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U.S. Department of Health and Human Services
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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.
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 This guidance finalizes the draft guidance of the same title, dated May 2008.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.
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).
The 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:
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 criteria 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”). 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).” 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:
B. Control of the Manufacturing Process
Manufacturing process variations may allow for increased yield and quality of islet cells. During investigational studies you should define the critical manufacturing steps that impact safety, purity, and potency and establish controls at these critical manufacturing steps. Examples of manufacturing controls that may improve allogeneic islet cell quality include:
For the manufacturing controls referenced above, you should develop and establish specifications that are appropriate for your manufacturing process. Data collected during investigational studies may be important to support both your established specifications and the established limits of process variation. This should allow some flexibility in the exact procedures used for a specific pancreas, but should also ensure that the process is standardized for consistency.
C. Potency Testing
For a BLA, you must use an appropriate assay to measure potency of your allogeneic islet product that meets the regulatory requirements under 21 CFR 610.10. In general, assays for product potency are intended to show the ability of the product to effect a given result (see 21 CFR 600.3(s)).
A. Goals of Preclinical Safety Studies
The overarching goals of preclinical safety studies are to: (1) provide supportive data for an initial safe starting dose and subsequent dose escalation scheme; (2) aid in determining a risk/benefit assessment for the proposed clinical studies; (3) identify potential endpoints for detection of toxicity and the clinical monitoring for those toxicities; and (4) guide in designing appropriate clinical trials. Frequently, many, if not all, of the regulatory expectations for preclinical data to support clinical studies of allogeneic islets can be met by submission of data from previously conducted studies (preclinical or clinical). However, there are circumstances for which additional preclinical studies may be appropriate prior to initiation of clinical studies. For example, novel routes of administration and untested immunosuppressive regimens may create the need for additional studies.
B. Animal Models Appropriate for Use in Preclinical Studies
Preclinical investigations of allogeneic islets have been supported by studies in a wide range of animal species (e.g., mouse, rat, dog, pig, monkey, and baboon). Many different approaches to generating animal models for diabetes have been used, for example, genetic mutation (i.e., inbred non-obese diabetic mice), medication/toxin-induced (i.e., streptozocin treatment, corticosteroid treatment) and pancreatectomy. Each of these models has inherent strengths and weaknesses, thus no single model is completely predictive of the safety and clinical efficacy. Regardless of the animal species used, to generate scientifically valid data for use in safety and “proof of concept” assessments, the allogeneic islet cell product being tested should be biologically active in that species.
C. Immunosuppressive Regimen
You should submit preclinical toxicology data in appropriate animal model(s) that are intended to support the safety of the short-term and long-term use of each individual immunosuppressive agent used, as well as any combination of agents, prior to initiation of a clinical trial proposing use of the respective regimen. Data derived from models of whole organ transplantation and previous clinical trials may be adequate to support the use of an immunosuppressive regimen in an IND study of allogeneic islet cell products.
In addition, we recommend that you discuss the adequacy of data from existing reproductive/developmental and carcinogenic toxicity testing of the intended immunosuppressive regimen(s) prior to phase 3 clinical trials.
D. Route of Administration
Some clinical investigators of allogeneic islet cell product IND studies have proposed innovative routes of administration as alternatives to the widely used percutaneous transhepatic portal vein delivery. Alternative routes (such as a trans-jugular approach or intra-operative administration) have been suggested to provide improved islet function, as well as a better overall safety profile. Consistent with the discussion in the March 20 and 21, 2000, Biological Response Modifiers Advisory Committee meeting (now the Cellular, Tissue, and Gene Therapies Advisory Committee), if you are proposing innovative delivery methods for allogeneic islet cell products, you should demonstrate an adequate safety profile (e.g., safety of the delivery system and interaction of cells with the components of the delivery system) in animals prior to proceeding to clinical trials.
E. Modified Allogeneic Islet Cell Products
Although recommendations regarding the manufacturing, preclinical, and clinical studies for modified allogeneic islet cell products are beyond the scope of this guidance, a manufacturing change that results in a significant modification of the product characteristics should lead to the consideration of the need for additional preclinical studies. Encapsulation of allogeneic islets provides a useful example of a modification for which additional preclinical studies may be needed. For example, you should consider the need to provide data that support the safety of both the encapsulation material, including the safety of any likely synthetic or degradation products, and the final encapsulated islet product. You should also consider “proof of concept” studies to demonstrate that the encapsulated islets are able to function in an animal model of disease for a sufficient duration to suggest that the risk of clinical administration of the product is likely to be outweighed by the potential clinical benefit. Although data on immunological effects of encapsulated islets should be collected to the degree possible from the safety and “proof of concept” studies, additional focused preclinical studies and/or clinical monitoring of immunological effects of the encapsulation (both on activity of the islets and potential autoimmune pathologies) should be considered for encapsulated islet products.
F. Potential for Reproductive, Developmental and Carcinogenic Risks
At this time, sponsors of clinical trials for the administration of allogeneic islet cell products which are collected, isolated, and/or processed by conventional methods that are frequently reported in the scientific literature, are not expected to submit preclinical studies to address directly reproductive, developmental toxicity, and carcinogenic potential of these allogeneic islet cell products (e.g., literature). However, the potential need for reproductive, developmental, and carcinogenicity studies should be discussed with us in the context of each individual IND submission as some or all of these studies may be appropriate for those innovative products that incorporate novel features such as encapsulation or non-traditional cell source.
Evidence of clinical safety and efficacy for licensure is generally derived from prospective, randomized, controlled clinical trials. However, for the evaluation of allogeneic islet cell products, a single-arm, open-label trial may be able to provide substantial evidence of efficacy and safety in subjects with metabolically unstable Type 1 diabetes. In this design, a historical control arm may be used.
Below, we will address trial design issues for the evaluation of allogeneic islet cell products in individuals who have not previously received an organ transplant (e.g., kidney transplant). These trials in patients who have not received an organ transplant are commonly referred to as islet alone trials. Subjects who have received an organ transplant will have ongoing requirements for systemic immunosuppression and therefore the risk/benefit estimate for these individuals will differ. Sponsors contemplating clinical trials to evaluate islet cell products in individuals who have previously received an organ transplant should discuss trial design with FDA as early as possible.
B. Eligibility Criteria
The following considerations apply specifically to phase 3 trials.
C. Study Conduct
Single-arm trials do not permit a detailed comparison of treatment group-related AEs. Further, small studies may provide an insufficient database to evaluate less common AEs. If you plan to supplement safety information obtained during the course of the study with that available in literature or in safety databases such as the Collaborative Islet Transplant Registry (CITR), you should consider using standard induction and maintenance protocols so that the data from your studies can readily be compared to those in the database.
D. Study Endpoints
As noted above (section IV.A.), single-arm, open-label trials with historical controls provide sufficient evidence of efficacy for patients with metabolically unstable Type 1 diabetes. In part, this is because the major observed benefits (insulin independence, spontaneous loss of hypoglycemia with attainment of good metabolic control) do not appear in the natural course of the disease. The rationale and the selection of endpoints should be discussed in advance with us (i.e., in end-of-phase 2 meetings).
E. Data Analysis Plan
A formal data analysis plan should be submitted to FDA for review, prior to initiation of the study. We recommend the use of composite endpoints that measure glucose metabolic control and the frequency of hypoglycemic events (described above in section IV.D.2.b and c). The primary analyses of all outcomes should be performed on an intent-to-treat (ITT) population. The ITT population should include all enrolled subjects who have received any single component of the transplantation regimen (i.e., attempted transplant) or one dose of an immunosuppressive medication. You should include in the data analysis plan the statistical assumptions, rules for imputation of missing data, and descriptions of how all subjects will be accounted for in the analysis. The data analysis plan should include methodology for analyzing the numerous secondary outcomes, recognizing that most of these are inter-related.
The primary analysis should be performed at least one year after the last islet cell transplant. The protocol should include measurement of the primary efficacy endpoint(s) and as many of the secondary endpoints as feasible, for at least an additional year (i.e., for at least two years after the final transplant).
Sponsors who intend to compare their outcomes, and/or supplement their safety databases, with results taken from a meta-analysis of published literature or from other sources (such as CITR) should discuss the suitability of the databases with us prior to initiation of the clinical trial. The statistical approaches to these comparisons should be part of the data analysis plan and should be discussed in advance with us.
Long-term follow-up is important to assess the results of islet cell transplantation as completely as possible. However, the limited number of subjects enrolled in a single-arm clinical trial, with a short study duration, and lack of concurrent controls (as described in section IV. A) preclude a formal assessment of the effect of islet cell transplantation on progression of major complications of diabetes (retinopathy, nephropathy, neuropathy and macrovascular events), long-term durability of therapeutic effect, and collection of AEs due to the islet cell product, or the concomitant immunosuppressive regimen such as an increase in malignancies or infections. Nonetheless, such trials should include provisions for long-term monitoring of renal, ophthalmological (e.g., worsening of retinopathy), neurological, and cardiovascular status (coronary artery disease and peripheral artery disease, including foot ulcers and amputations), islet function, and AEs. Accordingly, long-term follow-up should be built into each of these trials and the informed consent document must explain the purpose and expected duration of long-term follow-up observations, and a description of the procedures to be followed (21 CFR 50.25), which should include the timing and location (office visit, telephone contact, etc.) of data collection. Details of long-term follow-up should be discussed with us prior to initiation of pivotal clinical trials.
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 .