Guidance for Industry

Considerations for Allogeneic 

Pancreatic Islet Cell Products

DRAFT GUIDANCE

This guidance document is for comment purposes only.

Submit comments on this draft guidance by the date provided in the Federal Register notice 

announcing the availability of the draft guidance. Submit written comments to the Division of 

Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov. You should 

identify all comments with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

Additional copies of this draft guidance are available from the Office of Communication, 

Training and Manufacturers Assistance (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/cber/guidelines.htm. 

For questions on the content of this guidance, contact Keith Wonnacott, Ph.D., at 301-827-5102. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Biologics Evaluation and Research 

May 2008 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

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.............................................................................. 4

D. Route of Administration....................................................................................... 5

E. Modified Allogeneic Islet Products...................................................................... 5

F. Potential for Reproductive, Developmental and Carcinogenic Risks.............. 5

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 .............................................................. 8 

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 

Draft – Not for Implementation 

Guidance for Industry 

Considerations for Allogeneic Pancreatic Islet Cell Products 

This draft guidance, when finalized, will represent 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 is intended to provide 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 

may 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 may be 

needed to successfully support a biologics license application (BLA). 

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 (see e.g., 21 CFR Parts 600 through 680). Also, 

because allogeneic islets cannot be terminally sterilized, they must be manufactured using 

aseptic processing (21 CFR 211.113).1

 The following recommendations are intended to help you 

navigate some of the challenges unique to islet manufacture that you may encounter in collecting 

chemistry, manufacturing, and controls data to support approval of your BLA. 

 

1

 For additional information, see Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — 

Current Good Manufacturing Practice, available at http://www.fda.gov/cber/guidelines.htm. 

1 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

 

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 may wish to 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 tissue is excluded 

from manufacturing. At a minimum, the donor testing and screening must meet the 

requirements for donor eligibility described in 21 CFR Part 1271 (see final rule, 

“Eligibility Determination for Donors of Human Cells, Tissues and Cellular and TissueBased 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: 

• organ size, 

• extent of organ fibrosis, 

• donor health status (especially any diabetic conditions), 

• donor age, and 

• donor body mass index. 

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://www.fda.gov/cber/rules/suitdonor.pdf. Correction published March 24, 2006 (71 FR 14798) available at 

http://www.fda.gov/cber/rules/suitdonorcor.pdf. 

4

 Announced in the Federal Register of February 28, 2007 (72 FR 9007) available at 

http://www.fda.gov/cber/gdlns/tissdonor.pdf. 

2 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

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) and 

(e); see section 351(a)(2)(C) of the Public Health Service Act). Restoration of 

euglycemia in a diabetic nude mouse currently appears to be the most predictive assay of 

islet potency; however, results from the diabetic nude mouse model would not be 

available for product release as a result of the time required for the assay. Therefore, we 

recommend that, during the IND process, you explore the development of rapid analytical 

assays for potency. 

Collection of data using both the diabetic nude mouse model and your potency assay for 

product lots manufactured during your investigational studies should aid product 

development. For example, you could correlate the biological activity of the final 

3 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

product, as measured using the diabetic nude mouse assay, with a rapid analytical assay 

performed on the final product to ensure that your analytical assay is a reliable measure 

of potency. 

III. PRECLINICAL CONSIDERATIONS 

A. Goals of Preclinical Safety Studies 

The overarching goals of preclinical safety studies are: (1) to provide supportive data for 

an initial safe starting dose and subsequent dose escalation scheme; (2) to aid in 

determining a risk/benefit assessment for the proposed clinical studies; (3) to identify 

potential endpoints for detection of toxicity and the clinical monitoring for those 

toxicities; and (4) to 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. In order 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 the animal species used. 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. 

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. 

4 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

 

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,5

 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 details 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 

5

 Currently available at http://www.fda.gov/cber/advisory/ctgt/ctgtmain.htm. 

5 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

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 

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 

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. Stimulated C-peptide should be < 0.3 ng/mL. 

6 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

• 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 weights 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 (e.g., BMI > 28 kg/m2

) 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 

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; 

7 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

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. 

3. Adverse Experience (Risk) Reporting 

All adverse experiences (AEs), serious adverse experiences (SAEs), and deaths 

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 experiences and experience 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 

8 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

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 may 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 

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. 

9 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

 

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 must 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, twohour postprandial plasma glucose level, HbA1c level, and the mean 

amplitude of glucose excursion. Sponsors may also wish to 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.6

 

6

 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 

Draft – Not for Implementation 

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 subject’s 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 intentto-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 one further year (i.e., until 

two years after the final transplant). 

11 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

12 

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 duration of long-term followup observations, including the timing and location (office visit, telephone contact, etc.) of 

data collection (21 CFR 50.25). Details of long-term follow-up should be discussed with 

us prior to initiation of pivotal clinical trials.