All parents know the question “Are we there yet?” when on a long drive with kids in the back of the car: an expression of impatience and not understanding why it takes “forever.” Reality is often different than the perception of those in the back seat: we are driving as fast as speed limits allow, and we only left home a couple of hours ago.
The same feeling is present when clinicians speak with people with type 1 diabetes (T1D) and their families. Why does it take so long? Why haven’t you cured this disease? It becomes worse when other health care professionals come into the picture, in particular health care professionals who know of “success stories” close to biblical proportions, as in rheumatoid arthritis or inflammatory bowel disease. We find many answers in the article by Bingley et al. (1) in this issue of Diabetes Care. Dr. Bingley, one of the clinicians leading the long-term battle against T1D, has described together with her TrialNet colleagues what this initiative has achieved in the past decades. Importantly, they also give us glimpses of where they feel the field should go.
The long list of interventions tested in TrialNet confirms that we have not failed in preventing or arresting T1D for lack of trying but indicates that T1D has several specific hurdles that prevent us from reaching success (2). Hurdles include the lack of accessibility of the target organ (the insulin-producing β-cell buried in the islets of Langerhans in the pancreas), making direct histological observations or staging of the immune attack or level of β-cell destruction impossible in individual patients. What we did learn is that T1D is probably not the result of a single path to β-cell destruction (3). Heterogeneity exists, in the speed of onset, in the progression of β-cell destruction, and probably also in the immune cell types involved. Heterogeneity becomes even more impressive when one looks at the disease in a perspective broader than the typical Caucasian person with T1D, with clinical features like age of onset and even genetic predisposition being distinct between different ethnic populations, making the design of international trials challenging.
Another important obstacle is the lack of solid biomarkers of disease progression or therapeutic success. The only tissue accessible for immune follow-up is the peripheral blood, but most of the immune action is probably taking place in the pancreas, its draining lymph nodes, or more central immune organs like the spleen or thymus. When evaluating therapeutic effects of interventions in rheumatoid arthritis, one can see the effect in the clinical aspect of the joint, whereas decreased inflammation in the islets is much more difficult to pick up.
The observation that T1D occurs most frequently at very early ages and that insulin therapy is effective in many patients puts the bar for safety of interventions targeting the immune system very high, in particular in the context of evolving novel technologies available for the treatment of people with T1D (4). When looking at the “miracles” achieved in diseases like rheumatoid arthritis, the agents used are given long term and are often considered too aggressive for T1D interventions, making comparisons between diseases very difficult.
Another major obstacle is the fact that our animal models for T1D are far from ideal, with the most studied model, the NOD (nonobese diabetic) mouse, differing in many ways from the human disease (e.g., its dramatic immune infiltration in the pancreas rarely observed in humans). In defense of the NOD mouse, however, most often it is not the mouse giving false results, but it is the over- or wrong interpretation of the data coming from the murine experiments that misleads researchers. Indeed, many (more than 400!) strategies for disease prevention work in the NOD mouse, but only when these strategies are performed at a very early age, well ahead of autoimmunity or disease start. On the other hand, very few of these strategies work when given to the mouse after disease onset, a situation more akin to most human trials to date (5). In order to be able to intervene at these early stages in humans, TrialNet is considering expanding their efforts to other populations, in particular the general public, with suggestions of collaborations with other networks (6).
Here, we touch upon probably the most important hurdle to success to date: the lack of coordinated efforts. When trying to answer the question from patients as to why we “are not there yet,” remarks often come up concerning why we do not collaborate better and in particular why industry is not more closely involved. Hard to understand is also the gap between basic researchers and the clinical networks. The basic researchers keep bringing interesting suggestions to the table, in the domain of intervention but also in the area of better understanding the disease and development of promising biomarkers, but the machinery of the clinical networks is often slow to adopt these concepts. An example is the type of sample that is collected: if one wants to apply the novel insights on microRNAs as tools for profiling people at risk for T1D, one needs to have the blood samples collected with special excipients and in specific ways. Unfortunately, it often takes too long for the collection machinery to be adapted, making it difficult to use historically collected samples and forcing “repeated cycles of reinventing the wheel.”
Another important hurdle is the broad variety of international rules and regulations regarding ethics, sample transport, informed consent, and in particular the required steps for interventions to be approved. For instance, just by comparing the situation in the U.S. and the European Union (EU), one discovers major differences. As such, Dr. Bingley discusses the concept of one central ethics committee for approval that could help TrialNet. This is a U.S. discussion and does not apply to the EU, where there remain specific and individual rules per country. There is, however, a positive trend also in the EU for more and more centralized guidance, but we are not there yet. And the issues above described are just for the U.S. and the EU—for other regions in the world, different regulations often prevail.
The solution for moving forward and pushing all these collaborations to happen is lying right in front of our eyes but has been neglected for many years: get the most important stakeholders on board from the beginning—engage the people with T1D and their families. TrialNet took some time to realize this but is now catching up. The power of the patients and their families has been underappreciated: their political power, their voice when talking to regulators, to industry, and to funders is of the utmost importance (7).
Bingley et al. (1) touch on another crucial point briefly: the need to involve not only people with T1D but also regulators and industry in our endeavors. In the EU, an interesting project is ongoing. Called INNODIA (www.innodia.eu), it was conceived with exactly this in mind: bring academic researchers, from basic to clinical, together with industry and involve the most important stakeholders, the people with T1D and their families, from the beginning. INNODIA is a strange structure to understand from the outside, as it is funded partly through the European Commission (Innovative Medicines Initiative Joint Undertaking) and partly through industry (Sanofi, Novo Nordisk, GlaxoSmithKline, and Eli Lilly) and two international research-funding organizations, JDRF and The Leona M. and Harry B. Helmsley Charitable Trust. These companies and organizations themselves are integral and active partners in INNODIA and work intensively with academics from 25 institutions and 1 small to medium-sized enterprise in 14 EU countries to push the project forward. Importantly, INNODIA is closely guided by people with T1D and their families themselves through the Patient Advisory Committee, consisting of a group of T1D patients and parents, which provides continuous feedback on the research taking place in INNODIA and development of protocols and is crucial in disseminating the goals of INNODIA to the public. INNODIA is collecting in a standardized manner throughout Europe blood samples and data from newly diagnosed T1D patients and their first-degree relatives to learn more about the evolution of T1D and to develop new biomarkers and therapies. Innovative is that these samples are collected in a standardized manner, using tools that allow assays coming from the basic research in INNODIA to be applied without delay. A suite of standardized assays is run on these samples, and all clinical data are centralized together with data coming from basic research laboratories, e.g., sequencing and “omics” data, in the secure INNODIA database, thus establishing a systems biology platform allowing integrated analysis of all data and subsequent modeling of T1D in silico. Of relevance, the INNODIA project focuses on altering the way we perform clinical trials aimed at arresting T1D. Using data from the basic laboratories and clinical research, INNODIA is able to design adaptive trials, using a master protocol that allows testing of different interventions coming from industry or academic partners in a concise and personalized way. As such, INNODIA is different from TrialNet, but it is interesting to see that TrialNet is also now moving toward the direction taken by INNODIA from the start, i.e., mechanistic studies, emphasis on biomarkers, attention to the voice of the people with T1D, etc.
If we wish to increase the chances of positively answering the question “Are we there yet?” in the coming years, key points are collaboration between all initiatives, learning from each other, harmonizing protocols/biomarkers, and motivating funding agencies to provide long-term, stable funding for large joint initiatives. We should eventually be able to realize a “Worldwide TrialNet,” with stable funding in different areas of the world, taking the best from initiatives like INNODIA (engagement from industry, link between basic and clinical researchers, in-depth research embedded in targeted small-scale interventions, and a central role for people with T1D in design of research and trials) and TrialNet (major logistics organization, established and motivated network of sample collectors and trialists). If we want to convince all the complex structures funding these networks and initiatives to engage, we will have to make sure they understand that this is the only way to beat the very complex disorder that is T1D. To push this forward, the voice of the people with T1D all over the world, together with the collaborative work of devoted scientists and clinicians, will be crucial.
See accompanying article, p. 653.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.