The NIDDK Clinical Trial Development Process

Fradkin discussed the advantages and disadvantages of NIDDK’s process for developing and implementing clinical trials. Advisory groups first identify an important research question. Once the agency has determined that funding exists to support a new research initiative, a competitive Request for Applications (RFA) is issued. After reviewing applications submitted by investigators, NIDDK makes awards to a data coordinating center and clinical sites to design and implement the trial. At this point, the process can move quite slowly as a diverse group of diabetes and clinical trial experts have many different ideas about how the trial should be designed and conducted. In addition, a significant amount of money is flowing during the trial design process, and contracts and negotiations surrounding these financial transfers can affect general progress on trial development.

Fradkin explained that the RFA process for identifying diabetes trial investigators has advantages that include the diverse expertise that is brought to bear in the trial design phase and the rigorous, iterative process of site selection, which has resulted in highly robust multicenter clinical trials that have transformed diabetes therapy. When NIDDK issues an RFA for a new study, considerable uncertainty exists regarding such issues as the primary outcome of the trial, the sample size, the effect size, and the retention rate of trial participants. Because of these factors, the duration of the trial and its total budget are unknown throughout the RFA process. Thus, disadvantages of the RFA process are its length, uncertainty regarding the feasibility of the trial design, and the undetermined budget.

NIDDK recently tried a new approach to conducting diabetes clinical trials—the investigator-initiated planning grant. In this process, a principal investigator (PI) assembles a team of investigators and receives a planning grant to develop a trial protocol and a manual of procedures. Compared with the RFA process, the planning grant has the potential to be more efficient (shorter process, cost savings in the trial design phase, and a budget that is largely determined prior to initiation). On the other hand, because investigators are chosen by the PI, diverse viewpoints may be minimized in the planning grant process.

Developing Informative Clinical Trials for a Chronic, Heterogeneous Disease

Since NIDDK-sponsored clinical trials seek to examine approaches to diabetes therapy rather than particular drugs, subjects are often followed after the trial has ended or after its primary outcome measures have been assessed. Because diabetes is a chronic disease with complications that develop over a long period of time, lengthy follow-up increases understanding of the disease. Fradkin stressed that critical scientific findings have resulted from this follow-up after the completion of a trial. For example, the Diabetes Control and Complications Trial studied more than 1,000 type 1 diabetes patients, comparing intensive glucose control with standard glucose control over a 6.5-year study period. The trial revealed that intensive glucose control dramatically reduced the rate of development of complications associated with type 1 diabetes. By continuing to follow these patients for an additional 10 years, however, it was discovered that the benefits of the finite period of intensive glucose control were prolonged well into the future; a “metabolic memory” was created, even once the glycemic control of the two groups was similar. Trials in type 2 diabetes revealed similar findings. Fradkin noted that these findings from extended patient follow-up provided information on the importance of good glucose control early in the course of diabetes, before complications develop. In addition, significant pathophysiologic information gained from the prolonged follow-up provided a greater understanding of the etiology of the disease and how complications develop over time. At the same time, the resources expended on follow-up can limit the ability of NIDDK to initiate new studies, a consideration that becomes increasingly important as financial resources are limited and NIH funding remains flat.

A prolonged study time to evaluate the progression of diabetes also yields benefits for payers in the health care system. For instance, some outcomes in a randomized controlled trial (RCT) may be insufficient for payers. In the case of evaluating the effects of a lifestyle intervention to delay or prevent the onset of diabetes, payers seek information on the effects in preventing diabetes and on how durable those effects are. A study that evaluates the extent to which patients cross over the diabetes continuum (i.e., from pre-diabetes to diabetes) is generally less informative than one that evaluates the extent to which preventing diabetes stalls the complications of the disease. To provide more informative trial results on the long-term effects of diabetes prevention, NIDDK has invested significant resources in a follow-up study to the Diabetes Prevention Program (DPP).

Studying type 2 diabetes also introduces some challenges to the design of informative trials. For instance, the pathophysiologic heterogeneity of type 2 diabetes (i.e., the wide-ranging combinations of symptoms exhibited by patients) can make it difficult to identify which subsets of patients actually respond better to a certain drug or approach to therapy. For example, different type 2 diabetes patients have different combinations of insulin resistance and decreased beta cell function. When these heterogeneous manifestations of the disease are combined into a single group based on a given glycemic level for the purposes of a clinical trial, the opportunity to identify patients who benefit from a particular therapeutic approach can be lost. Fradkin mentioned that the heterogeneity of type 2 diabetes has assumed a larger role as the number of different classes of drugs to treat the disease has increased over the years, making it especially important to identify the subset of patients who respond better to a certain drug.

Fradkin also highlighted the success of NIH/NIDDK multicenter trials in recruiting racially and ethnically heterogeneous populations, suggesting that NIH studies have the advantage over industry-funded trials in this regard. For example, the government-sponsored DPP included 45 percent minority populations. The study looked at diabetes incidence rates for three study arms—lifestyle intervention, metformin, and placebo. The benefits of lifestyle interventions and metformin in reducing the incidence of type 2 diabetes appeared to be manifest across all of the ethnic and racial groups studied (see the further discussion of these results below). That is, the progression rate of type 2 diabetes in the placebo group did not differ by race/ethnicity. This is an especially critical finding given that type 2 diabetes affects minority populations disproportionately.

In addition to the inclusion of ethnically diverse populations, government-sponsored trials have excelled in characterizing patients with diabetes by phenotype. Careful phenotyping in the Diabetes Control and Complications Trial included measures of C-peptide, an indicator of how much insulin beta cells are producing, and resulted in the striking finding that patients with some residual C-peptide did better in terms of glycemic control and decreased hypoglycemia. As a result of this finding, the FDA has agreed to allow C-peptide to serve as a clinical endpoint for type 1 diabetes new-onset trials. This unanticipated finding resulting from phenotyping in the Diabetes Control and Complications Trial has had important effects on the development of type 1 diabetes trials. In the DPP, phenotyping by means of pharmacogenomics analyses revealed that even for those individuals at increased genetic risk for type 2 diabetes, lifestyle interventions were effective in decreasing their risk for the disease. Fradkin noted that this was a powerful result—genetics is not destiny in terms of developing type 2 diabetes.

NIDDK: A Model for Clinical Trial Collaborations

NIDDK’s research is highly collaborative—most of its studies involve working with other NIH institutes, according to Fradkin. These collaborations have resulted in unanticipated yet important findings. For example, in the collaboration with the National Institute on Aging (NIA) on the DPP, it was a prerequisite that at least 20 percent of the clinical trial participants be older patients. Initially, investigators were concerned that older patients would be unwilling to participate in the lifestyle intervention aspect of the study. NIA countered that the highest prevalence of diabetes is in older populations, so they should be included in the study. As it turned out, the study revealed that older patients were more sensitive than other age groups to the lifestyle change.

Given the prevalence of diabetes in older adults, the protracted time course of the disease, and the fact that diabetes is a major driver of Medicare costs, Fradkin believes diabetes is a good candidate for collaboration between NIH and the Centers for Medicare and Medicaid Services (CMS). Very few of the practices Medicare pays for have been rigorously examined in RCTs. Given NIDDK’s track record in conducting paradigm-shifting diabetes trials in diverse populations, conducting clinical trials in the Medicare population could offer an opportunity for cost savings. NIH would pay the research costs, CMS would pay the costs of providing clinical care, and the trial results would have the benefit of being conducted in a real-life health care setting. Tracking clinical trial results via Medicare beneficiary claims would generate meaningful, long-term outcomes with potentially compelling economic cases.

Patient Recruitment and Retention

Greenbaum described the process of identifying, screening, and recruiting patients to participate in a type 1 diabetes natural history/prevention trial. To achieve enrollment of the 300–400 patients necessary for a prevention trial, 200,000 relatives of people with type 1 diabetes will need to be screened, a number representing approximately 2–3 percent of the total potential pool of such individuals. About 4 percent, or 8,000, of these 200,000 individuals will be antibody positive—the necessary trait for participating in the trial. After 5 years of patient recruitment efforts, approximately 70,000 relatives have been screened; progress has been steady but remains a challenge. Greenbaum noted that the magnitude of the screening effort necessary to find the relatives at risk for type 1 diabetes and eligible for the prevention study is sustainable only with the broad support of a clinical research network, in this case TrialNet.

Limited information is available regarding how people approach the decision of whether or not to participate in a diabetes clinical trial. Greenbaum speculated whether people with diabetes know that their families are at 15 times greater risk for the disease than the general population, and whether they know that they can be tested or know but prefer not to be tested. In the absence of any systematic, rigorous study in this area, Greenbaum offered a few anecdotal thoughts about why people participate in diabetes trials. In her experience in the northwestern United States, rural participation in diabetes clinical trials is much greater than urban or suburban participation. Greenbaum hypothesized that in urban and suburban areas, families may already be so overwhelmed by such demands as having to take children to various school events and team practices that joining a clinical trial would be an additional, and unwanted, burden.

Greenbaum also described the age distribution of the relatives screened for the type 1 diabetes prevention study. Young adults (ages 19–32) are participating in research at a much lower rate than other age groups. In Greenbaum’s experience, the young adult population is difficult to recruit for clinical research because it is generally characterized by a level of self-absorption that does not lend itself to voluntary participation in a clinical trial that may or may not lead to any personal benefit.

In contrast to prevention studies, clinical trials on the new onset of type 1 diabetes have had greater success in identifying and recruiting participants. Figure 7-2 shows the recruitment rates for four such trials. Greenbaum discussed some of the factors associated with each study that she believes affected their ability to attract patients in an efficient manner.

FIGURE 7-2

Patient recruitment rates for four type 1 diabetes trials. SOURCE: Greenbaum, 2009. Reprinted with permission from Carla Greenbaum 2009.

For each trial depicted in Figure 7-2, the sites were large diabetes centers that are highly committed to recruiting patients. Thus, differences in recruitment rates should not be attributable to variation in the commitment level of trial sites. The trial that recruited 4.1 subjects per month required daily, chronic medication therapy. In the trial that recruited 5.4 patients per month, the drug treatment was two doses (not a chronic therapy), and some follow-up visits were required. The study with the most successful patient recruitment rate is surprising because it involved younger subjects, who, as noted, are typically difficult to recruit, for an intravenous (IV) infusion over 24 visits, one visit per month. In contrast, the study with the lowest recruitment rate has yet to recruit the 10 subjects it requires. Greenbaum explained that this is a phase I study, started at only one site and including only individuals aged 18 and older. In addition, subjects have to have been diagnosed with type 1 diabetes at least 4 years previously, but still have significant insulin secretion to qualify for enrollment in the study.

In light of these differences in recruitment rates, Greenbaum discussed factors that, in her view, can impact patient enrollment and retention:

• Enthusiastic health care providers—Greenbaum and Kahn both referred to the importance of having research teams that are supported by full-time equivalent (FTE) employees. With time dedicated to clinical research, staffs have a greater sense of responsibility for enrolling and retaining patients in a trial. Greenbaum indicated that within her home institution, the successful recruitment and retention of study participants is due to the connections research staffs have with patients and families. The relationship between staff and patients engenders a strong sense of loyalty to the study, as well as to each other.
• Patient vulnerability—There is a level of vulnerability associated with patients who are newly diagnosed with a disease. In Greenbaum’s experience, individuals entering clinical trials are looking to cure their diabetes, regardless of the information presented to them on consent forms. Perhaps people who are further from diagnosis are not enrolling in clinical trials at the same high rate as those who are newly diagnosed because they have adapted to the lifestyle of their condition and are more attuned to the risks and benefits of a particular study. Greenbaum also noted the high level of clinical trial participation among children and speculated that it may be associated with parents’ sense of guilt and fear and their desire to do anything they can to help their children, including enrolling them in clinical trials.
• Socioeconomic status—Greenbaum noted, as did Musa Mayer (Chapter 6), that variations in socioeconomic status (income, education, occupation) affect an individual’s level of engagement with the health care system and exposure to clinical trials. An individual with higher socioeconomic status may be more likely to be aware of the clinical research opportunities available and better equipped to weigh the risks and benefits of participating as a research subject.
• Physician support—The critical importance of physician support in recruiting and retaining patients in clinical trials was noted by Greenbaum, as well as a number of workshop participants. Most clinical trial subjects cite their physician’s encouragement as the reason why they decided to participate in a clinical trial.

Reflecting on her work with TrialNet, Greenbaum also highlighted a number of effective tools this network brings to the clinical trial process and to the recruitment and retention of patients. TrialNet uses FTE-supported clinical centers with dedicated time to conduct its trials. In addition, Trial-Net draws on a large affiliate network that includes several hundred physician practices across the country. It also uses a professional media group to draw attention to its research efforts. Most recently, the Jonas Brothers and Miss America have served as spokespersons for TrialNet studies. Also, an important attraction of TrialNet studies is the fact that the travel costs of clinical trial participants are paid for by the network. In addition, TrialNet is able to build on its connection with JDRF and ADA. JDRF’s website continues to be an important tool for referring patients to clinical trials.

Navigating the IRB Process

The reality of conducting clinical research today is that multicenter trials, with multiple local IRBs, are required to implement a trial capable of providing robust, informative answers. Greenbaum explained that TrialNet has put a great deal of effort into adapting to this situation. For one thing, it has adopted a proactive approach of providing explicit instructions to IRBs to help guide their decision-making process. For example, TrialNet protocols are drafted with specific language stating that it is permissible to study children in a particular trial and citing the guidelines and rules that apply. Greenbaum said IRBs appreciate the inclusion of this specific language in the protocol because it relieves them of the responsibility for making the decision as to which guidelines or rules apply in the case of a particular research study.

TrialNet also has a protocol template that includes a number of sections designed to facilitate the regulatory approval process. The sections range from substantial additions citing federal regulations regarding research in children to minor variations in the language of informed consent forms for patients. Greenbaum noted that in her experience, the key to creating a successful trial protocol (i.e., reducing the need for protocol amendments and deviations) is the inclusion of open wording. For example, a trial protocol might state that “no more” than a particular amount of serum or plasma will be drawn from each research subject in the trial. Because the amount of serum or plasma needed at a particular time in the study is likely to change, this wording allows for the necessary variation and eliminates the need to submit additional paperwork (i.e., a protocol deviation or resubmittal for a protocol revision). Preparing such carefully written protocols that include deliberate yet open wording has therefore helped TrialNet conduct more efficient clinical trials in terms of the recruitment and retention of patient subjects.

Informed Consent

Although efforts have been made to streamline and improve the informed consent process, it remains a challenge for both investigators and patients. Greenbaum stated that the overlap between the confidentiality language of informed consent forms and federal requirements under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) makes drafting clear, readable consent documents somewhat difficult. Despite the growing tendency in the field to emphasize obtaining the final patient signature on an informed consent document, TrialNet has tried to make informing and educating patients a priority instead of merely obtaining their signature. TrialNet has developed patient participant handbooks and quizzes separate from the consent process to ensure that patients really understand what the trial involves. In addition, TrialNet requires that physicians be actively involved in the informed consent process for patients, a feature not commonly found in other study settings, according to Greenbaum.

During the workshop discussion, Perry Cohen, a Parkinson’s patient advocate, noted that his organization, Parkinson Pipeline Project, has developed a research participant bill of rights and responsibilities. The document lays out the features of clinical research that patients desire if they are to participate in a trial. The declaration includes patient requests and responsibilities related to informed consent issues, as well as rights to post study data (e.g., trial results and options for care after the trial ends).²