Defining Pathways for Development of Disease Modifying Therapies in Children with Type 1 Diabetes

January 14, 2015: Alexandria, VA – Full Report – Draft

Executive Highlights

The ADA in collaboration with JDRF, T1D Exchange, Benaroya Research Institute, the International Society of Pediatric and Adolescent Diabetes (ISPAD), TrialNet, and the Immune Tolerance Network hosted a Consensus Conference last week in Alexandria, VA titled “Defining Pathways for Development of Disease Modifying Therapies in Children with Type 1 Diabetes.” The meeting, co-chaired by the highly respected Dr. Diane Wherrett (University of Toronto, Toronto, Canada) and Dr. Carla Greenbaum (Benaroya Research Institute, Seattle, WA), drew approximately 100 attendees from the research, industry, nonprofit, and regulatory sectors – we were particularly heartened to see a considerable number of FDA and EMA representatives in attendance and note that the meeting “sold out” quite quickly.

The primary goal of the conference was to discuss how type 1 diabetes differs in adults and children and how clinical research should be conducted in the pediatric population. For example, there is currently no clear consensus regarding whether such interventions must first be evaluated in adults (as is usually the case) or whether it would be possible to conduct studies only in children. It also remains unclear how such studies should be designed and what the ideal endpoints would be. At the end of the day, the consensus seemed to be that simply extrapolating clinical trial results from adults to children is not ideal (or possible) given the fundamental differences in disease pathophysiology between the two groups. Therefore, the current paradigm of demonstrating a treatment’s efficacy in adults before (or instead of) investigating it in children may well not be appropriate.

 Despite the vexing nature of the problem, we found it very stimulating and refreshing to see the interactions between academic scientists and FDA/EMA representatives throughout the day – the diabetes community always benefits from such cordial, frank, and open discussion, and the regulatory agencies appeared very receptive to considering novel approval pathways in this area. Good news all around for children with type 1 – we do also think that children with type 2 deserve more attention on the same topic and hope very much to see that in the future from advocates for that population, some of which are the same as the hosts for this meeting. While the relatively low incidence of frank type 2 diabetes in children may make recruitment for separate pediatric trials challenging, it could also open the door for an orphan disease designation that would significantly expedite approval of new therapies – this would of course require a consensus that the disease is fundamentally different in children vs. adults, which has not yet been established. See our coverage of an ADA 2014 symposium on “Strategies for a Pathway for Drugs and Devices for Pediatric Diabetes Care” for much more commentary on this topic, including an illuminating presentation by Dr. Wherrett on the challenges associated with the current clinical development paradigm.

Key Conclusions

  • Funders, patient advocacy groups, industry (both large pharma and small biotech), academics, and regulators from both the US and Europe all attended, highlighting the need to collaborate to bring clarity to this issue.
  • Despite technological advances in insulin, insulin delivery, and glucose monitoring, the majority of people living with type 1 diabetes – both adults and children - do not reach recommended glycemic targets and continue to experience complications. Therefore, according to the speakers and attendees, disease-modifying therapy is sorely needed.
  • Notably, and this is new news from our view, the clinical course of the disease appears different between those diagnosed as children compared to those diagnosed as adults. Specifically, the rate of progression to clinical disease in those with antibodies or antibodies and abnormal glucose tolerance is different, and the rate of C-peptide decline post-diagnosis varies significantly, with the rate of decline inversely proportional to age (i.e. younger children experience the fastest decline).
  • Fascinatingly, the efficacy of disease-modifying therapy may be different in those diagnosed as children compared to adults. This suggests the need to design clinical trials that evaluate therapeutic effects separately (and possibly concurrently) in children and adults.

Detailed Discussion and Commentary

Morning Session

Welcome and Meeting Objectives

Diane Wherrett, MD (University of Toronto, Toronto, Canada)

In her opening remarks, Dr. Diane Wherrett provided a definition of “disease modifying therapies” for type 1 diabetes (those that preserve beta cell function) and set the stage for a critically important concept: that the development of the disease has a very different pathophysiology in children compared to adults. Recognition and agreement that there are significant differences in children vs. adults implies that studies in adults would not be appropriate for approval of an intervention in children and that the key efficacy endpoints may well be different in the two populations. This important hypothesis framed the discussion for the remainder of the morning session, which was devoted to understanding and clarifying the pathophysiology of type 1 diabetes in children vs. adults.

Current Metabolic Control in Children and Adults

Linda DiMeglio, MD (Indiana University, Indianapolis, IN)

Dr. Linda DiMeglio provided an overview of the current state of type 1 diabetes in children. The numbers were sobering – two-thirds of type 1 diabetes patients are diagnosed under 18 years old and the incidence of the disease is doubling every 20 years. Dr. DiMeglio discussed how type 1 diabetes is typically managed in children (e.g., insulin regimens, pumps/CGM, education) and presented data from the T1D Exchange registry involving ~26,000 participants from 76 adult academic and community medical centers. A graph of A1c vs. age revealed that glycemic control was at its worst at age 12-22; the average A1c for that group was ~8.5%, with a peak of ~9% at around age 18. After age 22, the average A1c began to decline and remained steady at ~7.5% after age 30. Based on these statistics, Dr. DiMeglio argued that an intervention in adolescents that lowers mean A1c to 7.5-8% should in fact be considered a great success, not a failure. She also pointed out that only ~20% of registry participants age 2-17 were at their recommended A1c targets compared to 30% of adults, which she described as a “discouraging picture” – we certainly agree. Dr. DiMeglio then provided data on the rate of self-reported severe hypoglycemia (defined as hypoglycemia leading to loss of consciousness or seizure) in a subset of the registry. Approximately 7% of the population reported having one or more events in the last three months; notably, there was no relationship between participants’ A1c levels and rates of severe hypoglycemia, though the rate of DKA was positively correlated with A1c.

  • Dr. DiMeglio acknowledged that the T1D Exchange registry is not a random sample of the entire US population with type 1 diabetes, but she argued that it should provide fairly accurate estimates given its size and variety of sources. We assume the entire US population of people with type 1 diabetes is probably worse. In terms of demographics, approximately 50% of registry participants were female and 83% were non-Hispanic whites, with a duration of diabetes ranging from 1-86 (!) years; 28% were overweight. Dr. DiMeglio noted that the percentage of patients using insulin pumps (60%) and CGM (a meager 8%) shows that the uptake of such technological advances has much room to grow – we point out that those on pumps in this registry is nearly double of the commonly accepted one-third of people with type 1.

Complications and Morbidity/Mortality in Those Diagnosed as Children

Trevor Orchard, MD (University of Pittsburgh, Pittsburgh, PA)

The acclaimed epidemiologist Dr. Trevor Orchard shared data from a variety of registries, including his large, longitudinal Pittsburgh Epidemiology of Diabetes Complications (EDC) study, to discuss long-term complications and mortality in patients with type 1 diabetes diagnosed in childhood. On a positive note, as he has pointed out in earlier years at ADA, life expectancy in patients with type 1 diabetes diagnosed in childhood continues to improve – at this point, it is only approximately four years below that of the general population (we’d thought we’d heard more like one or two years different in earlier talks). He also noted that patients without albuminuria had a completely normal life expectancy, suggesting that urinary albumin may be more than simply a marker for kidney disease - i.e., it may be an indicator of vascular health as well (we had thought that was fairly accepted already). Dr. Orchard also showed data demonstrating that the chronic complications of diabetes rarely occur in childhood: one graph indicated that retinopathy rarely, if ever, occurs in the initial 13 years of diabetes duration and just begins to rise after ~15 years, and CVD is unheard of. These data indicate that the development of chronic complications cannot realistically be used as an endpoint in pediatric trials because of the decades-long follow-up that would be required to see an impact. As for potential surrogate endpoints, he shared data indicating that A1c is the most powerful predictor of long-term complications when high (>8.4%), but as it approached normal levels (<7.5%) its predictive power disappeared. This is also different from what we had thought was fairly accepted knowledge – that there was no lower threshold for reduced complications following a lower A1c. Dr. Orchard attributed the disappearance of predictive power to the role of genetic susceptibility to complications, which is masked at higher A1cs but becomes decisive once A1c is no longer a significant factor.

  • Dr. Orchard also reviewed newly released DCCT/EDIC data to emphasize the highly protective effect of early glycemic control. He acknowledged that that the DCCT enrolled relatively few adolescents and no one under age 13, so it does not provide a full picture of the importance of glycemic control in young children. As an audience member mentioned, the trial also enrolled very few participants with pre-pubertal onset of diabetes, so it is difficult to evaluate the impact of tight glycemic control in that cohort. Still, the results illustrate the critical importance of early control that allows for “some preservation of beta cell function.” Dr. Orchard admitted that there is little data on the effects of glycemic control in children under age 15 but said there is “no reason to believe that glycemic control in children is of no benefit.” (We certainly hope this is an understatement.) Given the dramatic effect of the six-year DCCT intervention and the value of “metabolic memory” that has been shown by DCCT/EDIC, it is logical to expect that starting earlier or maintaining control for a longer period would have even greater benefit.
  • Dr. Orchard noted that the DCCT/EDIC investigators have data (not yet analyzed) on C-peptide levels in the entire study cohort. This suggests that it should be possible to determine what degree of residual beta cell function is sufficient to confer protection from chronic complications. Such knowledge would be very helpful for designing clinical trials in pediatric patients because a successful outcome could be defined as the maintenance of C-peptide above that threshold.

Quality of Life in T1D in Those Diagnosed as Children

Alan Delamater, PhD (University of Miami, Miami, FL)

The distinguished psychologist Dr. Alan Delamater provided an overview of quality of life (QL) in diabetes. He presented data indicating that (i) QL improves with better glycemic control; (ii) an early age of onset is associated with better QL later in life; (iii) family conflicts and relationships are the strongest predictors of QL in children with diabetes; and (iv) there is no relationship between QL and duration of diabetes (absent chronic complications). He shared conflicting data on the relationship between QL and treatment regimens (i.e., use of pumps vs. MDI) – some studies show that the newer technology improves QL but others do not. He acknowledged that QL measures are different in children and adults and thus QL cannot be directly compared between the two populations. It would conceivably be possible to examine QL in adults whose age of onset was in childhood vs. adulthood, but that has not yet been studied. We were glad to hear, in response to a question from an EMA staffer, that Dr. Delamater believed QL should be an important outcome measure in pediatric trials. We often worry that not enough attention is given to the impact of better quality of life – better adherence leads to better clinical outcomes, which leads to economic benefit when DKA and severe hypoglcyemia are avoided. We believe that trial design by many investigators is aimed at making such benefits more explicit and we certainly hope to see this in results, since we are not sure of the value that payers put on improved quality of life, without seeing the explicit benefits.

Differences Between Pediatric and Adult Onset T1d

Stephen Gitelman, MD (University of San Francisco, San Francisco, CA)

Dr. Stephen Gitelman’s presentation (along with Dr. Desmond Schatz’s; see below) on the importance of C-peptide levels in children with diabetes was one of the most critical to the theme and purpose of the conference. The presence of C-peptide in type 1 diabetes confers protection from hypoglycemic events, and understanding the natural history of C-peptide concentrations as the disease begins has provided great insight into its pathophysiology and the potential impact of disease modifying therapies. Dr. Gitelman presented data demonstrating that C-peptide levels diminish as the disease progresses but that adults who were diagnosed after age 18 were more likely to have detectable C-peptide than those diagnosed earlier. In addition, the rate of decline in C-peptide is faster in people diagnosed at a younger age compared to those diagnosed in adulthood. Dr. Gitelman (and Dr. Schatz) also pointed out that disease progression is much faster in children with autoantibodies compared to adults. The main conclusion was that the pathophysiology of recent onset type 1 diabetes is fundamentally different in children vs. adults: children start (at diagnosis) with a lower C-peptide level and decline faster.

  • Importantly, there is evidence that immunotherapy may be more effective at preserving C-peptide levels in children than in adults, meaning that it may be easier to slow the pace of decline in this population. However, as the highly respected Dr. Kevan Herold (Yale University, New Haven, CT) pointed out, the C-peptide levels in question are very low regardless of age, and autoimmunity is far more aggressive in children than in adults. In addition, as discussed above, it is not yet known whether there is a specific C-peptide threshold that confers benefit. If such a level exists, it would serve as a critically important milestone for interventions to achieve in clinical trials.

History of Disease Modifying therapy Trials in Children

Desmond Schatz, MD (University of Florida, Gainesville, FL)

Dr. Desmond Schatz discussed many of the same points as Dr. Gitelman regarding the importance of measuring C-peptide levels in children with diabetes. He also argued that the field may be missing important information by lumping trial results for children and adults together, as the disease seems to differ significantly between the two populations. For example, when different age groups from the TrialNet studies have been analyzed separately, results have sometimes shown success in one population that was clouded when the data was combined – in many (though not all) cases, children responded better than adults. Importantly though, none of the TrialNet studies has revealed any differences in side effects in children vs. adults. Dr. Schatz also presented data showing that TrialNet subjects who were autoantibody positive at an early age progressed far more rapidly to diabetes than those who became autoantibody positive later in life (i.e., after age 30). In summary, he emphasized that “we can’t use data from adults to imply we’ll get the same results in children. We need to study each population” separately rather than attempting to extrapolate from one to the other.

  • Dr. Schatz also argued that most immune intervention studies have started too late in the progression of the disease and that intervention should ideally begin much earlier, such as when autoantibodies first appear. In addition, he noted that it is still unclear to what extent type 1 diabetes is purely an autoimmune disease and suggested that there might be other useful markers of disease beyond islet autoantibodies. This was really interesting, from our view, as it came close to arguing for treatment for pre-diabetes in type 1. There is, of course, no guidance document from FDA for therapies for people with either type 1 pre-diabetes or type 2 pre-diabetes.
  • During Q&A, Dr. Robert Nelson (Office of Pediatric Therapeutics, FDA, Silver Spring, MD) raised the point that it is important to consider the long-term effects of an intervention in addition to those demonstrated in clinical trials when assessing safety in children. The potential for adverse effects many years down the road should not detract from a drug’s approval, but long-term monitoring would likely be required.

Afternoon Session

Food and Drug Administration

Diane Murphy, MD (FDA, Silver Spring, MD)

Dr. Diane Murphy, Director of the FDA’s Office of Pediatric Therapeutics, provided an overview of the structure of the FDA and the laws pertaining to the approval of drugs for children. She shared that 546 products were approved for pediatric patients between 1997 and 2014 – a small number in our view given the total number of drugs approved in that time period (~1500 according to FDA records). Importantly, she also reviewed what the FDA believes are the necessary components of a clinical development program to support a pediatric indication, suggesting that at this point, drugs intended for children must be studied in children – simply extrapolating results from studies in adults is not sufficient. We hadn’t been aware that any organizations would have been advocating for approval in children without testing in children. Dr. Murphy suggested that companies should begin discussions with the FDA regarding possible pediatric indications at the time phase 2 trials are initiated in adults – this seems comparable to the current approach in Europe (see below). She also noted that there is close coordination between the FDA, the EMA, and Canadian and Australian regulatory authorities regarding the approval process for drugs with pediatric indications. We were glad to see that the FDA appears receptive to novel disease-modifying therapies for type 1 diabetes and eager to work with industry to facilitate their approval – we imagine there could certainly be potential for such products to receive “breakthrough therapy” designation given the dearth of existing treatment options.

  • One audience member inquired about the process for FDA orphan drug designation and whether type 1 diabetes could be considered an orphan disease. Dr. Murphy said that an orphan drug designation requires a disease prevalence under 200,000. Based on FDA precedent, it seems that new-onset type 1 diabetes qualifies as an orphan disease but that therapies aimed at the general type 1 population would not qualify unless there is a clearly justifiable subgroup that does not represent an arbitrary slicing of the population. It is not entirely clear whether pediatric type 1 diabetes would constitute such a subgroup, though we imagine that the low prevalence (most estimates place it right around 200,000) and the demonstrated differences in pathophysiology compared to adults could provide strong support for an orphan designation.   

European Medicines Agency

Paolo Tomasi, MD (EMA, London, United Kingdom)

Dr. Paolo Tomasi, Head of Pediatric Medicines at the EMA, discussed the EU’s approach to approving drugs for pediatric patients (see the EMA website for the agency’s complete list of guidelines). In Europe, sponsors are required to develop a “pediatric investigation plan” (PIP) by the time they are considering a drug’s indications for adults. This rule applies to all medications unless a product-specific or class-wide waiver is granted, and failure to have a PIP early in development can easily jeopardize approval in adults. Dr. Tomasi also discussed the conclusions of a workshop aimed at determining what endpoints would be desired for interventions targeted to children with type 1 diabetes. The first criterion was that the drug should show an improvement in C-peptide levels, but that alone would be insufficient to demonstrate efficacy. Other endpoints could include reduced insulin requirement, improved 24-hour glucose profiles, or change in A1c. The EMA also asks for randomized studies that last at least one to two years and are preferably double-blinded and placebo-controlled.  

Lessons From Other Diseases

Daniel Lovell, MD (Cincinnati Children’s Hospital, Cincinnati, OH)

Pediatric rheumatologist Dr. Daniel Lovell offered advice based on his field’s experience with drug development for adults and children. We found this to be a useful comparison, and we were struck by the many similarities between type 1 diabetes and autoimmune rheumatoid arthritis in adults and children. He indicated that drugs approved for the pediatric population must be studied in children; it is not possible to extrapolate to children based on studies conducted in adults. Pediatric dosing was also a critical component of the studies in children. Based on the successes of leveraging a strong clinical trial network to develop therapies for juvenile rheumatoid arthritis, his conclusion was that the type 1 diabetes community should apply the same principles. We thought his comments were a valuable summary of the steps a sponsor must take to develop a drug for pediatric patients and the best means of interacting with the FDA. That said – we’re not aware of any organizations suggesting different approaches.

Risk/Benefit: Ethical Issues in Studying Children

David Wendler, PhD (NIH Clinical Center, Bethesda, MD)

Dr. David Wendler, an intramural scientist at NIH, discussed the ethics of conducting studies in children. He recommended that pediatric studies begin when phase 3 studies in adults are underway for diseases with “sufficient treatments” already available for children. For diseases with few or no specific treatments for children, he recommended initiating pediatric studies when phase 2 studies begin in adults. He also argued that “children” should not be thought of as a single group with regard to the ethics of conducting trials; the ethical considerations are very different for teenagers than for children under 10 years old, for example. Dr. Wendler concluded by saying that it is reasonable to enroll children in clinical studies even if the participants will not directly benefit from the research, provided the risks are minimal and the trial is expected to produce valuable data.

Panel Discussion

Moderator: Dr. Carla Greenbaum, MD (Benaroya Research Institute, Seattle, WA)

Participants: Dr. Jean-Marc Guettier, MD (FDA, Silver Spring, MD), Dr. Kevan Herold, MD (Yale University, New Haven, CT), Dr. Bruce Schneider, MD (FDA, Rockville, MD), and Dr. David Wendler, PhD (NIH Clinical Center, Bethesda, MD)

The meeting wrapped up with a stimulating panel discussion moderated by Dr. Carla Greenbaum. To conclude, Dr. Greenbaum acknowledged that “we’re all struggling with how to show the efficacy of a new drug for children” and expressed hope that “perhaps it’s possible we can, for specific therapies, do clinical trials in children without having proven efficacy in adults.” She celebrated the wide variety of perspectives discussed at the meeting and the clear desire among the various stakeholders to “figure out the best way to move forward safely given the very tough and difficult issues surrounding this topic.”

  • Dr. Greenbaum began by asking the panelists what sort of evidence of potential benefit should be required to justify conducting studies of a novel disease-modifying intervention in children.
    • Dr. Herold responded that “we need a sound scientific rationale,” suggesting that “studies of the intervention in the NOD mouse” or “knowledge of how the intervention affects the immune system and if that effect may alter the course of the disease in children” would provide sufficient justification.
    • Dr. Guettier said that he believes it is more important to first evaluate the potential risks of a new therapy before considering its potential benefits – we wonder if this viewpoint is representative of the FDA’s general mindset.
    • Dr. Schneider indicated that if type 1 diabetes in children is a different disease than in adults, that would raise many questions that need to be addressed before starting studies. However, if the disease is similar in both populations, then he believes the potential value of the intervention should be determined based on its value in the adult population. He also indicated that the field needs better markers to suggest an intervention is effective so that a small pilot study could be used to justify a larger pivotal trial. We found this fairly depressing since new markers will likely be very hard to find if past experience is similar to current experience.
    • Dr. Wendler approached the question from an ethical point of view, suggesting that there needs to be a “non-zero chance that the intervention will help” and “the prospect of benefit needs to outweigh the prospect of risk.” We think this is challenging to extrapolate to all children or all patients given the potential for one person’s perception of risk (driven by hypoglcyemia, etc.) to be so different from another’s.
  • Dr. Greenbaum then offered her own (much more specific) criteria. She believes there are five pieces of evidence that would each by themselves provide a justification for a study in children: i) demonstrated efficacy in adults with type 1 diabetes; ii) demonstrated efficacy in adults with other autoimmune diseases; iii) demonstrated efficacy in children with other autoimmune diseases; iv) a mechanism of action known to be relevant to human type 1 diabetes; or v) evidence of a positive effect in animal models of type 1 diabetes.
  • Dr. Greenbaum then opened the discussion to attendees. Notable comments included the suggestion by Dr. Robert Ratner (ADA, Alexandria, VA) that regulatory agencies may have an ethical obligation to facilitate development of new therapies given the natural history of type 1 diabetes. Dr. Herold also raised the conundrum that no one had determined how long the benefit of an intervention needs to last for it to outweigh the risks.


-- by Emily Regier and Kelly Close