Expanding Treatment Options for Youth With Type 2 Diabetes

Current Problems and Proposed Solutions: A White Paper From the NICHD Diabetes Working Group

William V. Tamborlane; Morey W. Haymond; David Dunger; Ravi Shankar; Rose Gubitosi-Klug; Kathleen Bethin; Janina Karres; Paolo Tomasi; Ingrid Libman; Paula H. Hale; Ronald Portman; Georgeanna Klingensmith; Michael Reed; Jeffrey Blumer; George Giacoia

Disclosures

Diabetes Care. 2016;39(3):323-329. 

In This Article

Part 1: The Challenges

Limited Treatment Options for Youth With T2D

Glucose-lowering treatments for which efficacy and safety have been evaluated in completed randomized clinical trials in children and adolescents with T2D are extremely limited. This is in stark contrast to the multiple treatment modalities that have been evaluated for efficacy and safety and approved for use in adults with essentially the same disease. Metformin and insulin remain the only antidiabetes treatments approved by the U.S. and Europe for the treatment of youth with T2D. It is noteworthy that no pivotal clinical trial of insulin has yet to be completed specifically in pediatric T2D subjects.

Metformin is quite effective in achieving near-normal hemoglobin A1c (A1C) levels (i.e., <7.0%) in most adolescents early in the course of T2D. However, results of the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study in youth with duration of T2D <2 years suggest that T2D has a more aggressive course in adolescents than in adults. Despite mean baseline A1C levels of 5.9%, A1C levels increased to >8.0% in more than 50% of subjects treated with metformin monotherapy in the TODAY study over an average of 11 months.[2] However, assessment of medication compliance in the TODAY study was carried out with pill counts and the actual consumption of medications was unknown. The Pediatric Diabetes Consortium (PDC) established the first registry of youth with T2D in the U.S. in 2011. The clinical and demographic characteristics of the first 500 patients enrolled in the registry were very similar to other pediatric T2D cohorts, in that two-thirds were female, >90% were racial and ethnic minorities, and most patients were from economically disadvantaged families.[3] Data from the PDC (Table 1) show that treatment with insulin alone or metformin plus insulin usually fails to achieve target A1C levels of <7.5% that are recommended by the International Society for Pediatric and Adolescent Diabetes.[4] Difficulties in complying with complex insulin injection regimens may contribute to the elevated A1C levels in insulin-requiring pediatric T2D patients. These data also show that only 3% of the PDC T2D Registry patients were receiving off-label use of the newer antidiabetes drugs approved for use in adults with T2D.

Regulatory Framework

The U.S. FDA and the European EMA require pharmaceutical companies to describe, at an early stage in drug development, how they will develop new medicinal products for use in children (defined as age <18 years). Unless an exemption (waiver) is granted, the companies must agree to a research plan with each agency separately and, although the two agencies work closely together, their recommendations may occasionally differ.

Most of the pediatric research plans for each product consist of at least two separate studies:

  1. A pharmacokinetic (PK)/pharmacodynamic (PD) study (establishing dose and tolerability)

  2. A confirmatory efficacy and safety phase 3 study with a controlled phase of at least 12 weeks and a subsequent safety extension up to a total of 52 weeks to establish drug safety and efficacy

All of these studies include waivers for children <10 years of age based on the grounds that T2D is exceedingly rare in children <10 years of age.

A review of www.clinicaltrials.gov reveals a number of phase 3 studies that have been open for recruitment for up to 2–6 years (Table 2). In the case of saxagliptin, this includes two separate clinical trials involving the use of this drug as initial monotherapy versus metformin as well as add-on therapy in metformin-treatment failures versus placebo. In the case of sitagliptin, separate trials were undertaken to study its efficacy and safety when used in fixed-dose combinations with metformin, as well as when used alone. The requirement to carry out more than one pivotal trial for an individual drug has contributed to the problems in completing the trials of any new drugs in pediatric T2D. More recent examples of pediatric investigation plans (PIPs) for drugs in T2D proposed by industry and approved by the EMA are listed in Table 3. The proposed dates of completion of these studies stretches out to 2027 and more PIPs are in negotiation.

The reality is that most of the pivotal phase 3 studies that have been launched are finding it very difficult to enroll enough pediatric patients, despite recruitment of many centers in Europe, the U.S., and other countries around the world, underscoring the need to critically assess current study eligibility requirements and trial designs.

In 2014, it was estimated that conducting all of the individual pediatric T2D studies that companies have agreed to with the regulatory agencies will require up to 3,800 pediatric patients,[5] and this number continues to increase with every new study proposal. Having been first recognized in the 1990s, pediatric T2D is an epidemic in relative rather than absolute terms, and the number of pediatric patients with T2D remains small compared with the number of patients with T1D. On the basis of the SEARCH for Diabetes in Youth (SEARCH) study data, the estimated number of T2D patients between 10 and 18 years of age in the U.S. was ≤25,000[6] and the prevalence is much lower in Europe.[7,8] Moreover, the wide geographical distribution of patients in the U.S. results in relatively small numbers of patients in any single pediatric diabetes treatment center.

As in the TODAY study,[2] 85% of patients in the PDC T2D Registry were black and Hispanic adolescents from low-income families.[3] In these disadvantaged families, socioeconomic factors (e.g., parents missing work for study visits, transportation issues that restrict recruitment to a limited geographical area) and cultural/historical issues (e.g., mistreatment of minority subjects in past clinical trials) are major obstacles to recruitment. In Europe, the situation is different: the prevalence of T2D in young people remains lower than in the U.S. and migrant families from Africa, India, Pakistan, and the Middle East are overrepresented, thus creating additional challenges for recruitment.

Other common reasons why potential subjects are excluded from these studies are the presence of major medical and psychiatric conditions and treatment with glucocorticoids, atypical antipsychotics, and other excluded medications. In addition, most eligible subjects are teenagers who are often difficult to recruit and retain in clinical trials and are frequently lost to follow-up with treating physicians.[9]

Easing the Impact of Eligibility Restrictions

Eligibility criteria in many of the early T2D studies in pediatrics resulted in the exclusion of a substantial proportion of the relatively small pool of patients who might otherwise be available for participation in these studies. Until recently, most studies only included subjects with A1C levels ≥7.0%. As observed in the TODAY study in patients with T2D duration <2 years,[10] and substantiated by the PDC T2D Registry (Table 1), this criteria eliminates almost half of T2D patients who are well controlled on metformin alone or on treatment with lifestyle modification. In some more recent trials, the A1C inclusion criteria has been lowered to ≥6.5%, which increases the available pool of patients by an additional 10%. Nevertheless, ~35–40% of potential pediatric subjects with T2D who have A1C levels <6.5% would still be excluded. As the TODAY study showed that A1C levels rise rapidly in adolescents with T2D who are well controlled on metformin monotherapy, it might be possible to reduce the lower limit of A1C to values <6.5%.

Prior to the February 2013 EMA workshop in London, all but one of the active pivotal trials of pediatric T2D excluded patients on current treatment with insulin.[11] As indicated in Table 1, this exclusion criteria eliminated ~50% of pediatric patients with T2D. Currently, eligibility criteria in most but not all studies have been revised to allow inclusion of patients treated with insulin with or without metformin.

Obstacles to Participation in T2D Studies by Academic Pediatric Diabetes Centers in the U.S.

Most studies of T2D in pediatrics in the U.S. are carried out at academic medical centers, and there are a number of issues at these institutions that have made it difficult for investigators to participate in industry-sponsored T2D studies. Major problems include the ever-increasing time and effort required of investigators and research staff to complete the regulatory and certification processes, the lack of the administrative infrastructure to assist with regulatory approvals and negotiations of trial budgets, and the lack of clinical research infrastructure and experienced staff to carry out the studies. In T2D research in pediatrics, where local numbers of eligible participants are small, these hurdles often become insurmountable. A potential solution to this problem is the use of shared personnel, infrastructure, and other resources by investigators in different disciplines.

Most academic research institutions are accustomed to the budgeting of research grants and contracts based on the National Institutes of Health (NIH) model of committed full-time equivalent support for prespecified effort of investigators and research staff. Protected research time can be provided to investigators and personnel can be hired because the funds to support them are already committed over a specified period of time. In contrast, the predominant fee-for-service model of industry-sponsored trials provides piecemeal funding that is almost entirely dependent on the number of subjects who are enrolled in the studies. This method of funding poses a particular challenge for centers to participate in the current, short-term T2D trials that will enroll only a small number of patients.

Academic medical centers have traditionally placed limited scholarly value on their faculty's participation in industry-sponsored clinical trials as compared with peer-reviewed, investigator-initiated studies funded by the NIH or foundation grants. Clinical investigators, themselves, have had a vastly different approach to participating in NIH-sponsored than industry-sponsored multicenter clinical trials. The NIDDK-sponsored TODAY study provides an excellent example that is particularly relevant to this discussion.[12] In the TODAY study, 15 clinical centers enrolled >1,200 adolescents with T2D of <2 years' duration and 699 subjects were randomized into the study. In contrast, industry-sponsored clinical trials in pediatric T2D have enrolled hundreds of centers but the number of subjects who have completed the studies is very small. In Europe, although the incidence and prevalence of T2D has been well documented through robust diabetes population registries, there is currently no clinical trials network that compares with the TODAY study, although there are plans to establish a network through European Network of Paediatric Research at the EMA. Thus in Europe, recruitment to T2D studies has been through industry sponsorship and limited by the overall low numbers of eligible subjects.

Results of Pediatric Endocrine Society Survey of Diabetes Treatment Centers

Two of the authors of this white paper (R.G.-K. and K.B.) developed a survey that was sent by the Pediatric Endocrine Society to its members to ascertain the barriers to participation in industry-sponsored clinical trials in adolescents with T2D. The results of the survey support the challenges that have been described above. Specifically, the most common obstacles to participation included the following:

  • Clinics caring for ≤50 T2D patients under the age of 18 years

  • Lack of interest in participating in research by patients and families

  • Restrictive inclusion criteria

  • Exclusion of subjects due to past or current use of glucose-lowering agents other than metformin

  • Inadequate reimbursement

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