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On May 20 and 21, 2009, the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) convened a workshop to discuss priorities for thalassemia research and clinical trials. Thalassemia major affects approximately 1,000 persons in the U.S., however, increased immigration to the U.S. is increasing the prevalence and broadening the demographics of thalassemia. The goal of the workshop was to identify clinical research needs and trials to reduce the burden of disease.
Investigators, clinicians, and patient advocates identified priorities for clinical research and discussed study infrastructure and international collaborative opportunities. Key areas for the successful completion of clinical trials in thalassemia include:
Meeting attendees identified high priority scientific areas including:
Subcommittees of experts assembled before the workshop to develop opinions on five topics:
Each subcommittee considered four questions:
The first day of the workshop, representatives from each subcommittee presented recommendations for clinical research priorities. On the second day of the workshop, experts in thalassemia clinical trial research described the current status of clinical trials conducted in the U.S. and Thailand. The workshop was co-chaired by Drs. Suthat Fucharoen of the Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Thailand and Dr. Cheryl Hillery, Professor of Pediatrics at the Medical College of Wisconsin. The NHLBI Deputy Director, Dr. Susan Shurin, underscored the need for workshop attendees to address issues of public health, critical scientific questions and opportunities in thalassemia globally, such as the state of curative and supportive care, how to prolong longevity, and priorities for undertaking research activities that would yield the largest payoff for the most patients. Drs. Griffin Rodgers, Director, NIDDK, and Dr. W. Keith Hoots, Director, Division of Blood Diseases and Resources, NHLBI welcomed the participants and endorsed the need for a global approach to thalassemia clinical research. Information provided at the workshop will help inform NHLBI and NIDDK in the development of future thalassemia research initiatives.
Janet Kwiatkowski, MD, Thalassemia Program, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Ellis Neufeld, M.D., Ph.D., Children's Hospital Boston reviewed the accomplishments and challenges of the Thalassemia Clinical Research Network (TCRN).
The TCRN, funded by the NHLBI (2000-2005 and competitively renewed 2005-2010), consists of six core clinical sites, 26 satellite sites throughout the United States, Canada, and England, and a Data Coordinating Center (New England Research Institute). The TCRN's goal is to accelerate research in the management of thalassemia through multicenter trials.
The TCRN strengths include: the thalassemia experts and statisticians who develop studies and identify important research goals and findings; access to a critical mass of patients for studies; a website that facilitates communication, data analysis and publications; collaborations between core and satellite sites, and with CDC Surveillance Project, the Cooley's Anemia Foundation, other countries, other networks, and pharmaceutical companies; and, support for junior investigators to perform and publish clinical studies.
The TCRN developed a study Registry and the following Registry-based studies:
Five major interventional trials in the TCRN include:
The major challenges for the TCRN include: the slow pace of protocol development, patient enrollment, data analysis and manuscript completion; the need to recruit patients from outside the U.S. because of the small number of thalassemia patients in the U.S.; and, difficulties for launching international sites (translation of numerous trial forms, differences in local regulatory authorities, indemnification and insurance requirements in the European Union).
Francis P. Crawley, MA, FFPM, Good Clinical Practices Alliance Europe reviewed the European Directive as it pertains to conducting clinical trials in the European Union (EU). EudraLex includes the rules governing medical products in the EU, however, clinical investigators also must also adhere to local and national rules. The International Good Clinical Practices (GCP) framework includes: general?International Council on Harmonization Good Clinical Practices and World Health Organization (WHO) Good Clinical Practices; regional/applied?U.S. Code of Federal Regulations and EU GCP; and national/applied?GCP guidelines apply to India, China, Russia, Singapore, Malaysia, Indonesia, South America, South Africa, and Turkey.
The European Directive, implemented in 2001, directs national governments to implement laws on GCP in the conduct of clinical trials for medicinal projects for human use. This applies not only to pharmaceutical companies, but also to investigators conducting clinical trials. It defines the roles of the investigator, sponsor, competent authority (EU GCP inspections), and has a review timeline of 60 days from the date of receipt of a valid application to give its reasoned opinion. The structures and regulations differ in Member States for IRBs and ethics committees. Many of these countries have developed their own regulations for implementing the EU Directive. Differences among member states pose special challenges including:
Regulations governing pediatric clinical trials are similar to U.S. regulations. To undertake pediatric studies in Europe, the European Medicines Agency requires an early plan for review. The EU has regulations for orphan drug development.
Major challenges include the lack of consistency across member states for:
Gina Cioffi, National Cooley's Anemia Foundation, reviewed the Cooley's Anemia Foundation (CAF) perspective of clinical trials and provided recommendations to enhance patient enrollment in studies.
Patient recruitment and enrollment in clinical trials is a major challenge. Among people who suffer from severe chronic illness, only 6 percent participate in clinical trials. Almost 50 percent of trial delays result from patient enrollment problems and 86 percent of all U.S. clinical studies fail to recruit the required number of subjects on time. Industry wide there is a 20-30 percent patient dropout rate in Phase II/III studies.
The CAF informs patients and families about trials to further the conversation between the patient and the clinical investigator and the patient and his/her physician without dispensing medical advice or encouraging consent to take part in a trial. The CAF maintains a balance in presenting studies available without overtly promoting an opportunity through a Thalassemia Action Group newsletter, conferences and an interactive website listing studies and other relevant information.
Consideration of the patient point of view can enhance an investigational concept and lead to more rapid enrollment. Enrollment success depends on a good fit among the protocol design, participant sites, and the target population. The major challenges for patient are:
Patients would like trials designed more to their convenience:
Recommendations for specific areas of study include:
Suthat Fucharoen, MD, Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University provided on overview of thalassemia demographics in Southeast Asia.
There is a high prevalence of thalassemia and abnormal hemoglobin in Southeast Asia with variability of different ethnic-specific mutations in each country: ?-, ?-thalassemia and abnormal hemoglobins (Hb) such as Hb E and Hb Constant Spring are common in Southeast Asia; ?-thalassemia and Hb Constant Spring are scattered throughout the region at 1-8 percent, however, ?-thalassemia and Hb E are focal. In the northeastern part of Southeast Asia, near Laos and north Thailand, ?-thalassemia occurs at frequencies of 30-40 percent. Hb E is common among the Thai-speaking population living at the junction of Cambodia, Laos, and Thailand where the prevalence of Hb E reaches 50-60 percent.
Thalassemia presents an increasingly severe public health burden for many countries in Southeast Asia.
A WHO report adopted by the 57th World Health Assembly in 2004, Genomics and World Health, recommended that local networks should be established to help member countries evolve services. An Asian Network for Thalassemia Control was formed to disseminate good practice in the control and management of thalassemia in Asia and to provide a central forum for interacting with individual governments and international health agencies to provide support for the objectives. The objectives are:
Vip Viprakasit, MD, DPhil, FRCPT, Division of Haematology-Oncology and WHO Collaborating Centre for the Control of Thalassaemia and Haemoglobinopathies, Siriraj Hospital, Mahidol University Bangkok, Thailand reviewed the status of clinical trials of chelation therapy in Thailand.
There are at least 500,000 people with thalassemia in Thailand, with approximately 12,000 new cases annually, and 48,000 at-risk pregnancies. More than 20,000 transfusion-dependent patients require regular transfusion and life-long chelation therapy. An analysis of treatment compliance and related health and social determining factors in Thai thalassemia patients under long-term deferrioxamine (DFO) administration at Faculty of Medicine Siriraj Hospital, Bangkok revealed that 40 percent of 112 pediatric patients with severe thalassemia (49 percent receiving DFO therapy for 2-7 yrs and 51 percent receiving DFO therapy for 7-17 yrs) were reported by their parents as having good compliance with DFO therapy. However, only 14 percent of the cases studied had an average serum ferritin (assayed during the prior year) of less than 2,500 ng/ml (a surrogate marker for adequate chelation therapy with well-controlled iron burden).
Thailand is an ideal location for conducting an iron chelation trial because of its large patient population and its experience with: operating clinical studies under the GCP standard; thalassemia patient care; protecting patient safety; and excellent technical and MRI capabilities. Thailand has four transplant centers and is conducting a multi-center national study on Thai Government-made oral chelator (GPO-L-ONE or deferiprone, DFP) and also international studies on oral chelation therapy on Exjade (deferasirox, DFX).
Recent clinical studies on iron chelation therapy in Thailand include ICL670 (Exjade) trials:
Thailand also has undertaken multi-center national studies for clinical efficacy and adverse effects of GPO-L-ONE (deferiprone). This trial, which takes place at five centers in Bangkok, expects to enrol 150 patients (75 pediatric/75 adult) and to complete enrolment by the end of May 2009.
Susan Perrine, MD, Hemoglobinopathy Thalassemia Unit, Boston University School of Medicine reviewed her clinical trial experience with hemoglobin-switching agents.
The hemoglobin switching field was founded decades ago for the sole purpose of defining the molecular and cellular mechanisms of fetal globin gene reactivation, with the goal of developing therapeutics to reverse the natural silencing of the gene as a natural remedy for the beta globin diseases. Fetal globin gene induction as a therapeutic modality is particularly appealing because:
Although there are challenges to reactivating the endogenous fetal globin genes to therapeutic levels in the diverse thalassemias, the necessary target level has been accurately identified to induce ? globin expression enough for non-? globin chains to balance ? globin chain synthesis by 65-70 percent (thalassemia trait ratios).
The proof of concept in reducing anemia and eliminating long-term transfusion dependency in thalassemia has been established with three classes of therapeutic candidates. These classes of therapeutics have produced significant hematologic responses with rises in total hemoglobin (of 1-5 gms/dl) in the thalassemias:
The agents have corrected the phenotypes from thalassemia major, intermedia, and trait. Synergistic activity has been found when combining two groups of therapeutics: 5 azacytidine (demethylating agent) with butyrate, and butyrate with EPO.
Therapeutic agents are needed that are more feasible for widespread, global application?oral agents that act at lower doses and are patient friendly, ideally have dual actions of improving red blood cell survival, not reducing red blood cell proliferation, and are safe for long term use (not cytotoxic or mutagenic). One agent, HQK -1001, which was developed entirely with NIH funding, has begun clinical testing in Thailand and Lebanon for beta thalassemia and in the U.S. for sickle cell disease, supported by the biotechnology company HemaQuest Pharmaceuticals, Inc.
Factors that influence responses in to Hb F induction and require attention in clinical trial design include: baseline Hb F levels, baseline EPO levels, splenectomy status, and iron supplements. Other factors that affect responses include genetic modifiers and metabolism differences.
CAF |
Cooley's Anemia Foundation |
DFO |
Deferrioxamine |
DFP |
Deferiprone |
DNA |
Deoxynucleic acid |
EPO |
Erythropoietin |
EU |
European Union |
GPO-L-ONE |
Thai government-made oral chelator, deferiprone |
Hb |
Hemoglobin |
HPSC |
Hematopoietic stem cell |
L1 |
Deferiprone, manufactured by Lipomed AG, Switzerland |
mRNA |
Messenger ribonucleic acid |
NHLBI |
National Heart, Lung, and Blood Institute |
NIDDK |
National Institute of Diabetes and Digestive and Kidney Diseases |
NTBI |
Non-transferrin bound plasma iron |
RNA |
Ribonucleic acid |
SNP |
Single nucleotide polymorphism |
T2* |
A magnetic resonance imaging technique used to quantify tissue iron concentration in the heart and liver |
TCRN |
Thalassemia Clinical Research Network |
TLC |
Thalassemia Longitudinal Cohort Study |