Clinical Trials In BMT: Ensuring That Rare Diseases and Rarer Therapies are Well Done

OVERVIEW OF CHALLENGES FROM THE STANDPOINT OF A PUBLIC FUNDER

Susan Shurin, MD

Over the past decade, a transformation in the way the public and policy makers approach medicine has occurred, with emphasis upon the importance of basing interventions upon rigorous evidence, patient-centered and -reported outcomes, healthcare systems that are capable of learning and improving, and accountability of providers and institutions. All of these laudable goals require that there be data on short- and long-term effectiveness and toxicity—in other words, we are supposed to know what we are getting out, as well as what we are putting in.

This has increased the importance of research done to address both basic scientific questions and clinically important outcomes. Because only a small fraction of this research will result in new drugs, diagnostics, or devices, the bulk of the funding for conduct of this research comes from patient care costs and public funders, especially the National Institutes of Health.

There are several key challenges that face those who design and conduct trials in rare diseases in general, and all impact studies in hematopoietic stem cell transplantation. Overcoming these challenges is essential for research funders to justify affect significant investment in infrastructure, particularly in times of very stringent budget constraints. Design and conduct of research in multiple sites is necessary to ensure meaningful outcomes. Several points deserve emphasis.

1. Researchers using highly specialized therapies in uncommon diseases tend to be highly expert in their fields of interest, but may not be expert in the design of research studies and analysis of data. Interdisciplinary groups must be engaged in all stages of study design and conduct to ensure that the scientific question is clearly enunciated, the statistical requirements to achieve meaningful results are clear, and the data collected and analyzed is of high quality.

2. There are special problems in accrual of participants to these trials. The total number of eligible patients may be small, and imposing additional limits on eligibility (ie, creating subgroups) may further limit the number of available participants.

3. It may not be clear how many participants are likely to actually be available. The availability of registries of well-characterized patients who might be eligible greatly facilitates conduct of studies.

4. In some circumstances, especially in nonmalignant disorders and some pediatric conditions, other physicians may not recognize that transplantation is an option, may envision transplantation as an unacceptably toxic option, or may not know how to make referrals or talk to patients about the options. This has severely limited conduct of trials in hemoglobinopathies and some other inborn conditions.

Public and private funders have multiple demands upon their resources and are obligated to invest funds where there will be optimal payoff in both public health advances and scientific knowledge. Support of infrastructure for clinical trials must facilitate the conduct of those studies and the rapid dissemination and implementation of their results. Support of networks and resources that do not complete studies that will have high impact on the conditions under investigation diverts funds from other research projects.

Creation of networks and clinical trials groups requires a collaborative relationship between the funders and the investigators and their institutions. A well-run network brings several major benefits to research funders, including

• Improving the speed and efficiency of the design, launch, and conduct of clinical trials.

• Incorporating innovative science and trial designinto clinical trials.

• Improved prioritization, selection, support, and completion of clinical trials.

• Providing incentives for patients and physicians to participate in clinical trials.

• Providing a platform for engagement and training of new investigators and of multiple disciplines in clinical research.

The NHLBI has found several key features to successful networks and resources.

1. An organized, motivated investigator community capable of identifying key scientific questions and designing studies to answer those questions. This requires leadership, collaboration, and an ability to set priorities, because it is unlikely that all the important questions will be addressed.

2. A portfolio of scientific opportunities that can be addressed through studies and will have an impact upon meaningful aspects of patient outcome. The benefit of a network over a series of individual studies is its ability to conduct multiple and sequential studies, which requires that protocol development be continuous, and that the dedicated infrastructure be continuously used at full capacity.

3. Feasibility: the design of studies must be such that it will be possible to enroll participants in the specified amount of time, submit data, and have endpoints that can be achieved within the margins of the funding period.

   1. Accrual: there must be sufficient numbers of eligible participants who must be approached and invited to enroll. Addressing recruitment and referral issues early is essential; addition of sites after studies have opened adds costs and decreases the overall productivity of a network. The investigator group should be self-policing and hold its members accountable.
   2. Reasonable expectations of data capture, informatics, and coordinator support.

4. A strong investigator focuses on high-impact questions, creation of a culture supportive of research, and nurturing young investigators.

In this time of profoundly limited resources for biomedical research, network and group clinical research investments may play an important role [1,2,12].

DESIGN OF CLINICAL STUDIES IN RARE DISEASES

Jeff Krischer, PhD

There is no special dispensation given for conducting trials in rare diseases. Trials are held to the same ethical and scientific standards across all diseases. Trial designs lead to sample size requirements that address the study questions with the minimum accrual subject to the acceptable Type 1 and 2 error rates. Hence, they are inherently efficient in the projection of required sample sizes. Investigators have some latitude in phrasing the study question (improvement, noninferiority, difference). As well, although it is customary to use the threshold for significance at ≤0.05, there is a rationale to conduct studies in limited numbers of patients with power<80%. The choice of study endpoints along with the minimally clinically significant effect size to be detected also have a large impact on the requisite sample size. Continuous endpoints generally require a smaller sample size than discrete endpoints, and the effect size is a major driver of target sample sizes. In some designs, there is an inverse relationship between the numbers of individuals to be enrolled and the planned duration of follow-up needed to effectively power a study.

With these options in mind and the variety of clinical trial designs available, it is possible to successfully conduct research in rare diseases. Because things sometimes do not turn out as originally planned, trials should also incorporate milestones for determining feasibility, early emerging differences, and futility. Methods for the latter two are readily available, but feasibility rules need case-by-case discussion. Newer “adaptive” designs offer the prospect for making mid-course corrections along the way.

The use of surrogate outcomes offers promise in settings where outcomes are sparse or require a long time to observe. The bar for defining an acceptable surrogate outcome is quite high and often poorly understood. Where there is no surrogate, the concept of an “intermediate” outcome may be of value when screening potential treatments for those to proceed to a more definitive trial. For example, a short-term positive result may suggest the prospect of a long-term improvement, but the absence of a positive short-term result may dampen enthusiasm for proceeding to the long term.

The design and successful conduct of clinical trials in rare diseases are challenging but by no means unique to the diseases or the therapeutic options [3–6].

COORDINATED EFFORTS FOR SUCCESSFUL RARE DISEASES RESEARCH AND ORPHAN PRODUCT DEVELOPMENT

Stephen C. Groft, PharmD

There are more than 7000 genetic and acquired rare diseases affecting nearly 18 to 25 million Americans, approximately 6% to 8% of the population of the United States. A rare disease is defined as a disease with a prevalence of <200,000 persons in the United States. Most rare diseases affect several organ systems, requiring multiple clinical and research disciplines to be involved in conducting research and providing care for patients. Rare diseases know no geographic, political, or historic boundaries. The National Institutes of Health recognizes and acknowledges the need for collaborative efforts of multidisciplinary research teams and the need for new approaches to drug discovery and development [7,8].

If there is limited or no commercial interest in developing an intervention or a diagnostic for rare diseases, resources and commitments from many private and public organizations are required to advance research discoveries leading to the development of products for the diagnosis, prevention, or treatment of rare diseases. A global research infrastructure of qualified investigators is required to stimulate and coordinate research efforts by seeking ways to provide access to clinical trials at multinational research sites with common protocols and multidisciplinary research teams. A systematic coordinated approach to research and product development is needed and requires numerous partners from around the world, including industry collaborators, research investigators, federal research and regulatory agencies, private foundations, and patient advocacy groups. Remarkable accomplishments have been noted by using the strengths and resources from highly motivated partners. There are now several successful models of patient advocacy groups directing partnerships to reach their organizational goals of providing treatments for their patients. Organizations such as the Cystic Fibrosis Foundation, the Muscular Dystrophy Association, Alpha-1 Foundation, Friedreich Ataxia Research Association, and Parent Project for Duchenne Muscular Dystrophy, the Progeria Research Foundation, and others have expanded their traditional roles to move the rare diseases research advances into an emphasis on orphan products development.

Unlike more-common diseases, gaining access to a sufficient number of patients at any one location to participate in clinical studies can be problematic and requires collaborative efforts to include multiple investigators at research sites in the United States and around the world. These collaborations also require investigators to adhere to common research protocols, exchange biospecimen samples, provide medical information to patient registries, conduct natural history and longitudinal studies of rare diseases, and use the resources from data monitoring and coordinating centers. Interactions initiated at family, patient, and scientific conferences have often been the key link to the establishment of multinational research investigations.

The International Rare Diseases Research Consortium (IRDiRC)

A recently established organization comprised of research funders, patient advocacy groups, researchers, industry, and regulatory agencies have agreed to meet the goals to deliver by the year 2020 diagnostic tests for most rare diseases and 200 therapies for patients affected by rare diseases [9–11]. This ambitious vision will be realized though cooperation at the international level. IRDiRC will develop the scientific and policy framework to guide the research activities and foster collaboration among the stakeholders to systematically explore opportunities to accelerate the development of diagnostics and therapies for rare diseases. IRDiRC is committed to the promotion of public data sharing, as well as the sharing of research resources such as study designs, data analysis, data management tools, and, to the extent possible, patient samples. IRDiRC will work toward facilitating international clinical trials by sharing best practices and standard operating procedures; encouraging harmonized policies regarding sponsorship, clinical trial applications, ethical review, use of investigational medicines, liability issues; and identifying existing infrastructure programs that are working from established research consortia/networks, biobanks/biospecimen repositories, patient registries with commonly accepted Common Data Elements (CDEs), biomarkers, animal models, in vitro systems, and genomic analyses. Additional information about IRDiRC can be located at the following URL: http://ec.europa.eu/research/health/medical-research/rarediseases/irdirc_en.html.

The Institute of Medicine (IOM) Review of Rare Diseases Research and Orphan Products

The IOM Review of Rare Diseases Research and Orphan Products Development and Related Activities (ORDR) was completed in 2010 [12]. The report was sponsored by ORDR with support from the FDA Office of Orphan Products Development (OOPD). The report “Rare Diseases and Orphan Products: Accelerating Research and Development” was released in October 2010 and can be found at http://iom.edu/Reports/2010/Rare-Diseases-and-Orphan-Products-Accelerating-Research-and-Development.aspx. The Report provided an overview of elements of an integrated national strategy for rare diseases research and orphan products development. Selected IOM recommendations to the National Institutes of Health and FDA include the following:

• Increase examination of the epidemiology, impact, and treatment of rare diseases in the context of assessing research and development opportunities and activities;

• Investigate strengths and limitations of the current development pathways for drugs and medical devices for rare diseases;

• Provide additional support for further development of research and analysis strategies for small populations;

• Develop procedures to ensure design of NIH-funded product development studies meets FDA standards;

• Provide a centralized preclinical development service for rare diseases;

• Establish public–private partnerships to develop freely available platforms for creating patient registries and biorepositories; and

• Increase capacity and flexibility for conducting regulatory reviews of all phases of clinical research on rare diseases.