research protections can be loosened to allow further research in adolescents. In the case of the prescription of stimulants for ADHD, there are some indications that certain societal pressures may be placing adolescents in a position where they are vulnerable to receiving default treatment with stimulants that might not be the most appropriate path – the allure of stimulants to teachers and parents is simply too strong. FDA’s wholesale approval of stimulants for use in children over age six, along with their long-time patent expiration, has effectively eliminated any market incentives to investigate the full socio-cultural context of the treatment of ADHD through school-based, community-oriented initiatives. In this way, FDA’s fulfillment of its own regulatory “public health” mission may have stunted another component of the public health mission – health promotion and broad community education. FDA can accommodate this mission while continuing to execute its own by facilitating the dissemination of more holistic and comprehensive information about stimulants.
[*] JD candidate, Harvard Law School, degree expected June 2003. Paper prepared in fulfillment of the requirements for the HLS course in Food and Drug Law, taught in Winter 2003 by Peter Barton Hutt.
[1] James F. Childress, Ruth R. Faden, Ruth D. Gaare, Lawrence O. Gostin, Jeffrey Kahn, Richard J. Bonnie, Nancy E. Kass, Anna C. Mastroianni, Jonathan D. Moreno, & Phillip Nieburg, Public Health Ethics: Mapping the Terrain , 30 J. L. Med. & Ethics 170, 170 (2002).
[2] Pub. L. No. 75-717, 52 Stat. 1040 (codified as amended at 21 U.S.C. § 301 et seq. (2000)).
[3] See United States v. Article of Drug ... Bacto-Unidisk, 394 U.S. 784, 798 (1969) (construing the FD&C Act liberally, “consistent with the Act’s overriding purpose to protect the public health”). See also Food and Drug Administration: About the Food and Drug Administration, at http://www.fda.gov/opacom/hpview.html (“Stated most simply, FDA’s mission is to promote and to protect the public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use.”).
[4] Lawrence O. Gostin, Public Health Law: Power, Duty, Restraint 4 (2000).
[5] See id. at 18-21.
[6] Representative protective measures are: seizure actions for defective medical devices, unsafe drugs, or contaminated food; and occupational health and safety regulations. See id. at 86-87.
[7] The distinction I am making here – between health promotion and public health coercion – is different from the tension, described by Larry Gostin, between regulation and autonomy. Gostin’s distinction is between the necessity of government action in some cases and the necessary limits on that action in the name of constitutional liberty. I am articulating a distinction between two types of government action: one that imposes negative limits on personal (and commercial) behavior (usually public health law and regulation) and another that encourages positive action from a community (usually public health promotion activities).
[8] FDA’s regulatory action should thus be viewed as “coercive” under the public health law model.
[9] For the purposes of limiting its scope, this paper will focus on the conditions of depression and attention deficit hyperactivity disorder in adolescents, and will limit its discussion to the prescription of antidepressants and stimulants, respectively, for the treatment of those conditions.
[10] See 21 U.S.C. § 355 (2000) (providing for approval of drugs for use when studies have been conducted that show their safety and efficacy); see also 37 Fed. Reg. 16503 (August 15, 1972) (allowing for “off-label” prescription of drugs by physicians once the drugs have been approved as safe and effective by FDA for labeled uses).
[11] Pub. L. No. 107-109 (January 4, 2002).
[12] Adolescents are not merely big children, despite – like all children – having minor status up to age eighteen and being subject to the parceling-out of only very limited rights to autonomy in health care decision making, limited rights to drive, work – all of which slots adolescents into the category of children for legal purposes.
[13] Indeed, the outward signs of puberty may lead us to believe that adolescents are more mature psychologically or cognitiviely than they actually are. Anne C. Petersen & Nancy Leffert, Developmental Issues Influencing Guidelines for Adolescent Health Research: A Review , 17 J. Adolescent Health 298, 298 (1995) (“Despite the extent of biologic change associated with puberty, it is important to note that it does not produce maturation in other areas. Cognitive and psychosocial development may be on entirely different timetables.”). Adolescents cannot be considered small adults, despite the fact that they can be tried as adults for their crimes and that they often exhibit markedly autonomous decision making and risk-taking behavior. See also S. Rep. 105-43 (1997) (“Children have for years been wrongly considered ‘small adults’ when estimating the effect of prescription drugs on their overall health.”).
[14] Petersen & Leffert, supra note 13 (“The biologic changes that occur during this period are dramatic and relatively rapid.”).
[15] Id. at 300-01 (describing shift to autonomous functioning and conflict with parents). See generally Susan G. Millstein & Vivien Igra, Theoretical Models of Adolescent Risk-Taking Behavior , in Adolescent Health Problems: Behavioral Perspectives 52 (J.L. Wallander & L.J. Siegel eds., 1995).
[16] See Petersen & Leffert, supra note 13, at 299-300.
[17] At least 80% of adult smokers become addicted by the age of 18. Sharon Milberger, Joseph Biederman, Stephen V. Faraone, Lisa Chen, & Janice Jones, ADHD Is Associated with Early Initiation of Cigarette Smoking in Children and Adolescents , 36 J. Am. Acad. Child & Adolescent Psychiatry (1997) (citing American Health Association, Action Alert! , The Nation’s Health , October, 1995, at 4).
[18] Id.
[19] See, e.g., Nancy Gibbs, The Age of Ritalin , Time , November 30, 1998, at 17; LynNell Hancock, Mother’s Little Helper , Newsweek , March 18. 1996, at 51; Jeffrey Kluger, Next Up: Prozac , Time , November 30, 1998, at 21.
[20] Millstein & Igra, supra note 15, at 61 (“Risk-taking behaviors may serve to fulfill [adolescent] developmental needs ... such as autonomy, mastery, and intimacy. As such, many developmental theorists view risk taking as a necessary and important part of the growing up process.”). See also Lynn E. Ponton, The Romance of Risk: Why Teenagers Do the Things They Do (1997).
[21] See 16(2) NIH Consensus Statement No. 110: Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder (November 1998), at http://odp.od.nih.gov/consensus/cons/110/110_statement.htm (“All formal diagnostic criteria for ADHD were designed for diagnosing young children and have not been adjusted for older children and adults.”) [hereinafter NIH Consensus Statement ]; id. (“[T]here are no conclusive data on treatment in adolescents and adults with ADHD.”).
[22] See, e.g., Julie Magno Zito, Daniel J. Safer, Susan dosReis, James F. Gardner, Laurence Magder, Karen Soeken, Myde Boles, Frances Lynch, & Mark A. Riddle, Psychotropic Practice Patterns for Youth: A 10-Year Perspective , 157 Arch. Pediatrics Adolescent Med. 17 (2003).
[23] See id. at 22 (“Youths aged 10 to 14 years surpassed 5- to 9-year-olds as the predominant stimulant-treated age group, reflecting a lengthening of the duration of treatment.”).
[24] See Kluger, supra note 19; Mark Olfson, Steven C. Marcus, Myrna M. Weissman, & Peter S. Jensen, National Trends in the Use of Psychotropic Medications by Children , 41 J. Am. Acad. Child & Adolescent Psychiatry 514 (2002) (documenting “a sharp increase in the first onset of major depression during adolescence”).
[25] See, e.g. , Ronald C. Kessler, Shelli Avenevoli, & Kathleen Ries Merikangas, Mood Disorders in Children and Adolescents: An Epidemiologic Perspective , 49 Biological Psychiatry 1002, 1002 (2001) (“Epidemiologic studies show that major depression is comparatively rare among children, but common among adolescents, with up to a 25% lifetime prevalence by the end of adolescence .... Retrospective reports about age of onset in adult studies suggest that at least 50% of youngsters with major depression and 90% of those with mania continue to have adult recurrences.”).
[26] See id. (“It is noteworthy ... that studies of manic adults consistently find that between 25 and 40% of adults with a lifetime history of mania report that their first manic episode occurred during their childhood or adolescence.”). Mental illness, especially depression and mania, is strongly linked to biological causes, see id. (“Twin, family, and adoption studies all strongly suggest that genetic factors are important determinants of depression and even more so of bipolar disorder.”); but can also arise from, and be exacerbated by, certain social and environmental situations, such as childhood abuse; other trauma that results in post-traumatic stress disorder; inadequate education, health care and nutrition; and difficult socio-economic circumstances. See id. A catalog and discussion of the multitude of possible causes and symptoms of psychiatric disease, many of which occur as comorbidities for a sizeable proportion of those who are afflicted with mental illness, is beyond the scope of this paper.
[27] Id. Cohort studies also consistently show that fewer than 50% of adolescents with depression receive treatment before they reach the age of 18. Id.
[28] FDA approved Prozac for use in children and adolescents 7 to 17 years old only in January of 2003. See FDA Talk Paper, FDA Approves Prozac for Pediatric Use To Treat Depression and OCD , at http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01187.html [hereinafter FDA Talk Paper]. The approval was based on two recent placebo-controlled studies. Id. Drug information resource guides continue to caution that “further study is needed to more fully evaluate safety and efficacy” of selective serotonin-reuptake inhibitors such as Prozac. Fluoxetine Hydrochloride, AHFS Drug Information (2002).
[29] See, e.g., Fluoxetine Hydrochloride, AHFS Drug Information , supra note 28 (citing lack of overall efficacy of TCAs); cf. Paul Perry, Pharmacotherapy for Major Depression with Melancholic Features: Relative Efficacy of Tricyclic Versus Selective Serotonin Reuptake Inhibitor Antidepressants , Virtual Hospital: Clinical Psychopharmacology Seminar , December, 2000, at http://www.vh.org/adult/provider/psychiatry/CPS/14.html (reviewing studies and concluding that TCAs can work better for melancholic depression, but not separating effects on youths and adults).
[30] See, e.g., Norman Fost, Ethical Issues in Research and Innovative Therapy in Children with Mood Disorders , 49 Biological Psychiatry 1015 (2001) (“Efficacy [of drug treatment for mood disorders] may be confounded by problems with diagnosis, since mood disorders in children are not always well defined, and may be confounded by other affective, behavioral or environmental problems.”).
[31] See Peter S. Jensen, Lori Kettle, Margaret T. Roper, Michael T. Sloan, Mina K. Dulcan, Christina Hoven, Hector R. Bird, Jose J. Bauermeister, & Jennifer D. Payne, 38 J. Am. Acad. Child & Adolescent Psychiatry 797 (1999).
[32] Id. , see also Hancock, supra note 19 (“Finding someone who will [prescribe Ritalin] is distressingly easy.”).
[33] See Kessler, Avenevoli, & Merikangas, supra note 25 (noting that diagnostic “interviews [for depression] are typically administered to multiple respondents, usually including a parent, a teacher, and the child or adolescent” and describing the consequent “uncertainty as to how the data from these informants should be combined to yield diagnoses”).
[34] See, e.g., Olfson, Marcus, Weissman, & Jensen, supra note 24 (“[R]esearch comparing the tricyclic antideptessants [sic] to placebo consistently indicated that these antidepressants were not efficacious in children and adolescents .... [U]ncertainty continues to surround the effectiveness of the newer classes of antidepressant medications in the community treatment of childhood and adolescent depression and related anxiety disorders.”).
[35] See NIH Consensus Statement , supra note 21 (noting that “an independent diagnostic test for ADHD does not exist”); see also Mary Eberstadt, Why Ritalin Rules , Pol’y Rev. , at http://www.policyreview.org/apr99/eberstadt_print.html (describing the “causal fallacy prevalent in ADD literature – that if a child responds positively to Ritalin, that response ‘proves’ that he has an underlying biological disorder”).
[36] 37 Fed. Reg. 16503 (August 15, 1972).
[37] There is a third possible reason for lack of research: a pharmaceutical company may be concerned about the possibility of unfavorable research results for a particular population or disease. In this case, regulatory intervention may be needed to uncover the problems with the drug.
[38] See Jeffrey L. Blumer, Off-Label Uses of Drugs in Children , 104 Pediatrics 598 (1999) (“Along with pregnant women, infants and children remain therapeutic orphans. This condition is understandable because there are very few therapeutic indications that are unique to this patient population and the absolute quantities of drugs required by these patients remains relatively small.”).
[39] Id.
[40] For an excellent overview of these actions, see Derek Ho, Adopting the Therapeutic Orphan? A Legal and Regulatory Assessment of the FDA’s Pediatric Testing Rule , Winter 2000, unpublished manuscript on file with the author, at 13-17, 30-35. This paper will offer only a brief timeline of FDA and Congressional actions.
[41] Pediatric Use Labeling Rule, 59 Fed. Reg. 64,240 (1994).
[42] Pediatric Testing Rule, 63 Fed. Reg. 66,632 (1997).
[43] Pub. L. No. 105-115 (November 21, 1997).
[44] Pub. L. No. 107-109 (January 4, 2002).
[45] Association of American Physicians and Surgeons v. FDA, 226 F. Supp. 2d 204, 204 (2002).
[46] See Ritalin (Methylphenidate Hydrochloride) , Physicians’ Desk Reference (2002).
[47] See FDA Talk Paper, supra note 28.
[48] See NIH Consensus Statement , supra note 21.
[49] See FDA Talk Paper, supra note 28.
[50] See infra TAN 117-121.
[51] Julie Magno Zito, Daniel J. Safer, Susan dosReis, James F. Gardner, Karen Soeken, Myde Boles, & Frances Lynch, Rising Prevalence of Antidepressants Among U.S. Youths , 109 Pediatrics 721 (2002) (attributing a substantial portion of the prescription of antidepressants for youths to primary care providers, and suggesting that more research needs to be done regarding the effectiveness of antidepressants when prescribed in a nonpsychiatric setting). Even when antidepressants are not prescribed by a primary care provider, they are prescribed by a psychiatric subspecialist; rarely do non-medical professionals contribute substantially to the decision to treat an adolescent with an antidepressant.
[52] See Hancock, supra note 19 (“Almost half the pediatricians surveyed ... said they send ADHD children home in an hour. With such a rapid turn-around, many doctors never talk to teachers, review the child’s educational levels, nor do any kind of psychological work-up – all essential diagnostic elements. Most children only get a prescription.”).
[53] See Kessler, Avenevoli, & Ries Merikangas, supra note 25, at 1002, and TAN 25.
[54] See, e.g., Olfson, Marcus, Weismann, & Jensen, supra note 24 (“[T]here is a sharp increase in the first onset of major depression during adolescence.”).
[55] Zito, Safer, dosReis, Gardner, Soeken, Boles, & Lynch, supra note 51.
[56] See Legal Status of Approve Labeling for Prescription Drugs; Prescribing for Uses Unapproved by the Food and Drug Administration: Notice of Proposed Rule Making, 37 Fed. Reg. 16503 (August 15, 1972) (“Congress clearly required the Food and Drug Administration to control the availability of drugs for prescribing by the physicians .... As the law now stands, therefore, the Food and Drug Administration is charged with the responsibility of judging the safety and effectiveness of drugs and the truthfulness of their labeling. The physician is then responsible for making the final judgment as to which, if any, of the available drugs his patient will receive in the light of the information contained in their labeling and other adequate scientific data available to him.”).
[57] The rise of direct-to-consumer advertising has altered this balance in ways that some consider greatly troubling. A discussion of this new element in drug distribution is beyond the scope of this paper; it is sufficient to note that the great controversy surrounding the expansion of the drug “market” beyond the relationship between the pharmaceutical companies and physicians illustrates the otherwise entrenchment of the binary market and the near-exclusive focus on the relationship between pharmaceutical companies and physicians that I describe here.
[58] Pub. L. No. 107-109. The BPCA was enacted to extend relevant provisions of the Food and Drug Administration Modernization and Accountability Act of 1997, Pub. L. No. 105-115 [hereinafter FDAMA], which were set to sunset on January 1, 2002.
[59] FDAMA § 505A.
[60] This suggestion, of course, assumes that any area of drug development will be responsive to the BPCA; in other words, this argument assumes that the BPCA is actually an efficient and effective way to increase and improve any drug development for children. Given that assumption, the point is that drugs and disease that more closely align with the traditional model will be the ones most well-suited to take advantage of the relatively traditional market-based regulatory scheme laid out in the BPCA. Although the verdict is still out on its effectiveness, I argue here that as a matter of regulatory process the BPCA is the most appropriate next step in the attempt to improve the quality, safety and efficacy of antidepressant drugs for adolescents.
[61] Prozac was the first selective serotonin reuptake inhibitor to go off-patent in 2001, and its case illustrates this point nicely. One of the strategies employed by Lilly (in addition to litigation) to preserve its patent on Prozac was to conduct and report pediatric studies to FDA. In doing so, its right to market exclusivity was extended by FDA for the first six months of 2001. See Karena J. Cooper, Pediatric Marketing Exclusivity – As Altered by the Best Pharmaceuticals for Children Act of 2002 , 57 Food & Drug L. J. 519, 534 (2002).
[62] Moreover, Lilly still has the patent on the once-weekly formulation of Prozac, which could resolve many uniquely adolescent problems, such as compliance/monitoring, stigma, and the tedium of taking pills. Lilly thus has incentives to conduct some dose-related Prozac research in adolescents.
[63] See Committee on Drugs, Guidelines for the Ethical Conduct of Studies To Evaluate Drugs in Pediatric Populations , 95 Pediatrics 286 (1995) (“Placebo or untreated observational control groups can be used in pediatric studies if their use does not place children at increased risk.”); Norman Fost, Ethical Issues in Research and Innovative Therapy in Children with Mood Disorders , 49 Biological Psychiatry 1015 (2001) (“[A] placebo may be less toxic than the active treatment. Thus, if the trial is truly in equipoise, the investigator (and the informed patient) should be uncertain whether the patient will in fact be better off with the placebo or the active agent.”).
[64] 63 Fed. Reg. 66,632 (December 2, 1998) ( codified in scattered sections of 21 C.F.R.).
[65] See supra TAN 42.
[66] 226 F. Supp. 2d 204 (D.D.C. 2002).
[67] 21 U.S.C. §§ 352(a), (f), 355(d)(7), 321(n).
[68] 21 U.S.C. §§ 321(p), 331(a), (d), 355(a), (j), (d).
[69] 226 F. Supp. 2d at 218 (“FDA’s argument proves too much. If 21 U.S.C. § 355(d) truly gave the FDA the authority that it claims, the door would be open to FDA’s regulation of all off-label uses, based solely on the manufacturer’s knowledge that those uses are common-place. This authority would surely conflict with Congress’ will and would eviscerate the long-established foundation of federal food and drug law, which allows, not the FDA, but the ‘manufacturer of the article, through his representations in connection with its sale, [to] determine the use to which the article is to be put.’” (footnote and citation omitted) (alteration in original)).
[70] Id. at 213-14 (citing 21 U.S.C. § 321(n)) (first and second omissions in original); Ho, supra note 40, at 20-23, (arguing that the Pediatric Testing Rule was authorized under § 321(n)).
[71] See Ho, supra note 40, at 19 (citing cases supporting the idea that any FDA regulation should be upheld “as long as the regulation is designed to satisfy a congressional objective that is expressed somewhere in the FDCA”).
[72] See 226 F. Supp. 2d at 219-22 (finding that the legislative history regarding the BPCA Congress’s intent with respect to the Pediatric Testing Rule was inconclusive, yet finding that the BPCA and the Rule were incompatible regimes and striking down the Rule on that basis).
[73] Chevron, U.S.A., Inc. v. National Resources Defense Council, Inc., 467 U.S. 837 (1984).
[74] See generally Ho, supra note 40 (arguing that FDA should exercise its authority under the Pediatric Testing Rule if market incentives do not work).
[75] See Gostin , supra note 4, at 85-109.
[76] 226 F. Supp. 2d at 221.
[77] See Gostin, supra note 4, at 55-59.
[78] See supra TAN 36-50.
[79] Indeed, many of the most egregious instances of research abuse consisted of researchers taking advantage of vulnerable children unable to protect themselves from being included in potentially harmful studies. See Leonard H. Glantz, Research with Children , 24 Am. J. L. & Med. 213, 215-18 (1998).
[80] See supra TAN 54-55 (discussing similarities in antidepressant utilization and treatment patterns between older adolescent populations and adult populations).
[81] See U.S. Department of Health and Human Services, Food and Drug Administration, Guidance for Industry: E11 Clinical Investigation of Medicinal Products in the Pediatric Population 5 (“The development of many new chemical entities is discontinued during or following phase 1 and 2 studies in adults for lack of efficacy or an unacceptable side effect profile. Therefore, very early initiation of testing in pediatric patients might needlessly expose these patients to a compound that will be of no benefit.”) [hereinafter Guidance E11 ].
[82] See id. at 5-6 (“When a medicinal product is to be used in the pediatric population for the same indication(s) as those studied and approved in adults, the disease process is similar in adults and pediatric patients, and the outcome of therapy is likely to be comparable, extrapolation from adult efficacy data may be appropriate. In such cases, pharmacokinetic studies ... together with safety studies, may provide adequate information....”). Cf. Kessler, Avenevoli, & Merikangas, supra note 25 (describing the potential usefulness of making a diagnosis of adolescent mania by examining adult patients with mania and working backward to determine what their symptoms were in adolescence, but cautioning “that the meanings of individual signs and symptoms change with age. Clinging to a parent in public settings, for example, would not be considered a sign of pathology in a 2-year-old, whereas it would be in a teenager”).
[83] See supra TAN 58-63.
[84] The general human subjects protections are codified at 45 C.F.R. § 46 (2002). The Additional Protections for Children Involved as Subjects in Research are found at Subpart D of these regulations and are codified at 45 C.F.R. § 46.401 et seq. (2002).
[85] 45 C.F.R. 46.402(a) (2002).
[86] Abigail English, Guidelines for Adolescent Health Research: Legal Perspectives , 17 J. Adolescent Health 277, 282-83 (1995).
[87] Such blanket application of a parental consent requirement could sharply limit the access to participation in research for those adolescents who would otherwise, under the law of their state, be permitted to consent independently to receive psychotropic medications and who would be deemed by any objective measure to be mature enough to make the decision. See John S. Santelli, Walter D. Rosenfeld, Robert H. DuRant, Nancy Dubler, Madlyn Morreale, Abigail English, & Audrey Smith Rogers, Guidelines for Adolescent Health Research: A Position Paper of the Society for Adolescent Medicine , 17 J. Adolescent Health 270, 272 (1995) (suggesting that determination of adolescent capacity to consent independently to research participation be based on “an individual assessment of capacity”). Moreover, a rule requiring parental involvement could pose real barriers to older adolescents who might have strong reasons not to want to include their parents, but that do not rise to the level required for a waiver (e.g., child abuse). See Abigail English, Guidelines for Adolescent Health Research: Legal Perspectives , 17 J. Adolescent Health 277, 282 (1995) (noting the possibility of a waiver of parental permission for adolescents according to “factors related to the incidence or treatment of certain conditions in adolescents for which, in certain jurisdictions, they may legally receive treatment without parental consent” (quoting National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Report and Recommendations: Research Involving Children (1977)) (internal quotation marks omitted)).
[88] See, e.g., Cal. Fam. Code § 6924(f) (providing that a minor is not authorized “to receive ... psychotropic drugs without the consent of the minor’s parent or guardian”); Mich. Comp. Laws § 330.1707 (providing that although minors 14 years of age and older may receive certain mental health services without the consent or knowledge of their parents or guardian, they may not receive services for “the use of psychotropic drugs”).
[89] See English, supra note 86, at 281.
[90] Children participating in risky studies should not be asked to undergo experiences that differ greatly from their actual day-to-day experiences. Id.
[91] See Kathleen A. Mammel & David W. Kaplan, Research Consent by Adolescent Minors and Institutional Review Boards , 17 J. Adolescent Health 323 (1995) (conducting a survey and finding that IRBs are quite strict about allowing waiver of parental consent, often requiring it where the guidelines would not require it, and constructing a fairly logical continuum whereby the more anonymous and less invasive and risky the research, the more likely the IRB is to approve the research without requiring parental consent).
[92] See, e.g., American Medical Association, Policy Compendium on Confidential Health Services for Adolescents 2 (Janet Gans, ed. 1993); James M. Morrissey, Adele D. Hofmann, & Jeffrey C. Thrope, Consent and Confidentiality in the Health Care of Children and Adolescents: A Legal Guide (1986); Council on Scientific Affairs, American Medical Association, Confidential Health Services for Adolescents , 269 JAMA 1420 (1993).
[93] But see Robert J. Levine, Adolescents as Research Subjects Without Permission of Their Parents or Guardians: Ethical Considerations , 17 J. Adolescent Health 287, 295-96 (1995) (arguing that older adolescents should be presumed to be “mature minors,” and that their participation in research studies without parental consent should be expanded so that they can participate when they have the advice of a neutral adult advocate); id. at 294 (“If we are serious about the argument that mature minors have about the same capacity as adults to give informed consent to research, then it seems unduly protectionistic (or paternalistic) to limit their authority to consent to the level prescribed for children.”).
[94] For example, Subpart D allows waiver of parental consent for study of abused and neglected children. See English, supra note 86, at 282. A comparable waiver in studies of psychotropic medication might involve a study investigating the treatment of depression in victims of child abuse or sexual assault.
[95] See Ritalin (Methylphenidate Hydrochloride) , Physicians’ Desk Reference (2002).
[96] Methylphenidate Hydrochloride , AHFS Drug Information (2002).
[97] Id.
[98] Zito, Safer, dosReis, Gardner, Magder, Soeken, Boles, Lynch, & Riddle, supra note 22, at 22.
[99] See Gibbs, supra note 19; Hancock, supra note 19.
[100] See generally sources cited supra note 20.
[101] See sources cited supra note 35.
[102] Peter S. Jensen, Commentary: The NIH ADHD Consensus Statement: Win, Lose, or Draw? , 39 J. Am. Acad. Child & Adolescent Psychiatry 194 (2000) ([I]t remains unclear whether ADHD is best conceptualized as the far end of normal continuum (such as reflecting a more extreme manifestation of a set of temperamental characteristics) or whether it reflects a qualitatively different behavioral syndrome.”).
[103] NIH Consensus Statement , supra note 21.
[104] See id. (“[F]amily practitioners diagnose more quickly and prescribe medication more frequently than psychiatrists or pediatricians. This may be due in part to the limited time spent making the diagnosis. Some practitioners invalidly use response to medication as a diagnostic criterion, and primary care practitioners are less likely to recognize comorbid (coexisting) disorders.”); Jensen, supra note 102 (agreeing with the NIH Consensus Group’s finding of “widely varying, inconsistent, and sometimes poor quality assessment, treatment, and follow-up practices”); see also NIH Consensus Statement , supra note 21 (“There are wide variations in the use of psychostimulants across communities and physicians, suggesting no consensus regarding which ADHD patients should be treated with psychostimulants.”).
[105] DEA Congressional Testimony, Statement of Terrance Woodworth, Deputy Director, Office of Diversion Control, Before the Committee on Education and the Workforce: Subcommittee on Early Childhood, Youth and Families, May 16, 2000 [hereinafter Woodworth Statement].
[106] See Daniel J. Safer, Julie M. Zito, & Eric M. Fine, Increased Methylphenidate Usage for Attention Deficit Disorder in the 1990s , 98 Pediatrics 1084 (1996).
[107] Olfson, Marcus, Weismann, & Jensen, supra note 24.
[108] Woodworth Statement, supra note 105, citing INCB Report, 1999.
[109] Jensen, Kettle, Roper, Sloan, Dulcan, Hoven, Bird, Bauermeister, & Payne, supra note 32. There is also the possibility that the treatment “snowball” effect is due to some attempts at alleviating stigma: to the extent that children might feel isolated by their diagnosis and prescription to take Ritalin, see Hancock, supra note 19, they and their families have incentives to spread the news to their peers and friends so that the stigma of the medication is diluted.
[110] Zito, Safer, dosReis, Gardner, Magder, Soeken, Boles, Lynch, & Riddle, supra note 22, at 23 (“Medicaid prevalence rates [of psychotropic drug use] have been consistently higher than those reported for HMO-enrolled youths. In all likelihood, this is due to the fact that the Medicaid population includes more chronically ill as well as physically, developmentally, and psychologically impaired youths. Specifically, Medicaid includes youths in foster care and disabled youths ... who have clearly documented higher rates of chronic illness and psychotropic medication prevalence.”).
[111] Zito, Safer, dosReis, Gardner, Soeken, Boles, & Lynch, supra note 51.
[112] Olfson, Marcus, Weismann, & Jensen, supra note 24.
[113] Jensen, Kettle, Roper, Sloan, Dulcan, Hoven, Bird, Bauermeister, & Payne, supra note 31.
[114] Id.
[115] Jensen, supra note 102.
[116] See Kluger, supra note 19 (“Some doctors are worried that emotional development will suffer [from prescribing of Prozac .... It’s one thing to fool around with serotonin levels in a brain that’s already hardened and set, but quite another thing to manipulate a young, still elastic brain. And if children learn to medicate depression away, when do they develop the coping skills to weather psychic squalls on their own?”).
[117] See Woodworth Testimony, supra note 105.
[118] See Ann Chiumino, Student Article, Class Action Suits Prompt Governmental Action To Examine Ritalin Use and Regulation , 13 Loy. Consumer L. Rev. 380, 389 (2001) (collecting stories).
[119] United States General Accounting Office, Report to Congressional Requesters, Attention Disorder Drugs: Few Incidents of Diversion or Abuse Identified by Schools (September, 2001). The study only surveyed school principals, however, so it was not able to account for unperceived or unpunished Ritalin abuse in schools.
[120] NIH Consensus Statement , supra note 21 (noting that “an increased risk of drug abuse and cigarette smoking is associated with childhood ADHD”); see also Milberger, Biederman, Faraone, Chen, & Jones, supra note 17.
[121] See Timothy E. Wilens, Stephen V. Faraone, Joseph Biederman, & Samantha Gunawardene, Does Stimulant Therapy of Attention-Deficit/Hyperactivity Disorder Beget Later Substance Abuse? A Meta-analytic Review of the Literature , 111 Pediatrics 179 (2003) (reviewing six studies, two of which found that stimulants have an adverse effect on later substance use, while four of which found that stimulants have a protective effect on later substance use). The Wilens meta-analysis concluded that stimulants have a significant protective effect on later substance use, despite the conflicting nature of the underlying studies that it analyzed, but there are reasons to be cautious about the results: First, meta-analysis, because it manipulates data from underlying studies, is often criticized for producing dubious results that may simply replicate biases and other errors from the studies that they analyzed. Second, the study did not find as robust a protective effect for adults who were studied, which could mean that adolescents who are prescribed stimulants, while as or more likely to abuse substances later in life, simply do not initiate that use until later in adolescence or young adulthood. Id.
[122] Kluger, supra note 19.
[123] Cf. Milberger, Biederman, Faraone, Chen, & Jones, supra note 17 (“Notably, the disorders known to be associated with smoking [including depressive disorder] ... are also known to be elevated among children with ADHD. Thus, the examination of an association between ADHD and cigarette smoking should carefully consider comorbidity to determine whether the observed association is due to ADHD per se or the comorbid psychiatric condition.”).
[124] Olfson, Marcus, Weissman, & Jensen, supra note 34 (“In 1996, approximately one in three children who used antidepressant medication also used another class of psychotropic medication, and one in five children who used stimulants also used another class of psychotropic medication. Antidepressants were the medication most commonly coprescribed to children who used stimulants, and stimulants were the medication most commonly coprescribed to children who used antidepressants.”).
[125] See id. (“Because many children receive both antidepressants and stimulants, the clinical rationale and consequences of this practice may be a particularly important topic for practice-based research.”); Zito, Safer, dos Reis, Gardner, Soeken, Boles, & Lynch, supra note 111 (“[R]esearch shows that a substantial proportion of SSRI use occurs in combination with stimulants, a combination for which there are no effectiveness or safety data.”).
[126] Indeed, stimulants have been used successfully for decades. Hancock, supra note 19 (quoting a mental health expert as saying that “[s]timulants have been used since the late ‘30s ... with no evidence of long-term damage”).
[127] See American Academy of Pediatrics, Committee on School Health, Policy Statement: School Health Centers and Other Integrated School Health Services , 107 Pediatrics 198 (2001), available at http://www.aap.org/policy/re0030.html [hereinafter AAP, Policy Statement ].
[128] Id.
[129] Gostin , supra note 4.
[130] If Levine’s proposed model of waiving parental consent to research were to be adopted, see supra note 93, adolescent health advocates could easily be found within the walls of SBHCs.
[131] Jensen, Kettle, Roper, Sloan, Dulcan, Hoven, Bird, Bauermeister, & Payne, supra note 32.
[132] A side benefit would be that parents could address their children’s educational and health needs in the same building, and the two enterprises could be seen – appropriately, I think – as interconnected and mutually constructive.
[133] NIH Consensus Statement , supra note 21.
[134] Memorandum from Charles C. Edwards, FDA Commissioner, May 6, 1971, reprinted in Peter Barton Hutt & Richard A. Merrill, Food and Drug Law: Cases and Materials 1042, 1043 (2d ed. 1991) (emphasis added).