2010-09-16

Clinical research in hematology has never been more important, yet clinical hematology investigators are facing unprecedented challenges. Constantly changing and often inconsistent regulations, chaotic reimbursement policies, lack of insurance coverage of routine care associated with clinical trials, increasing demands on physician time, and scientific advances demonstrating the complex differences between individual patients, all complicate clinical research in both benign and malignant hematology.

The opportunities and the obstacles in clinical research are not unique to hematology, and include problems with how we organize, support and conduct clinical research. The Institute of Medicine (IOM) recently released a report that calls for an overhaul of the National Cancer Institute’s (NCI) Cooperative Group Program. The report, “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program,”¹ identifies four overarching goals:

• Improving the speed and efficiency of the design, launch, and conduct of clinical trials
• Making optimal use of scientific innovations
• Improving selection, prioritization, support, and completion of clinical trials
• Fostering expanded participation of both physicians and patients in clinical research

These are all vital issues, and addressing these goals is important for all aspects of hematology clinical research, not just those studies that are part of the NCI cooperative oncology groups.

ASH has identified a number of specific challenges facing clinical investigators in both malignant and benign hematology, including:

• Lack of harmonization of existing policies and regulations on clinical trial operations
• Insufficient insurance coverage for routine patient care
• Complex consent forms and language; and
• Inadequate support for benign hematology and rare diseases.

Each of these challenges is discussed in detail below, along with the Society’s recommendations for overcoming each specific challenge.

Current Challenges & ASH Recommendations

The future of hematology requires that research in diverse areas of basic science be translated into novel, decisive therapies that will effectively prevent or cure serious blood diseases. Clinical trials are pivotal in the research and treatment efforts of the Society's members who combat hematologic cancers as well as a multitude of non-malignant hematologic diseases and conditions. However, there are a number of existing and potential barriers to conducting clinical trials research:

Harmonization of Existing Policies and Regulations on Clinical Trial Operations

The federal government, through the Office of Protection from Research Risks (OPRR), within the NIH and the Department of Health and Human Services (HHS), has promulgated regulations and policies that govern the protections for human subjects who participate in federally-funded research. The federal government also propagates regulations governing human subject protections through the Food and Drug Administration (FDA). Investigators must comply with these complex regulations that not only lack harmonization between different agencies but, in fact, sometimes appear to be inconsistent with each other and with reimbursement policies established by the Centers for Medicare and Medicaid Services (CMS). In addition, most of these regulations were developed at a time when the vast majority of clinical research studies were taking place at single institutions and thus, rely heavily on local Institutional Review Boards (IRBs). Studies on the subject of research oversight have documented the adverse effects of regulatory burden on clinical, epidemiological, and health systems research.²

ASH recognizes the importance of providing strict policies and regulations that govern protections for human subjects who participate in federally-funded clinical trials. At the same time, concerns have been raised that the various agencies that fund or provide oversight of clinical trials have instituted different regulations that are often inconsistent and unnecessarily burdensome, especially for multi-institutional trials. This has inhibited the initiation of new trials and access to promising treatments for patients. ASH encourages the Department of Health and Human Services (HHS) to bring together leading researchers with experience in the operation of clinical trials and representatives from NIH, FDA, CMS, and other agencies to determine if changes could be made to better harmonize existing policies and regulations on clinical trial operations.

One possible short-term goal for this harmonization process would be the establishment of a national IRB. The future of hematology in particular requires that research in diverse areas of basic and clinical science be integrated and translated into novel, decisive therapies that will effectively prevent and treat serious diseases. The integrated national IRB will lift the regulatory burden, ease the administrative burden, and increase the harmonization of multi-institutional trials, thus increasing access to promising treatments for patients. The centralized rules will increase collaboration between multiple investigators around common themes to support novel clinical trials. ASH recommends the establishment of a national IRB that will ultimately accelerate the translation of biomedical research discoveries into approved diagnostics and therapies.

Insurance Coverage for Routine Patient Care

For many patients, standard therapy may not be beneficial. The tremendous advances in the treatment of cancer and many other hematologic diseases have been made largely because therapies have been tested in clinical trials and have been found to be significant improvements over standard therapy. Unfortunately, access to treatment through clinical trials is often denied, as many insurance companies refuse to cover routine patient care costs on the grounds that the care is “experimental.”

Although trial sponsors – either industry or government entities – must rightly assume the responsibility for the research costs of a clinical trial, including data collection and analysis, as well as providing the experimental agent free of charge, patients depend upon their insurance plan to cover diagnostic or supportive services – considered “routine care” – while enrolled in the clinical trial.

On the state level, a number of laws have been enacted that address the issue of clinical trials coverage in varying and inconsistent ways. This has created a patchwork of coverage that varies depending upon the state of residence of the patient and the vast majority of Americans still lack guaranteed access to clinical trial coverage. A provision of the 2010 health reform law would require all health insurance plans in the United States, including those offered in the Federal Employees Health Benefits Program, to cover the routine patient costs associated with participation in clinical trials beginning in 2014.

However, under a proposed federal regulation implementing the health reform law, certain health plans in existence as of March 23, 2010, when the health reform bill became law, were deemed to be "grandfathered" plans, and thus were exempted from many of the new law’s provisions. Included among the benefits that are not applicable to grandfathered plans is coverage of routine patient costs associated with participation in approved clinical trials. Only when a plan loses its grandfathered status will it be required to abide by the provisions of the health reform law that were not mandated on grandfathered plans, including coverage of clinical trials.

The clinical research process is a lifeline for those with life-threatening illnesses, and the failure of private and public insurers to cover the costs of routine patient care not only denies patients of the best care available, but also threatens the American clinical research enterprise as a whole. ASH recommends applying the clinical trials provision of the health reform law immediately to all insurers, including grandfathered plans, and removing coverage of routine patient costs associated with participation in approved clinical trials from the list of benefits that are not applicable to grandfathered plans.

Consent Forms and Language

Federal regulations require researchers to obtain and document informed consent from patients participating in clinical trials. Rigorous patient protection must be maintained. However, many of these regulations were developed in an era when multicenter studies were uncommon and communication and information technology were very different from what they are today.

Original informed consent forms were clear, concise, short, and in marked contrast to informed consent documents in current use. The forms have become so long and complex that they are no longer effective as documents that truly inform patients about the potential risks and benefits of participating in research. This creates a burden for both the patient who needs to read and understand the form and the physicians who needs to spend extra time explaining the forms to the patient. This, in turn, can deter both patients and physicians from engaging in clinical research.

Clearer, shorter, simpler informed consent documents would be easier for clinical investigators to present to patients, easier for those patients to understand, and would do a better job of protecting the rights of the patients. They would also result in enhanced accrual to clinical trials. Consistent with the recommendations in the recent IOM report on NCI’s Cooperative Group Program, ASH recommends that federal regulators clarify that patient consent forms for all clinical trials may be shortened and/or include an abbreviated and simplified summary to enhance the provision of informed consent.

Support for Non-malignant Hematology and Rare Diseases

The development of diagnostic and treatment strategies requires access to numerous patients to support clinical trials. However, many hematologic diseases and conditions, particularly those which are non-malignant, can be classified as rare disorders. As a result, in order to undertake clinical trials in one of these diseases, patient data must be pooled since no single center sees sufficient numbers of patients to constitute a valid sample size. ASH urges the establishment of a mechanism of support for clinical research for rare hematological diseases and disorders.

One such mechanism of support would be the creation of national resource centers. National resource centers focusing on blood diseases would have an important impact on research of these disorders. Collaborative networks of multiple academic medical centers would work together to design and prioritize clinical trials and coordinate the prospective recruitment and registration of patients with hematologic disorders into available clinical trials at the national level.

¹ IOM. A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Institute of Medicine. April 15, 2010.

² IDSA. Grinding to a Halt: The Effects of the Increasing Regulatory Burden on Research and Quality Improvement Efforts. Clinical Infectious Diseases 2009; 49:328–35.

Founded in 1958, ASH represents over 16,000 clinicians and scientists committed to the study and treatment of blood and blood-related diseases. These diseases encompass malignant hematologic disorders such as leukemia, lymphoma, and myeloma; and non-malignant conditions including anemia and hemophilia; and congenital disorders such as sickle cell anemia and thalassemia. In addition, hematologists have been pioneers in the fields of bone marrow transplantation, gene therapy, and many drugs for the prevention and treatment of heart attacks and strokes.

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