Summary and Recommendations
On September 14 ? 15, 2009, the National Heart, Lung and Blood Institute convened a State of Science Symposium in Transfusion Medicine and Hemostasis/Thrombosis. The aims of this symposium were to identify Phase II and III clinical trials that could have significant impact in advancing transfusion therapies or treatment for hemostatic or thrombotic disorders and to provide a forum for investigators to discuss clinical research needs. Oversight committees were established for both the transfusion medicine and hemostasis/thrombosis. The transfusion medicine group identified seven clinical research areas and the hemostasis/thrombosis group identified six clinical research areas. Subcommittees were formed to explore the clinical research needs and develop clinical trial concepts for each identified area. In addition, two External Panels, one for transfusion medicine and one for hemostasis/thrombosis, were established to evaluate the proposed clinical trial concepts and provide NHLBI with recommendations to develop future clinical research programs. During the first one and a half day open session of the symposium thirty clinical trial concepts were presented by the thirteen subcommittees. After the open session the two External Panels met separately and each provided recommendations to NHLBI.
(The summary and recommendations from the External Panel for transfusion medicine is at: Part II )
The six Hemostasis and Thrombosis subcommittees (Platelet Disorders: Bleeding; Platelet Disorders: Thrombosis; Thrombosis: Prevention; Thrombosis: Therapy; Hemophilia & von Willebrand Disease; and Pediatric and Neonatal) prepared 19 clinical trial concepts. The External Panel met, after the presentations, to review the clinical trial concepts and provide recommendations regarding the potential impact of the clinical trials and infrastructure needed to facilitate successful completion of trials. The clinical trial concepts were evaluated in regard to clinical importance, feasibility, clinical trial design, scientific merit, and personnel and infrastructure. Several of the concepts were considered exceptionally strong in all or most of these categories. This included trials in treatment of DVT in children, prophylaxis for adults with severe hemophilia, treatment of ITP, and prevention or therapy for venous thromboembolism in specific patient populations. The Expert Panel felt that it was clear that there is no shortage of investigators with an excellent grasp of next problems to be solved. The subcommittees demonstrated that there are numerous phase II-III clinical trials in hemostasis and thrombosis area that if conducted successfully could have impact on the standard of healthcare.
- Increase number of well designed phase II and III clinical trials that could lead to improved clinical care for hemostatic and thrombotic disorders
- Establish processes to assist planning, timely initiation and successful completion of investigator initiated clinical trials
- Develop programs to encourage clinical trials for rare bleeding and clotting diseases and for studies in pediatric populations, include processes for planning, initiation and successful completion of trials that meet the special needs of the selected population
- Identify new pathways to stimulate the development and conduct of clinical trials with the emphasis on personalized medicine and comparative effectiveness research that would not be supported by industry
- The perception of the panel is that there needs to be a mechanism for pairing investigators with a clinical trials core organization that can support the investigators for functions typically carried out by a contract research organization.
One model for clinical trial support discussed by the panel was the following:
NHLBI should establish clinical trials core organizations. These organizations need to be staffed by individuals with clinical trials experience in the area of thrombosis and hemostasis, and, for trials approved by NHLBI, would carry out functions such as development of consent forms, development of case report forms, execution of clinical trials agreements (contracts), and other sponsor functions as outlined in the Code of Federal Regulations. These cores should also have expertise in biostatistics and in trial design, and investigators should be encouraged to work with them at early stages to develop the best trial possible. Two such facilities at academic centers, one at McMaster and another at Duke University, readily come to mind, but other institutions would be able to provide the required services. The External Panel felt that the best course would be to have more than one of these centers. Their funding, as for the clinical trial itself, should be based on milestones and output rather than a baseline budget.
These cores would offer the opportunity to address some of the ongoing difficulties in multicenter trials. These include slowing of timelines due to what are usually minor changes to the consent form mandated by IRBs at different institutions, minor changes in clinical trials agreements mandated by various hospital legal departments, etc. The panel?s assessment is that standardizing the language in the consent forms and the clinical trials agreements would go far toward speeding implementation of NIH-funded clinical trials, and that the NIH is one of the few entities with the stature, leverage, and influence to propose universally accepted language.
- The panel recommends a 2-stage process for investigator initiated clinical trials.
The first stage for the investigator is to obtain a planning grant. This could be done by the R34 mechanism, which provides up to $450,000 over up to 3 years for the planning stage. This would provide opportunity for early interaction with the clinical trials core and support for finalizing the protocol, identification of participating centers, approval of the clinical trial by hospital IRBs, execution of clinical trials agreements, submission of an IND/IDE to Food and Drug Administration if required, refining recruitment strategies etc. During the planning grant stage, preparation and submission of an application to support the clinical trial should be encouraged. It is worthwhile to have expectations about how long it would take to go from concept to accruing subjects into the clinical trial. It may be appropriate for investigators to provide a timeline for the planning grant phase that goes from concept development to subject accrual.
The second stage would be full-scale implementation. Funding for this should be milestone-driven, i.e. funds should be tied to numbers of subjects enrolled. Again, there may be an opportunity here for NHLBI to improve the environment for clinical trials nationwide, for example by setting expectations for timelines for IRB review. Many protocols after a first review require only minor changes. Some IRBs have processes in place for expedited review of minor changes; this can save considerable amounts of time compared to a requirement to send the protocol back for full board review, which may not be necessary. NIH staff also pointed out processes for dropping investigators and sites that fail to enroll or that fail to obtain protocol approval in a timely manner. The processes include sequential warnings to lagging investigators, and identification of reserve sites that can be brought in to replace non-performing sites. These seem effective and should be adopted.
- To ensure that the clinical sites actively participate in the study and that subject recruitment is timely, the true costs should be covered so the site will be able to cover their costs on government-sponsored trials. This will be especially true for studies of rare patient populations where per-patient reimbursements currently rarely cover the costs of a site.
- The coordinating center needs to be vested in the studies. They need an incentive to make the trials go swiftly in the same way that a for-profit company has a vested interest in getting trials set up and done efficiently.
- The External Panel felt that greater use should be made of the ancillary study mechanism, so that protocols can be kept as simple as possible, but other hypotheses can be explored in the ancillary studies.
- The External Panel also recognizes that milestone-driven payments for NIH-funded studies do not match those of industry. This is a potential impediment to subject accrual. NIH funding brings other advantages, such as the ability for the investigator to design the trial himself/herself, rather than simply participate in an industry-designed study, but careful thought should be given to whether there are other maneuvers that may improve the competitive position for NIH-funded studies.
External Panel Members:
- Katherine High, M.D., Chair, Children?s Hospital of Philadelphia
- Sandy Shattil, M.D., University of California San Diego
- J. Evan Sadler, M.D., Ph.D., Washington University
- Gary Raskob, Ph.D., University of Oklahoma Health Sciences Center
- David Kuter, M.D., Massachusetts Hospital
Hemostasis/Thrombosis Oversight Committee:
- Morris Blajchman, M.D., Chair, McMaster University
- James Bussel, M.D., Weill Medical College of Cornell University
- Douglas Cines, M.D., University of Pennsylvania
- Andrei Kindzelski, M.D., Ph.D., NHLBI
- Rebecca Link, Ph.D., NHLBI
Last updated: May 4, 2010