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 Administrations (FDAs) 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. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs 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 FDAs 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 at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2006_register&docid=fr24mr06-
4.pdf. 
4 This guidance published in February 2007, and reissued with minor revisions in August 2007, available at 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Ti
ssue/ucm091345.pdf.  
2  Contains Nonbinding Recommendations 
 
  Organ size; 
  Extent of organ fibrosis; 
  Donor health status (especially any diabetic conditions); 
  Donor age; and 
  Donor body mass index. 
 
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: 
 
  Varying quantity (weight or units) of dissociation enzymes;  
  Varying digestion conditions such as time, temperature, and shaking; 
  Using certain additives (DNase, Pefabloc, etc.); and  
  Using short-term culture of varying length and condition. 
 
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.   
 
As part of establishing a processing algorithm, you should collect data to demonstrate 
how processing parameters affect the product potency.  We also recommend that you 
determine, to the extent possible, the effect of processing parameter changes on clinical 
outcome. 
 
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)).   
 
The accuracy, sensitivity, specificity, and reproducibility of the potency assay must 
demonstrate lot-to-lot consistency and stability of the product (21 CFR 211.165(a), (d), 
and (e); see section 351(a)(2)(C) of the Public Health Service Act  
(42 U.S.C. 262(a)(2)(C)).  Many of the currently utilized biological assays measuring 
islet function are not rapid enough for use in routine lot-release testing. Therefore, we 
recommend that, during the IND process, you explore the development of rapid analytical 
assays for potency.  For example, you could correlate the biological activity of the final 
product measured by restoration of euglycemia in a diabetic nude mouse with a rapid 
3  Contains Nonbinding Recommendations 
 
analytical assay.  This correlation would help to ensure that your analytical assay is a 
reliable measure of potency, which could then be used for lot-release and should aid in 
product development.5 
 
 
III.  PRECLINICAL CONSIDERATIONS  
 
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.   
 
Furthermore, the study should be long enough to provide data to support the proposed 
durability of the proposed treatment in clinical use.  The duration of the study depends 
upon the specifics of the animal model, the allogeneic islet cell product and the proposed 
clinical use.   
 
                                                 
5  FDA has issued a draft guidance entitled Guidance for Industry: Potency Tests for Cellular and Gene Therapy 
Products dated October 2008 (October 9, 2008, 73 FR 59635), which contains recommendations for developing 
tests to measure potency in certain products.  This draft guidance, when finalized, will represent FDAs current 
thinking on this topic.   
4  Contains Nonbinding Recommendations 
 
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),6 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. 
                                                 
6 Currently available at http://www.fda.gov/ohrms/dockets/ac/cber00.htm.  
5  Contains Nonbinding Recommendations 
 
 
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.   
 
 
IV.  CLINICAL STUDY PROTOCOLS 
 
A.  Design 
 
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. 
 
1.  Inclusion Criteria Considerations 
 
Subjects enrolled in trials of allogeneic islet cell products should have established 
Type 1 diabetes with a well-documented chronic history of severe metabolic 
instability.  Subjects most likely to benefit from islet cell transplantation are those 
who cannot achieve acceptable metabolic control without experiencing multiple 
episodes of severe hypoglycemia, often with unawareness.  Other eligible subjects 
may have lesser degrees of hypoglycemia, but still cannot be adequately managed 
with intensive insulin therapy alone.  In screening subjects for clinical trials, we 
6  Contains Nonbinding Recommendations 
 
recommend that you document that such metabolic instability has persisted 
despite intensive diabetes management delivered by a qualified diabetes team for 
at least six months prior to enrollment.   
 
You should consider the following specific inclusion criteria: 
 
  Subjects should be men or women > 18 years of age who have had 
documented Type 1 diabetes mellitus for at least five years prior to 
enrollment in the study.  There should be documentation of absent or very 
low C-peptide (e.g., absent basal C-peptide or stimulated C-peptide < 0.3 
ng/mL). 
  The distributions of body weight and body mass index (BMI) should be 
representative of the intended treatment population, subjects with brittle 
Type 1 diabetes.  Similarly, the baseline daily insulin requirements should 
generally conform to those of the target population.  It is best to exclude 
patients with extremes of body weight or insulin requirements. 
  Subjects should have a documented history of severe hypoglycemia, 
metabolic instability, or both.  The following are metabolic parameters 
that may be used for documentation of metabolic instability and 
hypoglycemia.  You need not use every one of these parameters, nor 
should you be restricted to this list alone.  We suggest that you discuss the 
following specific details with us during an end-of-phase 2 meeting:  
o  The number of severe hypoglycemic events (e.g., hypoglycemia 
requiring assistance of another individual) during the year prior to 
enrollment;  
o  Quantification of hypoglycemia and metabolic lability using for 
example, the hypoglycemic score (HYPO score) and Lability Index; 
o  Measurement of hypoglycemia unawareness using the Clarke scoring 
system;  
o  24-hour studies of the mean amplitude of glucose excursion; and 
o  History of frequent hospital admissions for diabetic ketoacidosis.  
 
2.  Exclusion Criteria Considerations 
 
You should consider the following specific exclusion criteria: 
 
  Subjects who are significantly overweight or underweight.  
  Subjects with high baseline insulin requirements (>1 unit/kg/day), as the 
mass of islets that can be successfully transplanted may not be able to 
supply adequate quantities of insulin to maintain euglycemia in such 
individuals.  
  Subjects with a history of the following diabetes-related complications:  
o  Unstable coronary artery disease;  
o  Active or untreated proliferative retinopathy;  
o  Macroproteinuria (> 300 mg albumin/gm creatinine);  
o  Elevated serum creatinine (e.g., > 1.6 mg/dL); or  
7  Contains Nonbinding Recommendations 
 
o  Clinically significant reduction in glomerular filtration rate (e.g., 
creatinine clearance < 70 mL/min).  
  Subjects with Hemoglobin A1c (HbA1c) > 12%.  
  Subjects with conditions that may place them at increased risk for the use 
of immunosuppressive agents:   
o  Untreated or inadequately treated hyperlipidemia (e.g., low-density 
lipoprotein  cholesterol (LDL-C) >130 mg/dL); 
o  Chronic infections such as hepatitis B, hepatitis C, human 
immunodeficiency virus, and/or tuberculosis; 
o  Lack of previous exposure to Epstein Barr Virus; or 
o  A history of malignancy with the exception of successfully resected 
squamous or basal cell carcinoma of the skin or cervical carcinoma in 
situ.   
  Subjects with inadequately treated blood pressure elevation (systolic blood 
pressure >160 mm Hg or diastolic blood pressure >100 mm Hg). 
  Subjects with any medical condition that would place them at increased 
risk during the islet infusion procedure (e.g., portal hypertension, history 
of bleeding diathesis, elevated liver function tests, cholecystitis, 
pancreatitis, or active ulcer disease).  
  Subjects with panel-reactive antibodies (PRA) to Human Leukocyte 
Antigens (HLA) > 20%.  In subjects with a PRA < 20% and measurable 
antibody levels, we recommend that antigen specificity be determined.    
  Subjects who require treatment with systemic glucocorticoids.   
  Subjects who have recently been treated with any anti-diabetic agent, 
other than insulin. 
 
C.  Study Conduct 
 
1.  Dosing 
 
Decision criteria for proceeding to a second or third islet cell infusion should be 
pre-specified in the clinical trial protocol.  We recommend that subjects receive 
no more than three islet cell infusions during the trial.  
 
2.  Immunosuppressive Regimens 
 
We recognize the increase in the number and variety of immunosuppressive 
regimens available to investigators.  For pivotal trials, we recommend that you 
utilize a single immunosuppressive regimen and suggest that you discuss the 
regimen with FDA.  
 
8  Contains Nonbinding Recommendations 
 
3.  Adverse Experience (Risk) Reporting 
 
Adverse experience (AE) must be reported as specified in FDA regulations  
(21 CFR 312.32).  In addition to the required reporting, you should conduct 
additional analyses focusing on procedure-related AEs and AEs related to the 
immunosuppressive medications. 
 
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. 
 
4.  Stopping Rules 
 
All pivotal islet cell transplantation trials should have pre-specified stopping 
rules, with periodic monitoring by an independent Data Safety Monitoring Board. 
 
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). 
 
1.  Primary Endpoint 
 
A composite endpoint consisting of normal range HbA1c level (e.g., HbA1c  
6.5%) and elimination of hypoglycemia is acceptable for licensure.  In addition to 
clinical importance, other advantages of this endpoint include ease of 
measurement, reproducibility, and relative durability.  The data analysis should be 
based on the proportion of subjects achieving both elements of this composite 
endpoint.  The two components should not be treated as separate co-primary 
endpoints in the primary efficacy analysis.  
 
Some islet cell transplant recipients who become free of hypoglycemia may 
demonstrate substantial reduction in HbA1c levels, but fail to achieve a target 
level of 6.5% or less.  This outcome might also represent a clinical benefit.  
Depending on the patient population, we may consider expanding the primary 
endpoint to include, for example, a clinically meaningful reduction in baseline 
HbA1c level and absence of hypoglycemia.  This endpoint is best reserved for  
9  Contains Nonbinding Recommendations 
 
subjects who have significant hypoglycemia at baseline, despite intensive therapy 
by a diabetes team.  Determination of appropriate reductions in HbA1c from 
baseline should be discussed with FDA prior to initiation of the pivotal trial. 
 
The primary endpoint should also assess the durability of islet cell transplantation.  
With this in mind, the primary endpoint should be measured at least 12 months 
after the final islet infusion. 
 
2.  Analysis of Other Key Clinical Outcomes 
 
a.  Insulin independence and hypoglycemia 
 
Insulin independence is almost always associated with freedom from 
severe hypoglycemia.  Insulin independence may be employed as a 
primary or secondary endpoint.  If insulin independence is chosen as the 
primary endpoint, it should be strictly defined, in consultation with us. 
 
b.  Measures of glucose metabolic control 
 
Improvements in metabolic control constitute important clinical outcomes 
of islet transplant trials.  Standard methods for measurement of the degree 
of control of blood glucose include the fasting plasma glucose level, two-
hour postprandial plasma glucose level, HbA1c level, and the mean 
amplitude of glucose excursion.  Sponsors may also measure such 
parameters as insulin sensitivity, glucose variability by continuous glucose 
monitoring, etc.  
 
Of these metabolic parameters, HbA1c levels have been most frequently 
used as an endpoint in diabetes trials.  HbA1c measurements are 
convenient, provide an integrated measure of glucose control over time, 
and have been shown to correlate with progression of diabetes 
complications.  HbA1c measurements can be compared to baseline or to a 
pre-specified target level (e.g.,  6.5%), that are justified by current 
practice guidelines.  Other glucose metabolic parameters may be used as 
secondary outcomes. 
 
c.  Loss of serious hypoglycemia/unawareness 
 
Hypoglycemia may be established and quantified by history (e.g., 
frequency of events requiring the assistance of another person) or by more 
precise quantitative means, such as HYPO scores or the Clarke 
hypoglycemia awareness score.  Lability of glucose control may also be 
quantified using the mean amplitude of glycemic excursion score or the 
more recently developed Lability Index.7   
                                                 
7 Ryan, E.A., et al., Assessment of the severity of hypoglycemia and glycemic lability in Type 1 diabetic subjects 
undergoing islet transplantation. Diabetes 2004, 53:955-962. 
10  Contains Nonbinding Recommendations 
 
 
3.  Secondary Endpoints 
 
a.  C-peptide 
 
Plasma C-peptide levels have proven essential in monitoring islet graft 
viability and function during clinical trials and C-peptide levels should be 
measured during pivotal trials.  C-peptide levels should not in themselves 
be used as primary clinical efficacy endpoints, but may be used as 
secondary endpoints. 
 
b.  Insulin requirements 
 
To the extent that the daily insulin regimen is simplified, reduction in total 
daily insulin may constitute an added benefit.  Furthermore, reduction in 
insulin requirements reflects graft function.  Accordingly, reduction in 
daily insulin requirements should be measured as a secondary outcome. 
 
c.  Health-related quality of life 
 
Although successful islet transplantation should have a major impact on 
quality of life, measuring the perceived positive and negative outcomes of 
the transplantation regimen, in an open-label trial is quite complex.  We 
recommend that any assessment of subject reported outcome evaluate both 
the positive and negative aspects of the subjects experience and that the 
choice of instrument be discussed with us prior to implementation.  
 
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).   
 
11  Contains Nonbinding Recommendations 
 
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. 
 
F.  Follow-Up 
 
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.  
12