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Enhancing Translational Research and Early Phase Trials for Cellular Therapy

Executive Summary


The Division of Blood Diseases and Resources of the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of scientific and clinical investigators on September 22-23, 2008 in Bethesda , Maryland , to discuss translational research for evaluating cellular therapies for blood diseases. In alignment with the Institute's Strategic Plan Goals 1, 2 and 3 (NHLBI Strategic Plan), the group focused on identifying the efforts needed in translational research to move basic discoveries from the laboratory into early-phase clinical trials and beyond.

The overarching objectives of the working group were to:

  • Identify the challenges presented by translational research and early-phase clinical trials for evaluating cellular therapies
  • Formulate potential solutions and recommendations for NHLBI to enhance translational research and early-phase clinical trials for evaluating cellular therapies


Over the past decade, cellular therapy has emerged as a promising means of promoting tissue regeneration and suggests new methods for treating hematological diseases including malignancies. Despite this tremendous potential, few innovative findings have been translated from the concept or discovery phase into proof-of-concept clinical trials. Research opportunities that are being translated may require 7 to 10 years from the initial preclinical discovery before advancing to a human trial. These earliest trials are designed to test safety while subsequent trials test efficacy.

Progress in the application of cellular therapy to specific disease indications has been delayed along the entire spectrum of activities from discovery to preclinical studies and animal models, validation of cell manufacturing, and finally to implementation of the early-phase clinical trials. Potential challenges include, but are not limited to, selecting among the diversity of the cells under consideration for clinical use, the time needed to obtain the appropriate data necessary to obtain an Investigation New Drug (IND) application utilizing a specific cellular therapy, the breadth of disease indications for which this therapy may hold promise, as well as resource limitations. A working group was convened to recommend ways to address these challenges so NHLBI can accelerate the translation of new cell therapies.

The meeting of the working group began with NHLBI staff and the Working Group Chair providing background information and a framework for the discussions. NHLBI staff reviewed current grant mechanisms and Institute-initiated programs and resources for basic and clinical research for cellular therapy indicating the limitations and challenges of each. The Working Group Chair presented an overview of the field of cellular therapy, an international perspective on this topic, and reiterated the charge to the working group. Thematic presentations followed where two scientists provided an overview and their perspectives on the following six topics:

  • Preclinical Research & Identifying Clinical Potential: Aspects of Preclinical Research Necessary to Obtain an IND
  • Cell Therapy for Disease Indications (Sickle Cell & Lung Diseases): State of the Science & Challenges for Moving the Fields Forward
  • Manufacturing Cells for Clinical Studies: Challenges Related to Single Institution and Multi-Site Trials & IND Applications
  • Early Phase Clinical Trials: Initiation & Conduct of Trials
  • Early Phase Clinical Trials using Cell Therapies: Considerations for Statistical Design, Coordination and Monitoring, & Patient Accrual
  • Biotech Experience & Perspectives on Private-Public Partnerships

Challenges and Recommendations

During the discussions that followed, the Working Group members identified key challenges and developed recommendations as to how NHLBI might best facilitate the field.

Challenge #1. Preclinical cellular therapy research funding: Current grant mechanisms and existing standing study sections are not well-suited to evaluate grant applications containing applied, preclinical studies. Of course, these studies are necessary for IND applications utilizing cellular therapies.


  • Support preclinical studies, including scale-up and validation of cellular products for the clinical trial, via grant mechanisms that utilize review criteria that do not require hypothesis-driven research.
  • Implement a separate preclinical mechanism, perhaps a planning grant application leading to a subsequent clinical trial (R34).

Challenge #2. Clinical cellular therapy research funding: Current grant mechanisms do not fit early-phase cellular therapy trials and existing study sections lack the expertise necessary to evaluate these applications.


  • Support clinical studies by constituting a specialized review panel with expertise necessary to evaluate early-phase trial studies. Membership should include regulatory, statistical, cell-manufacturing, and clinical expertise.
  • Introduce a funding mechanism similar to the National Cancer Institute’s “Quick Trial” to reduce the time from submission and review of a grant application to funding.
  • Permit multiple funding sources for the same trial by facilitating both private-public partnerships with Foundations and public-public partnerships with either State or other Federal funding agencies.

Challenge #3. Timelines: Timelines for funding are too long. The review and approval process for clinical trial protocols is cumbersome and often duplicative. For example, protocols are sequentially reviewed by an NHLBI-appointed Protocol Review Committee (PRC) and a Data and Safety Monitoring Board (DSMB). In addition, protocols also undergo several, additional reviews, such as Institutional scientific reviews, NIH’s Recombinant DNA Advisory Committee (RAC) for trials including gene therapy, the FDA, and an Institutional Review Board.


  • Eliminate the sequential reviews by the NHLBI-appointed PRC and DSMB by having ad-hoc content-specific experts provide their scientific review to the DSMB when the protocol is reviewed by the DSMB. Combining the PRC review with the DSMB review would shorten the review process by eliminating the requirement for a separate PRC meeting.

Challenge #4. Investigator recognition: Key cellular therapy team contributors are excluded from recognition as needed for promotion. This includes cell processing scientists and mid-level clinical investigators.


  • Establish a new “R” award for clinical investigators that provides protected-time and recognition of their contribution.
  • Publicize the importance of “Team Science” contributions to facilitate a change in academic promotions policies.

Challenge #5. Contract delays: Contract preparation and execution is frequently the rate-limiting step for the formation of academic-industry partnerships necessary for clinical trial initiation.


  • Encourage leaders from academia and industry to develop and utilize contract templates for academic-industry partnerships.
  • Foster academic-industry partnerships.

Challenge #6. Best models and assays: The most suitable animal models are uncertain and diverse assays are used to provide data for IND applications evaluating cellular therapies.


  • Co-sponsor consensus conferences with industry partners to define the most appropriate in vitro assays and suitable animal models for evaluating cellular therapies. Companies may welcome this opportunity to standardize methods. IND applications using agreed-upon standards would expedite FDA review and approval.

Challenge #7. Clinical trial experience: Many investigators with excellent new therapy ideas are unable to implement and conduct early-phase clinical trials. They may lack clinical trial experience and may not understand the process leading to a successful IND application.


  • Leverage existing NIH resources, such as the Clinical and Translational Science Awards (CTSA), to provide training in clinical trials methodology, GMP compliance, and other regulatory issues.
  • Establish a regular training course on IND preparation that is widely available. Encourage investigators to communicate with the FDA as early as possible during the discovery/pre-clinical phase.
  • Sponsor a consensus conference to define the most appropriate study designs for proof-of-concept and early-phase studies evaluating cellular therapies. Many protocols have been based on cancer drug study models that may not be appropriate for evaluating cellular therapies,
  • Foster novel early-phase trials using an existing clinical trials network infrastructure, preferably the Blood and Marrow Transplant Clinical Trials Network (BMT CTN).

Challenge #8. Patient accrual: Multiple factors including inadequate funding or infrastructure, and the paucity of eligible patients at clinical sites lead to slow accrual to early-phase clinical trials evaluating cellular therapies.


  • Leverage existing resources by allowing investigators with innovative concepts to conduct early-phase studies evaluating novel cell therapies under the umbrella of existing relevant NHLBI-supported programs, such as the BMT CTN. In addition to facilitating accrual, the Network’s expertise and infrastructure will assist protocol development and early-phase trial execution hastening the transition into future definitive trials of promising cellular therapies.
  • Continue support for NHLBI’s hematopoietic stem cell therapy programs, such as the BMT CTN, as this provides the potential to fast-track promising cell based therapies into large multisite trials using an existing infrastructure experienced with large multi-site trials and cell therapy.

Challenge #9. Capturing trial outcomes: Outcomes, in particular long-term outcomes from early phase cellular therapy trials, are not easily captured in data registries; rare, long-term effects may not be systematically captured.


  • Encourage existing organizations, e.g., Center for International Blood and Marrow Transplant Research and American College of Cardiology, to collaborate and to encourage investigators to collect and compile outcome information critical to understanding the long-term safety of cellular therapy for new indications, such as heart disease.

Challenge #10. Infrastructure: Infrastructure and support for gene and cell therapy is incomplete. Specialized Centers can provide a wide array of preclinical and clinical resources and support to program investigators. However, the Institute’s Gene Therapy Resources Program (GTRP) supports only lentiviral and AAV vectors, but not other vectors are being developed for clinical application.


  • Continue the Institute’s collaborative cellular therapy programs that focus on translation and early phase trials, such as the Specialized Centers for Cellular Therapy (SCCT).
  • Enhance the available resources for cell and gene therapy, such as resources available through the Institute’s Production Assistance for Cellular Therapies (PACT) and GTRP resource programs.

Challenge #11. New indications for cell therapies: Studies for cellular therapy for lung diseases lag behind other clinical areas despite the urgent need to manage pulmonary conditions and the availability of supporting preclinical findings.


  • This affords a unique opportunity to implement the strategies outlined in this proposal prospectively and to fast-track clinical research in this important area

Publication Plans

NHLBI website; publication in a scientific journal.

Working Group Members:

  • Armand Keating, MD. Princess Margaret Hospital, Toronto, ON (Working Group Chair)
  • Shelly Carter, ScD. The EMMES Corporation, Rockville MD
  • Robert J. Deans, PhD. Athersys Inc, Cleveland OH
  • Adrian Gee, PhD. Baylor College of Medicine, Houston TX
  • Helen Heslop, MD. Baylor College of Medicine, Houston TX
  • Mary M. Horowitz, MD, MS. Medical College of Wisconsin and Center of International Blood & Marrow Transplant Research, Milwaukee Wl
  • Edwin M. Horwitz, MD, PhD. The Children’s Hospital of Philadelphia, Philadelphia PA
  • Sally Hunsberger, PhD. Biometrics Research Branch, NCI, Bethesda MD
  • Yoken Saunthararajah, MD. Cleveland Clinic/University of Illinois at Chicago Taussig Cancer Institute, Cleveland OH
  • David Scadden, MD. Harvard Stem Cell Institute, Boston MA
  • Judith A. Shizuru, MD, PhD. Stanford University Medical Center, Stanford CA
  • Daniel Weiss, MD, PhD. University of Vermont, Burlington VT
  • Keith Wonnacott, PhD. Cellular Therapies Branch, FDA, Rockville MD

NHLBI Staff:

  • Nancy L. DiFronzo, PhD. Division of Blood Diseases and Resources (DBDR)
  • Simone Glynn, MD, MPH. DBDR
  • Susan B. Shurin, MD. DBDR
  • John W. Thomas, PhD. DBDR
  • Elizabeth Wagner, MPH. DBDR

Consulting Advisors:

  • Bruce Blazer, MD. University of Minnesota, Minneapolis

NHLBI Contacts:

Nancy DiFronzo, PhD. NHLBI, NIH
Telephone: 301-435-0065

John Thomas, PhD. NHLBI, NIH
Telephone: 301-345-0065

March 2009

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