Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Grants: Stimulating and Commercializing Tissue Engineering and Regenerative Medicine in Musculoskeletal and Skin Diseases and Disorders

March 1, 2008 and April 24, 2008 (historical)

INTRODUCTION

Back pain, osteoarthritis, fractures, chronic wounds, and sports and combined (musculoskeletal and skin) traumatic injuries to the musculoskeletal system contribute significantly to health care costs, as well as compromise the quality of life in a large number of affected individuals. Functional restoration and regeneration of these tissues using natural, developmentally-driven processes has the potential to reduce major sources of disability in society and substantially reduce health care costs. Tissue engineering and regenerative medicine (TE/RM) involves the engineering of functional tissues and organs in vitro for implantation in vivo, and the remodeling and regeneration of tissue in vivo for the purpose of repairing, replacing, maintaining, or enhancing tissue and organ function. It requires a complex approach combining living and biologically-derived components such as cells and proteins with synthetic components such as organic polymers and inorganic materials.

In 2008, the National Institute of Arthritis and Musculoskeletal Diseases (NIAMS) hosted two meetings to get input from the small business and scientific communities involved in the TE/RM research area. One meeting was held on March 1, 2008, in conjunction with the 54th Annual Orthopaedic Research Society Meeting in San Francisco, California, and another on April 24, 2008, with the Symposium on Advanced Wound Care and Wound Healing Society Meeting, San Diego, California. NIAMS scientific program staff met with investigators with a broad range of expertise including business representatives, clinicians, engineers, biomedical researchers, and National Institutes of Health (NIH) scientific review officers of small business applications. Both meetings were focused on how to better utilize the NIAMS small business investment in order to facilitate the translation of TE/RM research and, ultimately, the development of commercial products.

DISCUSSION SUMMARY

The meetings opened with a brief historical perspective of the NIH/NIAMS SBIR/STTR grants program. The meeting participants generally agreed that the small business programs are excellent mechanisms for translational work and often represent the best pathway for advancing basic science to commercial application. These programs fill critical needs in the area of product development and allow for the early stage efforts that are vital to attracting large investments from venture capitalists and others. When developing a clinically useful and commercially viable product, companies should:

  • Develop practical protocols for production, clinical testing and use of the product;
  • Keep product design as simple as possible to streamline the approval process by the US Food and Drug Administration (FDA, http://www.fda.gov/);
  • Engage the end-users (physician and patient); and
  • Consider the interests of third-party payers.

Traditionally, the NIAMS has used investigator-initiated grant mechanisms in SBIR/STTR to fund TE/RM translational research. The participants discussed the usefulness of solicited SBIR/STTR research through either Requests for Applications (RFAs) or Requests for Proposals (RFPs); contract mechanisms could also be a viable alternative to achieve product development. The US Department of Defense (DoD, http://www.defenselink.mil/) endpoint-driven application model for SBIR/STTR was mentioned as a potential approach for projects with clear endpoints. A contract mechanism with strong milestones and focusing on final products in defined areas may be a good approach. The communities felt that the first proof-of-principle clinical trials for specific classes of therapies need to be funded by the Government to stimulate investments from private sectors by reducing risk of failure.

Involving Clinicians in SBIR/STTR Applications

Physicians see unmet clinical needs every day. However, few clinically relevant ideas are pursued by the business community and become new treatment options. Communication gaps between health care providers and business entities are large and may seem insurmountable to busy clinicians. Physical and mental barriers between clinicians, engineers, entrepreneurs, and scientists must be overcome, either through meetings or other methods, to bring clinicians' practical needs into reality. Some suggested getting these communities together to:

  • Define unmet clinical needs
  • Evaluate the feasibility and cost of a therapy in clinical settings
  • Develop a list of TE/RM products that are important for progress

Developing Standardized Pre-clinical Animal Models for TE/RM

Validated animal models hold the key to successful TE/RM product development. Testing in rodents, while useful, does not always predict outcomes in humans. SBIR/STTR mechanisms can be used to develop and validate animal models for TE/RM studies. Standardized animal models could aid the developmental work required prior to commercialization. Buy-in from the FDA for any pre-clinical models may be necessary. The American Society for Testing and Materials International (ASTM) has developed standards in the area of tissue engineered medical products. Collaborations with the ASTM or similar organizations could assist in the development of standardized animal models for TE/RM.

Navigating Regulatory and Reimbursement Issues

Getting through the regulatory pathways (FDA) and reimbursement issues (CMS - Centers for Medicare and Medicaid Services http://www.cms.hhs.gov/) was very much on all of the participants' minds. The regulatory process for products that combine cells, biomaterials, and/or biologics are not well known and have few precedents at the FDA. In particular, it is difficult to get approval for therapies involving cell implantation; early communication with the FDA is essential. In the near-term, TE/RM products developed using biomaterials and biomolecules in the absence of cells may present an easier regulatory pathway. A proactive approach is to engage the FDA and/or CMS early in product development. FDA or CMS datasets can be mined for outcome measures when designing products. Information on product labeling is also critical, as the product efficacy will ultimately have to reach a clinical endpoint to support a claim worthy of FDA approval and third-party reimbursement. Therefore, clinical outcome measures should be encouraged to define a product's superiority over existing treatments.

Achieving Successes in the Near-Term

Getting FDA approval for cell-based therapies can be a long regulatory process. Cell-free, scaffold-based regenerative technologies are likely to be brought into the clinical arena in the short-term. Class I medical devices (http://www.fda.gov/CDRH/devadvice/3132.html#class_1) may have the best chance for commercialization within 5 years. Furthermore, repair may be easier to achieve than regeneration as demonstrated in the TE/RM efforts to date, and therefore is more likely to become standard of care in the near-term.

Developing Enabling Technologies for TE/RM

While it is important to continue finding the best cell sources, developing novel scaffolds and studying stem cell interaction with scaffolds, there are tremendous needs and opportunities in enabling technologies for TE/RM product development which are relevant to the missions of multiple NIH Institutes and Centers. These enabling technologies include:

  • Acellular strategies to avoid lengthy regulatory and process issues. BMP-2 is an excellent example of successful acellular approaches for tissue repair.
  • Novel biomaterials that do not cause problematic inflammation. Host response to biomaterials is often the critical determinant of success. Testing for host response should include evaluation of the effects of degradation or leachable by-products on the innate and adaptive immune response.
  • Scaffolds to induce site-specific differentiation.
  • Large animal models in which new biomaterials can be tested.
  • Site-specific gene transfer and/or endogenous gene activation methods to mediate biointegration of tissue engineered constructs or pseudoblastema formation.
  • Improved vectors for in vivo gene transfer to facilitate connective tissue regeneration.
  • Minimally invasive methods and devices to deliver scaffolds in situ (e.g., the "cartilage patch" for joints or the spinal column that is delivered with the ease of inserting a stent).
  • Non-invasive imaging tools to monitor functions of tissue engineered constructs and scaffolds.
  • Universal culture systems with broad applications for manufacturing different types of TE/RM constructs, scaffolds, or implants.
  • Sterilization methods for natural materials and artificial scaffolds.
  • Cryopreservation or similar methods to distribute or deliver TE/RM products.
  • Technologies for scaling-up, GMP (Good Manufacturing Practice) facilities, and guidelines/outcome measures for safety and toxicity.
  • Artificial, in vitro systems to test toxicity before in vivo studies begin.
  • Predictive surrogate markers to analyze effectiveness or failure of a TE construct.
  • Safe and effective allogeneic cell sources, or tools to isolate autologous cells for "intra-operative" (in the same operating room and during the same procedure) cell therapy.
  • Standardized, in vitro human cell testing systems for safety and toxicology studies.

NIAMS Role in SBIR:

The meeting participants suggested that the NIH/NIAMS consider the following modifications to its SBIR program:

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  • Increase SBIR Phase I budget cap
  • Support long-term in vivo preclinical studies and Phase I clinical trials because Phase I clinical data reduce risks for investors and directly helps product development.
  • Fund Phase III grants to get clinical data for regulatory approval since toxicity studies and clinical trials are very costly.
  • Consider program project style awards with several small companies to create combination therapies with multiple drugs and/or devices.
  • Facilitate partnerships among foundations, large industry, universities, small business, and clinicians.
  • Encourage analysis of failed devices/reconstructions because much can be learned from them. Such "retrieval analyses" or "failure analyses" should be incorporated into the developmental cycle and will require support from funding agencies.

NIH SBIR/STTR Application Process

The lengthy time to funding for an NIH SBIR/STTR grant is viewed as a disadvantage and often results in significant delays in the development of a new, fast-moving technology in TE/RM. Many up-and-coming technologies are paced to move faster than the standard NIH timeline for research grants. Small companies also have a high risk of losing their employees due to a hiatus of funding that can be caused by the significant lag between grant submission and funding. Therefore, there is an urgent need to have faster review and feedback for SBIR/STTR applications, especially for Phase I submissions. The current NIH review process for SBIR/STTR applications correctly emphasizes good science. However, there is a perceived over-emphasis on 'exciting science' and reviewers could instead place emphasis on market potential and important clinical impact as well as new, high-risk approaches.


NIAMS Small Business Program Meeting
March 1, 2008 - Participants

Held in conjunction with the 54th Annual Orthopaedic Research Society (ORS) Meeting
San Francisco, California

Barbara D. Boyan, Ph.D.
Professor, Price Gilbert, Jr. Chair in Tissue Engineering
Wallace H. Coulter Dept. of Biomedical Engineering
Georgia Institute of Technology
Atlanta, GA 30332-0363
(404) 385-4108
barbara.boyan@bme.gatech.edu

Faye H. Chen, Ph.D.
Cartilage Biology and Orthopaedics Branch
Intramural Research Program
NIAMS, NIH, DHHS
Bethesda, MD 20892
(301) 451-1206
chenf1@mail.nih.gov

Luke Evnin, Ph.D.
Managing Member, MPM Capital, LLC
San Francisco, CA
levnin@mpmcapital.com

Farshid Guilak, Ph.D. (co-chair)
Laszlo Ormandy Professor
Depts. of Surgery-Orthopaedic Surgery, Biomedical Engineering, and Engineering and Materials Science
Duke University Medical Center
Durham, NC 27710
(919) 684-2521
guilak@duke.edu

Warren O. Haggard, Ph.D.
Professor, Herff Chair of Excellence in Biomedical Engineering
Department of Biomedical Engineering
The University of Memphis
Memphis, TN 38152
(901) 678-5243
jbmgrdnr@memphis.edu

John Holden, Ph.D.
Scientific Review Officer, Musculoskeletal, Oral and Skin Sciences (MOSS) Integrated Review Group
MOSS Orthopaedic Small Business Special Emphasis Panel
Division of Physiology and Pathology
Center for Scientific Review, NIH, DHHS
Bethesda, MD 20892
(301) 496-8551
holdenjo@csr.nih.gov

Joshua J. Jacobs, M.D. - mail participant
Crown Family Professor and Chairman
Department of Orthopaedic Surgery
Rush University Medical Center
1725 West Harrison Street, Suite 1063
Chicago, IL 60612
(312) 243-4244
Joshua.jacobs@rushortho.com

Martha Murray, M.D.
Assistant Professor in Orthopaedic Surgery
Harvard Medical School
Orthopaedic Surgeon, Children's Hospital Boston
Boston, MA 02115
(617) 355-7132
martha.murray@childrens.harvard.edu

Gabriele G. Niederauer, Ph.D.
Vice President, R&D
ENTrigue Surgical Inc.
San Antonio, Texas 78249
(210) 298-6398
gabi.niederauer@entriguesurgical.com

Glenn D. Prestwich, Ph.D.
Presidential Professor of Medicinal Chemistry and Research Professor of Biochemistry
University of Utah Health Sciences Center
Salt Lake City, UT 84108-1257
(801) 585-9051
gprestwich@pharm.utah.edu

Anthony Ratcliffe, Ph.D.
President and CEO
Synthasome, Inc
San Diego, CA 92109
(858) 490-9401
anthonyratcliffe@synthasome.com

Paul Robbins, Ph.D. - mail participant
Professor, Microbiology and Molecular Genetics and Biochemistry
University of Pittsburgh
Pittsburgh, PA 15621
(412) 648-9268
probb@pitt.edu

Edward M. Schwarz, Ph.D. - mail participant
Professor of Orthopaedics and of Microbiology and Immunology
University of Rochester
School of Medicine and Dentistry
Rochester, New York 14642
(585) 275-3063
Edward_Schwarz@urmc.rochester.edu

Rocky Tuan, Ph.D.
Chief, Cartilage Biology and Orthopaedics Branch
Intramural Research Program
NIAMS, NIH, DHHS
Bethesda, MD 20892
(301) 451-6854
tuanr@mail.nih.gov

NIAMS Extramural Program Staff

Joan McGowan, Ph.D.
Director, Division of Musculoskeletal Diseases
NIAMS, NIH, DHHS
Bethesda, MD 20892
(301) 594-5055
mcgowanj@mail.nih.gov

Fei Wang, Ph.D. (co-chair)
Program Director, Musculoskeletal Development, Tissue Engineering and Regenerative Medicine
Division of Musculoskeletal Diseases
NIAMS, NIH, DHHS
Bethesda, MD 20892
(301) 594-5055
wangf@mail.nih.gov

Elijah Weisberg, M.S.E.
Research Program Analyst
Division of Musculoskeletal Diseases
NIAMS, NIH, DHHS
Bethesda, MD 20892
(301) 594-5055
weisberge@mail.nih.gov


NIAMS Small Business Program Meeting
April 24, 2008 - Participants

Held in conjunction with the Symposium on Advanced Wound Care (SAWC) and
Wound Healing Society Meeting (WHS)
San Diego, California

B. Lynn Allen-Hoffmann, Ph.D. (co-chair)
Professor, Department of Pathology
University of Wisconsin
Madison, WI 53706
(608) 262-2884
blallenh@wisc.edu

Michel Alvarez, MBA
Chief Operating Officer
Healionics, Inc
Redmond, WA 98052
(425) 818-1987 x306
michel@healionics.com

Damien Bates, M.D., Ph.D. FRACS (Plast.)
Vice President of Medical Affairs
Organogenesis, Inc.
Canton, MA 02021
(781) 615-1832
DBates@Organo.com

Sufan Chien, M.D.
Noveria, LLC
Louisville, KY 40202
(502) 852-4418
s0chie01@louisville.edu

Sandra Dethlefsen, Ph.D.
Genzyme Corporation
Cambridge, MA 02139
(617) 252-7837
sandra.dethlefsen@genzyme.com

Gautam Ghatnekar, D.V.M, Ph.D.
Adjunct Assistant Professor - MUSC
President, COO
FirstString Research, Inc.
Research Triangle Park, NC 27709
(866) 986-7227
ghatnek@musc.edu

Peter C. Honebein, Ph.D.
Research Scientist
The Academic Edge, Inc.
Reno, NV
(775) 849-0371
peter@academicedge.com

Shuan Huang, Ph.D.
Research Director
Auxagen, Inc.
St. Louis, MO 63132
(314) 993-2508
shuanh@gmail.com

Jonathan Mansbridge, Ph.D.
Distinguished Research Fellow
Tecellact LLC
Smith and Nephew Wound Management
La Jolla, CA 92037
(858) 552-8585 x3246
Verajonath@aol.com

Andrew Marshall, Ph.D.
Principal Scientist
Healionics, Inc
Redmond, WA 98052
(425) 818-1987
andrewm@healionics.com

Grove Matsuoka, MBA
Vice President - Commercialization
CoDa Therapeutics, Inc
San Diego, CA 92121
(858) 677-0474
grove@codatherapeutics.com

Anthony Ratcliffe, Ph.D.
President and CEO
Synthasome, Inc
San Diego, CA 92109
(858) 490-9401
anthonyratcliffe@synthasome.com

Bill Tawil, Ph.D., MBA
Director - Global Strategy, Scientific Initiatives
Global Marketing, Orthobiologics
Biotherapeutics & Regenerative Medicine
Westlake Village, CA 91362
(805) 372-3588 x 870
btawil@baxter.com

NIAMS Extramural Program Staff

Cheryl Lapham, Ph.D. Program Director, Skin Immunobiology and Immune Diseases Program
Division of Skin and Rheumatic Diseases
NIAMS, NIH, DHHS
Bethesda, MD 20892
(301) 594-5032
clapham@mail.nih.gov

Carl Baker, M.D., Ph.D. (co-chair)
Program Director, Keratinocyte Biology and Diseases Program
Division of Skin and Rheumatic Diseases
NIAMS, NIH, DHHS
Bethesda, MD 20892
(301) 594-5017
bakerc@mail.nih.gov


APPENDIX: Currently Active NIAMS SBIR Funding Opportunities*

6/2/2009 RFA-OD-09-009, Recovery Act Limited Competition: Small Business Catalyst Awards for Accelerating Innovative Research (R43/R44)

4/24/2009 RFA-AR-10-004, Translation and/or Commercialization of Musculoskeletal and Skin Tissue Engineering and Regenerative Medicine Research - SBIR (R43/R44)

4/6/2009 PA-09-127, Multiplex Assay Development for Arthritis and Musculoskeletal and Skin Diseases (R43/R44)

2/26/2009 PA-09-113, Manufacturing Processes of Medical, Dental, and Biological Technologies (R43/R44)

1/22/2009 PA-09-080, PHS 2009-02 Omnibus Solicitation of the NIH, CDC, FDA and ACF for Small Business Innovation Research Grant Applications (R43/R44)

10/7/2008 PA-09-006, Innovative Toxicity Assays of Pollutants, Therapeutics, and Drugs (R43/R44)

4/9/2008 PA-08-114, Lab to Marketplace: Tools for Biomedical and Behavioral Research (R43/R44)

12/12/2006 PAR-07-160, Innovations in Biomedical Computational Science and Technology Initiative (R43/R44)

*June 2009 Data from the NIAMS Funding Opportunities List website: http://www.niams.nih.gov/Funding/Funding_Opportunities/filter.asp.