Clinical Research in Pediatric Dermatology

Federal category

Requirements needed for IRB approval

§46.404: Research not involving greater than minimal risk

1. Research presents no greater than minimal risk; and

2. Adequate provisions are made for soliciting assent of the child and the permission of the parents or guardians

§46.405: Research involving greater than minimal risk but with the prospect of direct benefit to the participating child involved in the research

1. Risk is justified by anticipated benefit to the subject;

2. The relation of the anticipated benefit to the risk is at least as favorable to the child as available alternative approaches; and

3. Adequate provisions are made for soliciting assent of the child and the permission of the parents or guardians

§46.406: Research involving greater than minimal risk and no prospect of direct benefit to the individual child involved in the research, but likely to yield generalizable knowledge about the child’s disorder or condition

1. The risk of the research represents a minor increase over minimal risk;

2. The intervention or procedures are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations;

3. The intervention or procedure is likely to lead to generalizable knowledge about the child’s disorder or condition which is of vital importance for the understanding or amelioration of the child’s condition; and

4. Adequate provisions are made for soliciting assent of the child and the permission of the parents or guardians

§46.407: Research that the IRB believes does not meet the conditions of 45 CFR 46.404, 46.405, or 46.406, but finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children

1. After consulting with a panel of experts in pertinent fields along with the opportunity for public review and comment, the Secretary of the Department of Health and Human Services, or his or her designee, determine that either: (1) that the research in fact satisfies the conditions of 45 CFR 46.404, 46.405, or 46.406, or (2) the following:

– The research is an opportunity to further understand, prevent, or alleviate a serious problem affecting the health or welfare of children;

– The research will be conducted in accordance with sound ethical principles; and

– Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians

In general, the first category of the federal regulations allows for participation in research that does not involve greater than minimal risk as long as both parental permission and child assent (when applicable) are obtained. The second category describes research involving greater than minimal risk with the prospect of direct benefit for the subject and, again, parental permission and child assent must be obtained. Research involving greater than minimal risk and no prospect of direct benefit to the subject, but likely to lead to generalizable knowledge about the child’s conditions is described under category 3. The risk must only be a “minor increase over minimal risk” as determined by the specific IRB. Finally, category 4 is research not otherwise approvable but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children as decided by the IRB. Furthermore, for this category, a panel of experts is consulted to review the proposed research plan [6].

The federal definition of minimal risk is based on the risk children face in daily life or during routine examinations or tests [18]. The risk children face in daily living undoubtedly varies from one child to another, leaving room for individual IRBs to interpret minimal risk differently. It was Dr. David Wendler and his colleagues who attempted to quantify this variation by randomly selecting IRB chairpersons in the United States to complete a survey. The survey consisted of 21 questions on topics that included the risk of various research procedures and whether or not different interventions had any direct benefit to subjects. Interestingly, allergy skin testing was categorized as minimal risk by 43 chairpersons (23 %), a minor increase over minimal risk by 81 (43 %), and more than a minor increase over minimal risk by 51 (27 %) [23]. Such results suggest that there are IRBs approving studies while other IRBs are being overly stringent in their interpretation of minimal risk [24].

Inset 9.3

Interventional studies can use something as simple as hot water, or dilute bleach baths.

Volunteers with plantar warts were either treated with hot water or placebo. The feet were soaked for 30 min with each treatments. Treatments were at 44° in the hot water group and 25° in the placebo group. Treatments were administered daily for 3 consecutive days at the beginning, and for 2 consecutive days 2 weeks later. All subjects were assessed 3 months after the start of the study. Over half of the hot water group subjects [53 % (15/28)] were clear of warts, while only a small fraction of placebo-treated subjects were clear [11 % (3/26)].

Local hyperthermia at 44 °C for the treatment of plantar warts: a randomized, patient-blinded, placebo-controlled trial. Huo W, Gao XH, Sun XP, Qi RQ, Hong Y, Mchepange UO, Li XD, Xiao BH, Lin JP, Jiang Y, Zhang L, Li YH, Xiao T, Chen JZ, Chen HD. J Infect Dis. 2010;201(8):1169–72.

This was a randomized investigator-blinded placebo-controlled trial of 31 patients, ages 6 months to 17 years with moderate to severe atopic dermatitis and evidence of secondary bacterial infection. They were treated with cephalexin and randomly assigned to receive dilute bleach baths and intranasal mupirocin or plain water baths and intranasal petrolatum for 3 months. Treated subjects had reduced EASI scores for the body (submerged in the bath), but not the head and neck.

Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Pediatrics. 2009;123(5):e808–14.

As seen in Table 9.1, category 46.405 and category 46.406 allow for children with disorders or conditions to be exposed to greater than minimal risk. The same ambiguity that applies to the concept of minimal risk is present for “a minor increase over minimal risk” and “greater than minimal risk” as described by these codes. Furthermore, the categories do not allow for the use of healthy pediatric controls in studies that have more than minimal risk, a major obstacle for conducting quality research. Take for example a personal investigator (PI) whose aim is to assess the histopathological differences of the skin of children with atopic dermatitis, during periods of clinical remission, with healthy controls. With the current Codes of Federal Regulation, however, a skin biopsy could not be utilized for the control group as it presents more than minimal risk. Notably, no such federal category exists for adults as they are deemed autonomous and capable of making decisions regarding risk [25]. In other words, in the example given, even if the adult patient will derive no potential benefit from the procedure, the individual should simply be made fully aware of this and given written consent for the skin biopsy.

9.5 Autonomy in Pediatrics

Adults, in general, are deemed competent individuals able to analyze and determine whether or not they are willing to take on the risks of a study in the process of informed consent. In children and adolescents competency varies greatly; and is not only dependent on age, but also on the maturity level of a specific child. In one study, 81 child–parent pairs completed a survey separately in order to assess the willingness to enroll the child in non-beneficial research that posed either mild or moderate risk. Among the paired cohorts, 71 % of children and 72 % of the parents would allow their child to participate in a study that did not benefit the child and posed a risk of a headache. For a research study that was described as one that would not benefit the child and posed a very small chance of a broken leg, 48 % of the children were willing to participate and 26 % of the parents would allow their child to participate [26].

While it cannot be concluded what percentage of children and parents will agree to participate in a non-beneficial study, some interesting points can be extrapolated from the results. First, the willingness to participate in studies that offer minimal risk is evident from children and parents alike [19]. If appropriate recruitment strategies are utilized by a research team, subjects will partake. Second, the direct concerns and interests of children and adolescents may be different than the parents and even the investigators. This is especially true in disorders or disease states that are decently controlled, treated, or cured with available therapies. Take for example, an investigator who wants to study an alternative treatment for impetigo with the proposed study design requiring 2 weeks of placebo for half of the subjects enrolled. With a readily available, effective treatment alternative such as oral cephalexin, the risk-to-benefit ratio analysis for subjects, their families, and the entire research team is very different compared to a study investigating novel treatment options for life-threatening toxic epidermal necrolysis.

Importantly, the Codes of Federal Regulations do not explicitly address placebo-controlled trials, which are considered the gold standard when studying new drugs. Many believe that if a new treatment is being compared to an active control, rather than placebo, it is difficult to determine the true efficacy of the treatment [27]. While scientifically justified, some argue that withholding therapy is not ethical, such as in the study above, when assessing the efficacy of a novel drug versus placebo in the treatment of impetigo. Yet, the American Academy of Pediatrics (AAP) released “Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations,” in 1977, 1995, and again in 2010 in which placebo control groups and the ethics surrounding them are addressed. The AAP lists five conditions in which the use of placebo control groups is ethical:

When there is no commonly accepted therapy for the condition and the agent under study is the first one that may modify the course of the disease process.

When the commonly used therapy for the condition is of questionable efficacy.

When the commonly used therapy for the condition carries with it a high frequency of undesirable adverse effects and the risks may be significantly greater than the benefits.

When the placebo is used to identify incidence and severity of adverse effects produced by adding a new treatment to an established regimen; or

When the disease process is characterized by frequent, spontaneous exacerbations and remissions and the efficacy of the therapy has not been demonstrated [28].

9.6 Consent in Pediatrics

While the concept of consent is well established and understood in research with adult subjects, the translation into pediatrics is not always clear. For the most part, federal regulations allow children to be involved in research only when parental or guardian permission is obtained, known as consent by proxy. Importantly, for research that is covered by code 46.406 and 46.407 (Table 9.1), permission should be acquired from both parents unless one parent is incompetent, not reasonably available, unknown, deceased, or when one parent has legal responsibility for the care and custody of the child [22]. These requirements of having both parents sign consent forms can be quite limiting, especially with a significant percentage of divorced families in the US population.

Inset 9.4

This is a prospective labor and time-intensive study of a fairly large population which examines a simple, yet important intervention in children. A major source of bias is reporting bias in this study. In this study, 1,812 children ages 2–7 from 78 day care centers in Germany were evaluated. Total body nevi were counted. Parents were interviewed regarding sun exposure and sun protection precautions. There were no significant protective effects of applying sunscreen. However, there was an inverse correlation between the quantity of clothing and the number of nevi.

Effect of sunscreen and clothing on the number of melanocytic nevi in 1,812 German children attending day care. Bauer J, Buttner P, Wiecker TS, Luther H, Garbe C. Am J Epidemiol. 2005;161(7):620–7.

In school aged children, who are developmentally mature, assent from the child becomes important, as it serves to empower children to the extent of their capacity [29]. Assent is defined by Title 45 Code of Federal Regulations Part 46.402 as a child’s affirmative agreement to participate in a clinical investigation. Mere failure to object in involvement, in the absence of affirmative agreement, is not enough to be interpreted as assent [30]. Factors that should be taken into consideration when assessing capacity include age, maturity, and psychological state of the patient [31]. The National Commission proposed that all children over 7 should participate in the assent process [32]. Over 35 years later, the AAP still considers 7 as a reasonable minimum age for involving children in the assent process [33].

For the older child or adolescent, assent should play an even larger role. Some even argue that assent in the adolescent should be viewed as an adult informed consent, in an attempt to respect the autonomy of the child, even if parental permission is required [34]. For young adults who are emancipated or have adequate decision-making capacity informed consent should be obtained directly from the patient such as that in the adult counterpart.

9.7 Incentives

Incentivizing participation in research is another important, yet debated topic in pediatric research. Some believe that paying individuals to participate in a study can distort the “volunteer” component of research and can also alter the decision-making of both parents and children [35

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