Guidance for Industry Considerations for Allogeneic Pancreatic Islet Cell Products Additional copies of this guidance are available from the Office of Communication, Outreach and Development (OCOD) (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852- 1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/defaul t.htm. For questions on the content of this guidance, contact OCOD at the phone numbers listed above. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research September 2009 Contains Nonbinding Recommendations Table of Contents I. INTRODUCTION............................................................................................................. 1 II. MANUFACTURING QUALITY AND CONTROL CONSIDERATIONS................ 1 A. Demonstrating Quality Source Material ............................................................ 2 B. Control of the Manufacturing Process................................................................ 3 C. Potency Testing ..................................................................................................... 3 III. PRECLINICAL CONSIDERATIONS ........................................................................... 4 A. Goals of Preclinical Safety Studies ...................................................................... 4 B. Animal Models Appropriate for Use in Preclinical Studies.............................. 4 C. Immunosuppressive Regimen.............................................................................. 5 D. Route of Administration....................................................................................... 5 E. Modified Allogeneic Islet Cell Products.............................................................. 5 F. Potential for Reproductive, Developmental and Carcinogenic Risks.............. 6 IV. CLINICAL STUDY PROTOCOLS................................................................................ 6 A. Design..................................................................................................................... 6 B. Eligibility Criteria................................................................................................. 6 1. Inclusion Criteria Considerations .....................................................................6 2. Exclusion Criteria Considerations ....................................................................7 C. Study Conduct....................................................................................................... 8 1. Dosing...............................................................................................................8 2. Immunosuppressive Regimens .........................................................................8 3. Adverse Experience (Risk) Reporting ..............................................................9 4. Stopping Rules..................................................................................................9 D. Study Endpoints.................................................................................................... 9 1. Primary Endpoint..............................................................................................9 2. Analysis of Other Key Clinical Outcomes......................................................10 3. Secondary Endpoints ......................................................................................11 a. C-peptide...................................................................................................11 b. Insulin requirements..................................................................................11 c. Health-related quality of life.....................................................................11 E. Data Analysis Plan .............................................................................................. 11 F. Follow-Up............................................................................................................. 12 i Contains Nonbinding Recommendations Guidance for Industry Considerations for Allogeneic Pancreatic Islet Cell Products This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION This guidance provides recommendations to you, manufacturers, sponsors, and clinical investigators involved in the clinical studies of allogeneic pancreatic islet cell products for the treatment of Type 1 diabetes mellitus. We, FDA, are issuing this guidance to assist you by identifying data and information obtained during investigational new drug (IND) studies that might be helpful in establishing the safety, purity, and potency of a biological product. This guidance is not intended to identify all of the product, preclinical, and clinical data that might be needed to successfully support a biologics license application (BLA). This guidance finalizes the draft guidance of the same title, dated May 2008. FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA’s guidances means that something is suggested or recommended, but not required. II. MANUFACTURING QUALITY AND CONTROL CONSIDERATIONS For a BLA, the manufacturing process and the manufacturing facility must be in compliance with the current good manufacturing practice regulations (cGMP) under Title 21 Code of Federal Regulations (21 CFR) Parts 210 and 211 and with the standards of safety, identity, purity, and potency (General Biological Products Standards; 21 CFR Part 610), as well as the other applicable regulations for biological products (e.g., 21 CFR Parts 600 through 680) and human cells and tissues (e.g., 21 CFR Part 1271). Also, because allogeneic islets cannot be terminally sterilized, they must be manufactured using aseptic processing (21 CFR 211.113).1 The 1 For additional information, see the FDA guidance entitled “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice” dated September 2004 (October 4, 2004, 69 FR 59258). Currently available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070342.pdf. 1 Contains Nonbinding Recommendations following recommendations are provided to help you navigate some of the challenges unique to manufacturing islets that you may encounter in collecting chemistry, manufacturing, and controls data to support approval of your BLA. A. Demonstrating Quality Source Material Health Resources and Services Administration (HRSA) regulates organ procurement and allocation (see 42 CFR Part 121). However, consistency of islet cell product manufacturing is highly dependent on the quality of the organ delivered to the manufacturing facility. Therefore, you should consider having discussions with your local organ procurement organization, regarding collection of data for things such as: • Organ harvesting procedures; • Ischemia time (both warm and cold); • Organ preservation methods; and • Shipping containers and conditions. These data will be most useful in manufacturing if they are collected in a way that will allow you to correlate each parameter with manufacturing consistency and clinical outcome. These data should help you and your organ procurement organization to standardize procedures and establish predefined acceptance criteria2 for harvesting, packaging, and shipping the organ. Regardless of the degree of standardization of organ procurement, acceptance criteria for organ quality should be established to ensure that unsuitable pancreatic tissues are excluded from manufacturing. At a minimum, the donor testing and screening must meet the requirements for donor eligibility described in 21 CFR Part 1271, Subpart C – Donor Eligibility (see final rule, “Eligibility Determination for Donors of Human Cells, Tissues and Cellular and Tissue-Based Products”).3 In addition, FDA has published a “Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps).”4 We recommend that you review this guidance to ensure that the donor qualification criteria described in your IND are consistent with current recommendations. Additionally, you should collect data and consider establishing acceptance criteria for other characteristics that may affect the quality of the final allogeneic islet cell product such as: 2 Acceptance criteria means numerical limits, ranges, or other criteria for the tests described (21 CFR 600.3(kk)). See also HRSA regulations at 42 CFR 121.6(c). 3 Published in the Federal Register of May 25, 2004 (69 FR 29786) available at http://frwebgate.access.gpo.gov/cgi- bin/getdoc.cgi?dbname=2004_register&docid=fr25my04-11.pdf. Correction published March 24, 2006 (71 FR 14798) available