Briefing Document.docx

1、Briefing DocumentBriefing DocumentBiological Response Modifiers Committee Meeting # 37Cellular Products for the Treatment of Cardiac DiseaseMarch 18-19, 2004INTRODUCTION 1MEETING GOALS 1BACKGROUND 2General: 2Regulatory: 3MANUFACTURING INFORMATION 4Cellular Products Manufactured Without in vitro Cult

2、ure Methodology 4Cell Collection 5BMSC & PBSC Processing 5Cellular Products Manufactured With in vitro Culture Methodology 5Myoblast Collection and Processing 6Mesenchymal Stem Cell (MSC) Collection and Processing 6Unique Issues with Cellular Products 6Microbiological Safety 6Product Formulation 7Pr

3、oduct Characterization 7Manufacturing Questions 7PRECLINICAL STUDIES 8Cellular Products Manufactured Without in vitro Culture Methodology 9Cellular Products Manufactured With in vitro Culture Methodology 9Preclinical Summary 11Preclinical Questions: 11INVESTIGATIONAL CATHETERS FOR DELIVERY OF CELLUL

4、AR PRODUCTS TO THE HEART 12Infusion of Cellular Products into Coronary Arteries: 12Intramyocardial Injection of Cell Suspensions through Cardiac Catheters: 15Device Question: 18CLINICAL STUDIES 18Cellular Products Derived from Bone Marrow: 18Overview: 18Delivery Methods: 19Outcomes: 19Cells Derived

5、from Skeletal Muscle: 20Overview: 20Administration: 21Outcomes: 21Clinical Questions: 22List of Questions: 24Manufacturing: 24Preclinical: 24Device: 25Clinical: 26Attachments: 27Cited References 28INTRODUCTIONThis Biological Response Modifiers Advisory Committee (BRMAC) is convened to provide the FD

6、A with insight and perspectives regarding the major issues confronting the development of cellular products for the treatment of cardiac diseases. These issues include manufacturing, catheter-product interactions, the nature and quantity of preclinical data and concerns related to early phase clinic

7、al studies. Controversy surrounds the extent and nature of manufacturing information and preclinical data necessary to support the introduction of these cellular products into clinical studies. Because the majority of these cellular products are autologous, some investigators have cited them as inhe

8、rently safe and have suggested that preclinical studies may be unnecessary. Some investigators have proposed initiation of phase 2 clinical studies without exploration of safety in phase 1 studies. Others have suggested that without a detailed understanding of the cellular products characteristics a

9、nd exploration of safety and mechanisms of action in preclinical studies, it is impossible to design and safely conduct clinical studies. Given these widely divergent opinions, FDA has convened this BRMAC to discuss the issues in a public forum. No specific products are being presented for regulator

10、y review at this meeting and no data presented at the meeting will have undergone FDA review for completeness or accuracy. Instead, published information will be presented and leading researchers in the field will present their viewpoints on the major issues confronting this area of research. Member

11、s of the BRMAC will be requested to consider these publications and view points and provide a response to FDA questions. While a consensus response to these questions is desirable, no consensus is required. Since the field is rapidly developing, FDA anticipates that all opinions are tentative and su

12、bject to reconsideration based upon accumulating data. MEETING GOALSThis meeting is organized to achieve the following goals regarding the development of cellular products for the treatment of cardiac diseases: Provide FDA with perspectives on the types of manufacturing and preclinical data critical

13、 to the initiation of clinical studies Provide FDA with perspectives on the major issues in the design, conduct and analyses of exploratory clinical studies Provide a public forum to discuss the major controversies in developing these productsBACKGROUNDGeneral:Despite many recent advances, ischemic

14、heart disease and congestive heart failure (CHF) remain the major causes of morbidity and mortality in the USA. Despite the important advances in therapy of the last two decades, CHF continues to be a disease characterized by high morbidity and mortality. CHF because of its high prevalence (1-2% of

15、the adult population in the U.S.A) and frequent requirement for hospitalization is among the most costly medical problems in the country. CHF continues to increase in prevalence because 1) the incidence is related to age and the average age of the American population is increasing and 2) reperfusion

16、 therapy has led to growing numbers of patients surviving acute myocardial infarction with diminished cardiac reserve. Similarly, despite advances in medical therapy and percutaneous interventional techniques, ischemic heart disease remains a major cause of morbidity and mortality. A recent paper es

17、timated that 100,000 to 200,000 patients per year develop coronary artery disease not amenable to conventional revascularization, either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) (Mukherjee, Bhatt et al. 1999).Further, many more patients would benefit from re

18、vascularization techniques that are less invasive, more durable, and more complete. Cellular therapies for cardiac disease are a burgeoning field of clinical research as potential treatments for patients with congestive heart failure and/or ischemic heart disease. This research to date has involved

19、cells derived from autologous muscle biopsies, hematopoietic stem cells from autologous peripheral blood after mobilization, or mesenchymal or hematopoietic stem cells obtained from bone marrow. They have been/or are proposed to be administered through catheters into the coronary arteries, transendo

20、cardially through injection catheters into the left ventricular myocardium, or transepicardially through a needle during concomitant CABG.Cellular products to be discussed at this meeting consist of the following: Cellular products manufactured without in vitro culture methodology, a group that incl

21、udes most peripheral blood and/or bone marrow-derived cells, and Cellular products manufactured with in vitro culture methodology, a group that includes cells derived from skeletal muscle biopsies and certain types of bone marrow-derived cells.In general, the cellular products to be discussed are ad

22、ministered by one of the following routes: By transepicardial injection into the left ventricular myocardium during thoracotomy; in this procedure the cellular product is injected into the myocardium using a needle and syringe under direct visualization, By transendocardial injection into the left v

23、entricular myocardium via percutaneous catheterization; in this procedure the cellular product is injected using an investigational catheter which is passed retrograde through the aorta into the left ventricle; the investigational catheter contains a needle and once the catheter is placed against th

24、e left ventricular endocardium, the needle is extruded, and the cellular product injected into myocardium, By injection through a catheter into the coronary artery lumen; the coronary artery lumen is occluded by a balloon and the cellular product infused into the distal coronary artery lumenDiscussi

25、ons of peripheral blood and/or bone marrow-derived cells and cells derived from skeletal muscle biopsies will focus primarily on the use of autologous cellular products, because only autologous cells have been described in published clinical reports. Citations to “stem cells” will occur frequently i

26、n this document. Bone marrow and growth factor mobilized peripheral blood have been widely described as containing stem cells, capable of regenerating and assuming phenotypic characteristics of a variety of tissues, including cardiac tissue. Consequently, in this document these cells will be referre

27、d to as “bone marrow stem cells” (BMSC)” or “peripheral blood stem cells” (PBSC). Cellular products derived from skeletal muscle biopsies are most commonly cited as consisting of differentiated skeletal muscle cells that are capable of regeneration. These cells are commonly referred to as “myoblasts

28、” and are not usually cited as “stem cells.” The reader is referred to the NIH document attached to this document for a glossary of the terms related to stem cells. Of note, stem cell products derived from human embryonic tissue are not a discussion focus for this meeting. Regulatory:FDA regulates c

29、ellular products for cardiac diseases as drugs and biological products. This regulatory paradigm is based, in part on manufacturing procedures, the use of investigational devices in some studies, the non-homologous use of the cellular products and safety concerns associated with administration of th

30、ese products. Consequently, FDA requires Investigational New Drug Applications (IND) for cellular products being evaluated for the treatment of cardiac diseases. The regulatory pathway for cellular products is an evolving process and certain issues related to the ultimate licensure of cellular produ

31、cts remain to be resolved. Hence, this meeting will focus solely upon the scientific basis for clinical development of cellular products to be used in the treatment of cardiac diseases. Conceivably, FDA may request future BRMAC meetings or other venues to discuss the regulatory issues associated wit

32、h late-phase clinical development of these cellular products. For ease of reference, questions to the BRMAC are cited within the text of this document and also are listed at the end of the document. MANUFACTURING INFORMATIONMost investigational cellular products are intended to replace missing, damaged or diseased cells with cells that are healthy and functional. Attempts to develop a cellular product that can restore defective cardiac function with cells not derived from cardiac tissue assumes the presence of undiffere