**Guidance for Industry**

**Exocrine Pancreatic Insufficiency Drug Products --**

**Submitting NDAs**

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**April 2006**

**Clinical/Medical**

**Guidance for Industry**

**Exocrine Pancreatic Insufficiency Drug Products --**

**Submitting NDAs**

*Additional copies are available from:*

*Office of Training and Communications*

*Division of Drug Information, HFD-240*

*Center for Drug Evaluation and Research*

*Food and Drug Administration*

*5600 Fishers Lane*

*Rockville, MD 20857*

*(Tel) 301-827-4573*

*http://www.fda.gov/cder/guidance/index.htm*

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**April 2006**

**Clinical/Medical**

##  {#section .TOC-2}

# TABLE OF CONTENTS {#table-of-contents .TOC-1}

#  {#section-1 .TOC-1 .unnumbered}

# I. INTRODUCTION [1](#i.-introduction)II. BACKGROUND [1](#ii.-background) {#i.-introduction-1ii.-background-1 .TOC-1}

# III. CHEMISTrY, MANUFACTURING, AND CONTROLS SECTION OF THE APPLICATION [3](#iii.-chemistry-manufacturing-and-controls-section-of-the-application) {#iii.-chemistry-manufacturing-and-controls-section-of-the-application-3 .TOC-1}

## A. Drug Substance [3](#a.-drug-substance) {#a.-drug-substance-3 .TOC-2}

## B. Drug Product [4](#b.-drug-product) {#b.-drug-product-4 .TOC-2}

## C. Stability [4](#c.-stability) {#c.-stability-4 .TOC-2}

## D. Overages [5](#d.-overages) {#d.-overages-5 .TOC-2}

## E. Dissolution Method [5](#e.-dissolution-method) {#e.-dissolution-method-5 .TOC-2}

# IV. NONCLINICAL PHARMACOLOGY AND TOXICOLOGY SECTION [5](#iv.-nonclinical-pharmacology-and-toxicology-section) {#iv.-nonclinical-pharmacology-and-toxicology-section-5 .TOC-1}

## A. Toxicology [5](#__RefHeading___Toc121554180) {#a.-toxicology-5 .TOC-2}

## B. Pharmacology [5](#b.-pharmacology) {#b.-pharmacology-5 .TOC-2}

# V. Human Pharmacokinetics and Bioavailability Section [6](#v.-human-pharmacokinetics-and-bioavailability-section) {#v.-human-pharmacokinetics-and-bioavailability-section-6 .TOC-1}

# VI. clinical studies FOR PEP NDAS (section 505(b)) [6](#vi.-clinical-studies-for-pep-ndas-section-505b) {#vi.-clinical-studies-for-pep-ndas-section-505b-6 .TOC-1}

## A. Considerations for Clinical Trial Development [6](#a.-considerations-for-clinical-trial-development) {#a.-considerations-for-clinical-trial-development-6 .TOC-2}

## B. Patient Populations in Clinical Studies [7](#b.-patient-populations-in-clinical-studies) {#b.-patient-populations-in-clinical-studies-7 .TOC-2}

## C. Endpoints (Outcome Measures) Efficacy [7](#c.-endpoints-outcome-measures-efficacy) {#c.-endpoints-outcome-measures-efficacy-7 .TOC-2}

## D. Safety [7](#d.-safety) {#d.-safety-7 .TOC-2}

## E. Design [8](#e.-design) {#e.-design-8 .TOC-2}

### 1. Parallel Studies [8](#parallel-studies) {#parallel-studies-8 .TOC-3}

### 2. Randomized Withdrawal [8](#randomized-withdrawal) {#randomized-withdrawal-8 .TOC-3}

### 3. Crossover Studies [9](#crossover-studies) {#crossover-studies-9 .TOC-3}

# VII. PEDIATRIC STUDIES FOR PEPs [9](#vii.-pediatric-studies-for-peps) {#vii.-pediatric-studies-for-peps-9 .TOC-1}

# References [11](#references) {#references-11 .TOC-1}

**Guidance for Industry**[^1]

**Exocrine Pancreatic Insufficiency Drug Products --**

**Submitting NDAs**

# 

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 FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of this
guidance.

# I. INTRODUCTION

The purpose of this guidance is to assist manufacturers of exocrine
pancreatic insufficiency drug products in preparing and submitting new
drug applications (NDAs). On April 28, 2004 (69 FR 23410), the Food and
Drug Administration (FDA) announced that all orally administered
pancreatic enzyme products (PEPs) are new drugs that will be approved
for prescription use only, and explained the conditions for continued
marketing of these drug products. This guidance pertains to products
that contain the ingredients pancreatin and pancrelipase; these
ingredients, which are of animal origin, contain the following enzymes:
lipases, proteases, and amylases. These enzymes break down fats
(lipases), proteins (proteases), and carbohydrates (amylases) into
elementary units of small size that can traverse the intestinal mucosa,
incorporate into the blood stream, and work as sources of energy and
building blocks of cells.

FDA's guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency'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 Agency guidances means that
something is suggested or recommended, but not required.

# II. BACKGROUND

Pancreatic enzyme preparations of porcine or bovine origin have been
available in the United States for the treatment of exocrine pancreatic
insufficiency (EPI) in children and adults with cystic fibrosis (CF) and
chronic pancreatitis (CP) since before the enactment of the Federal
Food, Drug, and Cosmetic Act of 1938 (the Act). Under the Act, beginning
in 1938, new drugs were required to be the subject of approved NDAs.
With the exception of one PEP approved in 1996, PEPs have been marketed
without NDAs.

There are approximately 30,000 pediatric and adult patients with cystic
fibrosis in the United States. Pediatric patients affected with cystic
fibrosis and patients with chronic pancreatitis who have significant
reduction of pancreatic function are unable to digest fats, proteins,
and carbohydrates. As a consequence, the absorption of these nutrients
is impaired, with the resultant malnutrition and a host of secondary
complications, including retarded growth and development, impaired
immune response, infections, and bleeding tendencies, among others.

In the *Federal Register* of November 8, 1985 (50 FR 46594), the FDA
published a notice of proposed rulemaking to establish a monograph for
over-the-counter (OTC) EPI drug products. The Agency accepted the
recommendations of the Advisory Review Panel on OTC Miscellaneous
Internal Drug Products (the Panel) that EPI drug products be considered
safe (generally recognized as safe (GRAS)) and effective (generally
recognized as effective (GRAE)) and not misbranded.[^2] Interested
persons were invited to submit new data, written comments, objections,
or requests for an oral hearing on the proposed rulemaking. Based on the
information received, the FDA reconsidered the approach described in the
November 8, 1985, proposed rulemaking and concluded that: (1) an OTC
monograph would not be sufficient to adequately regulate these drug
products; (2) preclearance of each product to standardize enzyme
bioactivity would be necessary; and (3) because continuous physician
monitoring of patients would be necessary as a collateral measure to
ensure the safe and effective use of these products, such products
should be available by prescription only. In the *Federal Register* of
July 15, 1991 (56 FR 32282), the FDA withdrew the November 8, 1985,
proposed rule and proposed a regulation to declare that OTC drug
products used to treat EPI are not GRAS and GRAE and are misbranded. The
final rule, which affected only OTC products, published on April 24,
1995 (60 FR 20162).

In the 1991 and 1995 proposed and final rules, the FDA discussed its
review of the scientific data that provide the basis for the FDA's
decision to require approval of PEPs through the new drug approval
process under section 505 of the Act.

At this time, the FDA expects to receive only NDAs, including section
505(b)(2) applications, and not abbreviated new drug applications
(ANDAs) for these products. For a pancrelipase or pancreatin product to
be approved as an ANDA under section 505(j), the proposed drug product
must be shown to contain the same active ingredients as an approved
reference listed drug (21 CFR 314.92(a)(1)). Because of the complexity
of pancreatic extract products, it is unlikely that currently available
physiochemical and biological analytical tools would be able to
demonstrate that the active ingredients in pancreatic extract products
from two different manufacturers are the same. Therefore, the Agency has
concluded that pancreatic extract drug products currently are not likely
to be appropriate for ANDAs. Nonetheless, manufacturers with further
questions about the feasibility of submitting ANDAs for pancreatic
extract products are advised to contact the Office of Generic Drugs
(HFD-600, Center for Drug Evaluation and Research, Food and Drug
Administration, 7500 Standish Pl., Rockville, MD 20855).

If a sponsor markets or wishes to market more than one PEP, the number
of NDAs it needs to submit will depend on the composition of the
products. If the products vary by active ingredient (e.g., product 1:
amylase and lipase; product 2: amylase and protease), then separate NDAs
should be submitted. If the products vary only by potency ratios of the
same active ingredients (e.g., product 1: amylase, 15,000 amylase units,
lipase, 1,200 lipase units, and protease, 30,000 protease units, and
product 2: amylase, 15,000 amylase units, lipase, 1,500 lipase units,
and protease, 35,000 protease units), then separate NDAs need not be
submitted. Different strengths or concentrations can be submitted in the
same NDA.

# III. CHEMISTrY, MANUFACTURING, AND CONTROLS SECTION OF THE APPLICATION

To be approved, an NDA must meet the requirements described in 21 CFR
314.50 regarding chemistry, manufacturing, and controls information. We
recommend that applicants consult the FDA guideline *Submitting
Supporting Documentation in Drug Applications for the Manufacture of
Drug Substances* and the guidance for industry *Submitting Documentation
for the Manufacture of and Controls for Drug Products*.[^3] We also
recommend that applicants consult relevant International Conference on
Harmonisation (ICH) guidance documents (e.g., Q1A, Q2A, Q2B, Q3C, Q5A,
Q5C, and Q6B). The following sections describe additional information
unique to PEPs that should be provided in NDAs or Drug Master Files.

## A. Drug Substance 

For the starting material used in the manufacturing process, information
on animal species, tissue types, and countries of origin should be
provided. Animals used should have been raised with the intent for use
as human food. The source documentation should include animal origin,
identification, and movement since birth; maintenance animal medical
records; surveillance of herds; and documentation of feeds. Feeds should
not contain any reprocessed animal products.

The manufacturing process should be validated for its capability to
remove and/or inactivate viral agents as recommended in ICH Q5A.[^4] A
full viral risk assessment should be made and justified.

The drug substance should be adequately characterized using appropriate
chemical, physical, and biological testing. Batch-to-batch consistency
with respect to chemical identity, biological activity of different
classes of enzymes including specific activity, identity, and purity
level should be demonstrated. Purity can be evaluated by enzyme-specific
activity. Identity can be demonstrated by fingerprint analysis, using
(but not limited to) the following methods:

-   Chromatography (e.g., ion-exchange or reversed phase high-pressure
    liquid chromatography (HPLC))

-   Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)

-   Isoelectric focusing (IEF)

-   New analytical technologies, when appropriate

Nondrug substance-related impurities such as process-related impurities,
inorganic impurities, and residual solvents should be controlled.
Estimates of the amounts of inactive cell components and product-related
impurities including inactive enzymes present in the drug substance
should be made.

Specifications for the drug substance should include tests for identity,
biological activity of different classes of enzymes, purity, and other
relevant attributes. Appropriate acceptance factors (e.g., limits and
ranges) should be established and justified for lipases, amylases, and
proteases.

## B. Drug Product 

Specifications for the drug product should include tests for identity,
biological activity of different classes of enzymes, degradants,
dissolution, and other relevant attributes. Pancreatic enzymes from
natural sources are a mixture of lipases, amylases, and proteases, which
are present in varying proportions. Appropriate acceptance criteria
should be established and justified for these enzymes. However, for
purposes of labeling, product potency should be expressed as lipase
activity. When a novel or non-novel, but noncompendial, excipient is
included in the formulation of the drug product, manufacturing and
control information on the excipient should be provided. Refer to
related sections in ICH Q6B.[^5]

## C. Stability

Due to the inherent lability that has been observed with PEPs, stability
data through 12 months at the recommended storage temperature as well as
3 months of accelerated stability data should be provided.

Additional stability data can be submitted as an amendment during the
review process, and an expiration date will be determined based on the
review of the stability data in the NDA.

Primary stability data should be generated according to the guidance
developed in ICH Q1A and Q5C.[^6] Primary stability studies should be
performed with batches that are formulated to be released at 100 percent
of the label-claimed potency for lipase.

Existing stability data not obtained under ICH conditions can be
submitted as supporting data.

## D. Overages

Since high doses of pancreatic enzymes have been associated with safety
problems (see 69 FR 23411), the finished product should be formulated to
100 percent of the label-claimed lipase enzyme activity. With suitable
justification (e.g., manufacturing losses), however, overages may be
acceptable. Amylase and protease activity in the formulation should
remain within justified limits.

## E. Dissolution Method

An appropriate in vitro release test method should be developed.

# IV. NONCLINICAL PHARMACOLOGY AND TOXICOLOGY SECTION

To be approved, an NDA must meet the requirements described in 21 CFR
314.50 for nonclinical and toxicology data.

[]{#__RefHeading___Toc121554180 .anchor}

## A. Toxicology

No toxicology studies are needed if excipients are classified as GRAS
for oral administration or are USP/NF compendial excipients and are
present at levels previously found acceptable.[^7] If the excipients are
not classified as GRAS or have not been previously approved for the same
route of administration, amount, or therapeutic use, safety should be
established through toxicology studies. For new excipients without
previous clinical data, clinical trials of the drug product containing
the new excipients should also be performed. If the new excipients are
classified as GRAS but are present in quantities in excess of the
allowed levels, their safety should be established at the higher levels
through toxicological studies of the excipients or the drug product
containing the higher levels of the excipients. To determine their
safety, the toxicology program for new excipients or for excipients with
higher levels than listed for GRAS should supply data from long-term
studies in both rodent and nonrodent mammalian species plus standard
reproductive toxicity and genotoxicity information (Steinberg et al.
1996).[^8] Information from published reports of toxicology studies
should also be included in the NDA.

## B. Pharmacology

## 

Because of the extensive use of the currently marketed PEP products, no
new pharmacology studies for such products are necessary. The FDA
recommends that applicants summarize the published literature about the
pharmacology of their particular PEP and submit this summary with the
bibliography as part of a 505(b)(2) application. In addition, we
encourage submission of all available nonclinical information including
any pharmacological data generated with the drug substance and/or drug
product.

# V. Human Pharmacokinetics and Bioavailability Section

To be approved, an NDA must meet the requirements in 21 CFR 314.50 for
human pharmacokinetic and bioavailability information. The bioactivity
and/or bioavailability of the active ingredients should be determined at
the site of action (gastrointestinal tract). The lipase, amylase, and
protease activities should be determined from aspirates from the stomach
and duodenum. The data should be obtained under fasting conditions as
well as after a standard meal stimulation.

The use of any inactive ingredient in the formulation to prevent or
minimize the hydrolysis of the enzymes in the stomach should be
supported with in vitro and/or in vivo release data. An appropriate in
vitro release test method should be developed.

# VI. clinical studies FOR PEP NDAS (section 505(b))

To be approved, a PEP NDA must meet the requirements for clinical
studies described in 21 CFR 314.50. The Agency has determined that there
is a considerable body of evidence that replacement of pancreatic
enzymes has clinical benefit for patients with cystic fibrosis and
chronic pancreatitis (69 FR 23410). This section summarizes general
approaches to the design of clinical studies intended to provide such
evidence of effectiveness and safety in support of an NDA for currently
marketed PEPs of animal origin. The discussion includes guidance on
patient populations that should be studied, endpoints (outcome measures)
to evaluate efficacy and safety, and suggestions for the design of
clinical studies.

## A. Considerations for Clinical Trial Development

Currently marketed PEPs differ in their composition, enzymatic
activities, formulation, method of manufacture, stringency of quality
control during manufacturing, stability, and bioavailability (i.e.,
bioactivity in the small intestine). These differences have led to
highly variable PEP quality and therapeutic performance among
manufacturers. For any given manufacturer, such differences over time
can lead to batch-to-batch inconsistency and to unacceptable variability
in PEP quality and therapeutic performance. With improvements in quality
as outlined in the guidance, therapeutic performance may be better
predicted from in vitro studies or from in situ measurements of PEP
bioactivity in the small intestine.

For NDA approval of any particular PEP, clinical studies should
demonstrate a relationship between the extent of clinical benefit and
the amount of PEP administered (e.g., empirical demonstration of
dose-response relationships in clinical trials).

NDAs filed under section 505(b)(2) of the Act may include published
articles along with a bibliography of clinical trials in lieu of
clinical data.

## B. Patient Populations in Clinical Studies 

Two distinct populations have the largest clinical need in practice for
PEPs: (1) pediatric and adult patients with cystic fibrosis; and (2)
adult patients with chronic pancreatitis. Both conditions can cause
pancreatic insufficiency and maldigestion, leading to malabsorption of
dietary nutrients and subsequent malnutrition. Different dosages of PEPs
may be recommended to treat these two populations. ***At a minimum,
because cystic fibrosis is primarily a pediatric disease, the efficacy
studies in the NDA should include clinical studies in pediatric patients
with cystic fibrosis.***

## C. Endpoints (Outcome Measures) Efficacy

Although demonstrating a beneficial effect on clinical outcomes is
desirable in clinical trials (e.g., weight gain or nutritional status),
efficacy can also be demonstrated by showing a meaningful beneficial
effect on appropriate pharmacodynamic measures such as steatorrhea. Some
examples are provided here:

-   Demonstration that administration of the PEP to patients with
    exocrine pancreatic insufficiency causes a meaningful decrease in
    stool fat as evaluated in a 72-hour quantitative stool collection

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-   Demonstration that administration of the PEP to patients with
    exocrine pancreatic insufficiency causes significantly more
    responders than in a comparison group (e.g., stool fat originally
    higher than 14 g/day decreased to less than 7 g/day)

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-   Demonstration that administration of the PEP to patients with
    exocrine pancreatic insufficiency causes significantly fewer
    patients to withdraw from blinded therapy because of steatorrhea
    than in a comparison group

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-   Other quantitative endpoints can be considered

## D. Safety

Safety variables that should be assessed in clinical trials with PEPs
include symptoms and signs of malabsorption, such as manifestations of
steatorrhea; complaints of bloating; flatus; abdominal pain; loose and
frequent stools; overt diarrhea; blood in the stool; and uric acid
elevations.

With regard to safety, we note that the etiology of fibrosing
colonopathy has not been completely elucidated. In an effort to minimize
development of fibrosing colonopathy that has been assumed to be related
to high doses of PEPS, the FDA, in conjunction with the Cystic Fibrosis
Foundation (CFF), recommends a starting dose of 500 to 1,000 lipase
units /Kg/meal with titration to less than 2,500 units/Kg/meal or less
than 4,000 lipase units/g fat/day (FitzSimmons et al., 1997; Borowitz et
al., 2002). Doses in excess of 2,500 USP lipase units/Kg/meal should be
used with caution and only if their benefit is documented by 3-day fecal
fat. Doses in excess of 6,000 USP lipase units/Kg/meal have been
associated with fibrosing colonopathy. This dosing recommendation,
applicable to any formulation, was made on the basis of concern over
dose-related colonic strictures in cystic fibrosis and the likelihood
that maximal efficacy is achieved at the recommended ceiling dose of
2,500 USP lipase units/Kg/meal.

## E. Design

The clinical studies confirming efficacy of the specific PEP can be: (1)
parallel; (2) randomized withdrawal; or (3) crossover designs. The
designs of these studies for PEP products are discussed below. Other
designs, such as those in which patients are challenged with increases
in dietary fat, can also be considered.

The clinical studies confirming efficacy of the specific PEP should
include appropriate controls, such as dose-comparison controls, or
active treatment controls. Placebo may be appropriate with a rescue
protocol to protect patients. As noted in the following sections, if a
placebo is not used (such as in a comparison of two doses of a PEP, or
in a comparison of one PEP with another (e.g., an active control)),
differences between treatments should be demonstrated to help interpret
results. If desired, the efficacy and dose response of the PEP can be
demonstrated in the same study.

Duration of the entire trial could be days to 2 to 3 weeks, depending on
the design chosen. Blinding and randomization are recommended to reduce
bias. Diets may need to be standardized. The total number of patients in
the study can be between 10 and 25, depending on study design. Either
two studies or one adequate and well-controlled clinical investigation
and confirmatory evidence may be appropriate.

### 1. Parallel Studies

Parallel studies can be used to demonstrate efficacy of a PEP, such as
when the effects of the PEP are compared to other doses of a PEP and/or
to another active product (such as another PEP) or placebo.

### 2. Randomized Withdrawal

A randomized withdrawal study should have two phases: a run-in phase and
a randomized withdrawal phase. In the run-in phase, patients should be
administered the PEP under study and the dose should be adjusted (e.g.,
titrated) to achieve and stabilize at the desired clinical outcome
(e.g., control of stool fat excretion). An open-label design is
appropriate for this phase. In the next phase (the withdrawal phase),
patients who have apparently responded to the PEP should then be
randomized in a double-blind fashion to either continued treatment with
the PEP or, as is typical, to placebo. At the end of the withdrawal
phase the effects of the two treatments should be compared. For example,
the primary efficacy endpoint could be a quantitative measure of stool
fat over 72 hours (e.g., the mean change in stool fat or the number of
nonresponders who have recurrent steatorrhea). In some cases at the
outset of the randomized withdrawal period, it may be desirable to
discontinue treatment gradually to avoid sudden onset of symptoms of
pancreatic insufficiency.

Patients should be monitored even during the withdrawal phase to allow
discontinuation from randomized study treatment if clinically
appropriate (e.g., for clinically worrisome diarrhea). Patients who
discontinue study treatment can then be given appropriate medical
therapies. If prespecified in the protocol, a count of these treatment
failures (nonresponders) can be incorporated into the primary efficacy
analysis. In such cases, the protocol should define specific
discontinuation criteria for patients who fail treatment.

A randomized withdrawal design also can be adapted to incorporate a
dose-response evaluation of a PEP. At the outset of the withdrawal
phase, for example, patients can be randomized to placebo and to two or
more dosage levels of a PEP. The response of patients at the different
dosage levels (including placebo) can then be compared. Although
inclusion of a placebo arm is often the most usual and straightforward
way of demonstrating efficacy, this arm can sometimes be excluded.

### 3. Crossover Studies

In a crossover study, each patient in the study is treated with all or
most of the treatments under investigation, usually in a randomized
sequence.

A crossover study allows for a paired statistical analysis of the data
(i.e., each patient serves as his or her own control), thereby
decreasing the effects of interpatient variability, which otherwise
might obscure true drug effects. In general, fewer patients are needed
to perform a crossover study than a parallel study. However, because
each patient is administered several treatments, each patient's study
involvement is longer than in a parallel study. Moreover, sponsors are
strongly cautioned that if baseline conditions are not reestablished
between treatment periods, or if treatment in one period carries over
into the subsequent period or periods, the results likely will not be
interpretable using a paired statistical analysis. Although data from
the first period could still be analyzed as in a parallel study
(unpaired statistical analysis), the main advantage of using a crossover
design would have been lost.

In a randomized, two-period, placebo-controlled, crossover study of a
PEP, for example, patients should first be stabilized on existing
therapy to establish baseline conditions. Patients should then be
randomized to receive one of two treatment sequences: placebo-PEP versus
PEP-placebo. If quantitative determination of stool fat is used as the
primary endpoint, each period should last at least 72 hours to allow for
adequate collection of stool specimens. Reestablishment of baseline
conditions should be documented between periods.

# VII. PEDIATRIC STUDIES FOR PEPs

A significant portion of the target population for PEPs includes
pediatric patients with cystic fibrosis, a congenital genetic disease in
which there is chronic exocrine pancreatic insufficiency dating from
birth. These patients represent the majority of pediatric patients with
exocrine pancreatic insufficiency. At the time of publication of this
guidance, the only PEP approved for use in pediatric cystic fibrosis
patients is an immediate-release formulation, and that product is not
currently marketed.

To comply with the Pediatric Research Equity Act of 2003 (PREA) (21
U.S.C. 355c), the application must contain data that are adequate to
assess the safety and effectiveness of the PEP for the claimed
indications in each of the appropriate pediatric subgroups (newborns,
infants, children, and adolescents). The data should be adequate to
support dosing and administration in each pediatric subpopulation for
which the drug has been assessed to be safe and effective. Studies may
not be needed in each pediatric age group, if data from one age group
can be extrapolated to another. Whether or not pediatric studies in more
than one age group are necessary depends on expected therapeutic benefit
and use in each age group, and on whether safety and effectiveness data
from one age group can be extrapolated to other age groups. As with the
use of adult data, the extrapolation can be supplemented with data to
define dosing and safety for the relevant age groups. Because solid
dosage forms of PEPs cannot be swallowed by young pediatric patients
(i.e., generally six years of age or younger), under PREA, sponsors must
attempt to develop age-appropriate formulations for this patient
population.

# References

Beverley, DW, J Kelleher, A MacDonald, JM Littlewood, T Robinson, and MP
Walters, 1987, Comparison of Four Pancreatic Extracts in Cystic
Fibrosis, *Archives of Disease in Childhood*, 62:564-568.

Borowitz, D, RD Baker, and V Stallings, 2002, Consensus Report on
Nutrition for Pediatric Patients with Cystic Fibrosis, *Journal of
Pediatric Gastroenterology and Nutrition,* 35:246-259.

Briars, GL, DM Griffiths, IE Moore, PH Williams, K Johnson, and CJ
Rolles, 1994, Letter to the Editor, *Lancet*, 343:600.

Campbell, CA, J Forrest, and C Musgrove, 1994, Letter to the Editor,
*Lancet*, 343:109.

Cystic Fibrosis Foundation, 1993, Results of a Survey of 114 Cystic
Fibrosis Care Centers in United States, Patient Registry 1992 Annual
Data Report, Bethesda, MD, October 1993, in OTC Vol. 17BFR, Docket No.
79N-0379, Division of Dockets Management.

Dutta, SK, VS Hubbard, and M Appler, 1988, Critical Examination of
Therapeutic Efficacy of a pH-Sensitive Enteric-Coated Pancreatic Enzyme
Preparation in Treatment of Exocrine Pancreatic Insufficiency Secondary
to Cystic Fibrosis, *Digestive Diseases and Sciences*, 33:1237-1244.

Fatmi, AA and JA Johnson, 1988, An In Vitro Comparative Evaluation of
Pancreatic Enzyme Preparations, *Drug Development and Industrial
Pharmacy*, 14:1429-1438.

FitzSimmons, SC, GA Burkhart, D Borowitz et al., 1997, High-Dose
Pancreatic Enzyme Supplements and Fibrosing Colonopathy in Children with
Cystic Fibrosis, *New England Journal of Medicine*, 336:1283-1289.

Graham, DY, 1979, An Enteric-Coated Pancreatic Enzyme Preparation that
Works, *Digestive Diseases and Sciences*, 24:906-909.

Graham, DY, 1977, Enzyme Replacement Therapy of Exocrine Pancreatic
Insufficiency in Man: Relation Between In Vitro Enzyme Activities and In
Vivo Potency in Commercial Pancreatic Extracts, *New England Journal of
Medicine*, 296:1314-1317.

Hendeles, L, A Dorf, A Stecenko, and M Weinberger, 1990, Treatment
Failure After Substitution of Generic Pancrelipase Capsules: Correlation
with In Vitro Lipase Activity, *Journal of the American Medical
Association*, 263:2459-2461.

Knabe, N, M Zak, A Hansen, J Moesgaard, N Kvist et al., 1994, Letter to
the Editor, *Lancet*, 343:1230.

Littlewood, JM, J Kelleher, MP Walters, and AW Johnson, 1988, In Vivo
and In Vitro Studies of Microsphere Pancreatic Supplements, *Journal of
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[^1]: This guidance has been prepared by the Division of
    Gastroenterology Products in the Center for Drug Evaluation and
    Research (CDER) at the Food and Drug Administration.

[^2]: For a discussion of the conditions for general recognition as
    safe, effective, and not misbranded, see 21 CFR 330.1.

[^3]: We update guidances periodically. To make sure you have the most
    recent version of a guidance, check the CDER guidance Web page at
    http://www.fda.gov/cder/guidance/index.htm.

[^4]: See ICH guidance for industry *Q5A Viral Safety Evaluation of
    Biotechnology Products Derived From Cell Lines of Human or Animal
    Origin* (http://www.fda.gov/cder/guidance/index/htm).

[^5]: See ICH guidance for industry *Q6B Specifications: Test Procedures
    and Acceptance Criteria for Biotechnological/Biological Products*
    (http://www.fda.gov/cder/guidance/index/htm).

[^6]: See ICH guidance for industry *Q1A(R2) Stability Testing of New
    Drug Substances and Products* and ICH guideline for industry *Q5C
    Quality of Biotechnological Products: Stability Testing of
    Biotechnological/Biological Products*
    (http://www.fda.gov/cder/guidance/index/htm).

[^7]: GRAS listings are included in 21 CFR parts 182 and 582 and are
    updated each year.

[^8]: See also the guidance for industry *Nonclinical Studies for the
    Safety Evaluation of Pharmaceutical Excipients*.
    (http://www.fda.gov/cder/guidance/index.htm)