Demarcating the procedures

In this section, I will demarcate the therapeutic and non-therapeutic research procedures of the growth hormone trial. Which procedures are therapeutic? Therapeutic procedures are those administered on the basis of evidence that they may benefit individual research subjects. These include both procedures administered during the course of a trial that are also part of standard medical care (and would likely be performed irrespective of a person’s research participation) as well as experimental interventions aiming to benefit a subject.

It follows that demarcating the therapeutic procedures of this trial depends on identifying the components of standard care for the eligible study population. What does

standard clinical care involve for a child with idiopathic short stature? The diagnosis of idiopathic short stature is made by excluding underlying medical causes of short stature. Thus, when a very short child (and her family) seek medical help, standard care usually involves a number of procedures, most of which aim to exclude the possibility that she has a disease causing her short stature.

The first step is for a doctor to perform an initial evaluation to exclude any non- endocrine systemic diseases that may be causing the growth failure (Moshang, 2005, p.159). This evaluation includes a detailed history (including family history) and a comprehensive physical examination involving phenotypic characteristics, body proportions, and pubertal staging (Cohen et al., 2008; Van den Brande & Rappaport, 1993, p.192). A critical part of these examination are accurate height and weight measures in addition to carefully plotted growth curves (Moshang, 2005, p.157). When the medical history and physical examination do not suggest a particular diagnosis, a variety of screening lab tests are recommended (Cohen et al., 2008). A bone age x-ray should be examined to help determine the child’s growth potential and to narrow the differential diagnosis, a measurement of IGF-I (insulin-like growth factor test), and in some instances, a skeletal survey (Cohen et al., 2008).

Once non-endocrine underlying diseases have been ruled out, a pediatric

endocrinologist examines whether the child has a growth hormone deficiency. No single test or set of tests can accurately identify growth hormone deficiency. Consequently, this diagnosis requires clinical as well as biochemical evaluation (Cohen et al., 2008). If growth hormone deficiency is ruled out and a child is determined to have idiopathic short stature, no treatment is usually prescribed, but regular doctor’s visits are recommended to evaluate growth patterns. And at times, if puberty is significantly delayed, a clinician may also consider giving a 3 to 6 month course of sex hormones (Van der Brande &

Rappaport, 1993, p.192).

Information about the procedures undertaken in standard care helps to determine which of the study procedures are therapeutic. Any intervention that a child seeking medical intervention would undergo irrespective of trial participation should be

considered a therapeutic procedure. Consequently, a number of the trial interventions are therapeutic. All the procedures involved in the three day initial evaluation—hGH

response tests, blood and urine tests, tests of growth and bone maturity, nude photos against a height grid, blood samples, as well as behavioural and psychological assessments—are part of (or very similar to) the process a child would undergo in standard care as a clinician makes a diagnosis of idiopathic short stature. Thus, these are therapeutic procedures. Some of the follow up visits at regular intervals (the annual visits) repeating measurements are also therapeutic, as they resemble the interventions a child would undertake in standard care.

The visit at six months that repeats the procedures performed during the initial evaluation is harder to demarcate. Repeating the procedures of the initial evaluation seems superfluous to a child’s care, which suggests that these are non-therapeutic procedures. But there may be good medical reasons for repeating the procedures. It is difficult to accurately diagnose hGH deficiency; no single test or set of tests can make an accurate diagnosis (Cohen et al., 2008). Further, a particular series of tests may suggest a child to be non-deficient even if she actually lacks adequate growth hormone (Tauer, 1994). Given that different treatment is suggested for children who are GH deficient, it may be in the medical interests of a child to undergo further testing to help confirm the diagnosis of idiopathic short stature. Thus, repeating these interventions may help to rule out the possibility that a child’s short stature is the result of an endocrine dysfunction requiring treatment and may be best understood as part of good or optimal clinical care. Accordingly, these procedures should also be considered therapeutic.

In addition, the study’s main active interventions, the therapeutic growth hormone injections and the no treatment control are therapeutic procedures. These are therapeutic procedures not because they are part of standard care, but because they are research interventions administered based on evidence that they may be in the medical interests of the research subjects.

It seems reasonably straightforward that the study’s main non-therapeutic interventions are the three weekly injections for children randomized to the placebo group. These interventions are administered in the interest of answering the study question and not to benefit particular research subjects. In addition, the three-day overnight visits to the NIH clinical centre (to determine study eligibility and then

measurements are non-therapeutic procedures. These procedures are not part of standard care and are not administered in the therapeutic interests of the research subject.