MD7090 022210s000crossr

User Manual: MD7090

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CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

22-210

CROSS DISCIPLINE TEAM LEADER REVIEW

Cross-Discipline Team Leader Review

Date August 21, 2009

From Anil Rajpal, MD, Acting Clinical Team Leader

Division of Gastroenterology Products

Subject Cross-Discipline Team Leader Review

NDA/ BLA # NDA 22-210

Applicant Eurand Pharmaceuticals, Inc.

Date of Submission December 22, 2008; Received December 23, 2008

PDUFA Goal Date September 23, 2009

(includes three-month extension for a major amendment)

Proprietary Name /

Established (USAN) names Zenpep®

pancrelipase

Dosage forms / Strength Zenpep® (pancrelipase) delayed release-capsules for oral

administration, in USP units

 Zenpep 5,000 lipase/17,000 protease/27,000 amylase

 Zenpep 10,000 lipase/34,000 protease/55,000 amylase

 Zenpep 15,000 lipase/51,000 protease/82,000 amylase

 Zenpep 20,000 lipase/68,000 protease/109,000 amylase

Proposed Indication For the treatment of exocrine pancreatic insufficiency due

to cystic fibrosis or other conditions

Recommended Action: Approval under 21 CFR 314

Table of Contents

1. Introduction....................................................................................................................... 2

2. Background ....................................................................................................................... 2

3. CMC.................................................................................................................................. 6

4. Nonclinical Pharmacology/Toxicology .......................................................................... 15

5. Clinical Pharmacology/Biopharmaceutics...................................................................... 16

6. Clinical Microbiology..................................................................................................... 17

7. Clinical/Statistical- Efficacy ........................................................................................... 18

8. Safety .............................................................................................................................. 19

9. Advisory Committee Meeting......................................................................................... 22

10. Pediatrics......................................................................................................................... 22

11. Other Relevant Regulatory Issues................................................................................... 23

12. Labeling .......................................................................................................................... 24

13. Recommendations/Risk Benefit Assessment.................................................................. 27

APPENDIX 1.......................................................................................................................... 31

APPENDIX 2.......................................................................................................................... 33

APPENDIX 3.......................................................................................................................... 37

APPENDIX 4.......................................................................................................................... 39

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

1. Introduction

This resubmission, received December 23, 2008, is a complete response to the Approvable

(AE) Letter sent by the Division on June 16, 2008, and represents the second review cycle for

Zenpep (pancrelipase), an enteric-coated, delayed-release pancreatic enzyme product (PEP);

Zenpep is an exogenous source of porcine-derived pancreatic enzymes intended for treatment

of exocrine pancreatic insufficiency (EPI).

In the first review cycle, deficiencies were identified by the Chemistry, Manufacturing, and

Controls (CMC) discipline, and by the Clinical Pharmacology discipline. CMC deficiencies

in the AE letter were related to: (1) process validation; (2) enteric coating; (3) stability data;

(4) storage conditions; (5) drug substance (separate letter with 18 items sent to the DMF

holder; included viral issues); (6) olive oil qualification; (7) drug product acceptance criteria;

(8) RP-HPLC assay validation; (9) qualification of the reference standard; and (10) USP

lipase reference standard used. A clinical pharmacology deficiency was the eleventh item in

the AE letter: (11) a clarification about in vitro stability data.

No clinical deficiencies were identified in the first review cycle. The initial submission

contained results from three clinical studies: (a) pivotal study (EUR-1008-M; randomized

double-blind cross-over study; n=34); (b) supportive study (EUR-1009-M; open-label;

uncontrolled; n=19); and (c) bioavailability study (PR-001; n=11). The current submission

contains a safety update to March 30, 2008.

It should be noted that during the current review cycle, information became available that the

Applicant was continuing to market another pancrelipase product “in association with IND

70,563 and NDA 22-210.” Complete safety information was required to be submitted for the

unbranded pancrelipase product; this was received on June 15, 2009 and constituted a major

amendment that led to the three-month extension of the PDUFA date.

The primary emphasis of this memorandum is on the issues to be resolved in the current

review cycle.

2. Background

2.1 Clinical Background

Exocrine pancreatic insufficiency (EPI) typically results from chronic loss of pancreatic

tissue due to a number of underlying diseases. The most common cause of EPI in children is

Cystic Fibrosis (CF); the most common cause of EPI in adults is chronic pancreatitis (CP).

There are many other causes, such as pancreatectomy.

The predominant clinical manifestations of EPI are steatorrhea, abdominal pain, weight loss,

and nutritional problems (e.g., fat-soluble vitamin deficiencies) due to malabsorption. The

administration of pancreatic enzyme replacement therapy with exogenous sources of PEPs is

the mainstay of therapy for steatorrhea and malabsorption due to EPI, regardless of cause.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

Dosing is individualized based on age, body weight, fat content of the diet, and control of

clinical symptoms such as steatorrhea; this is described in the Consensus guidelines

established by the Cystic Fibrosis Foundation (CFF).

1,2,3

Fibrosing colonopathy (FC) is an important safety concern regarding PEP use. Although the

etiology of FC is not known with certainty, FC has been associated with high dose PEP

exposure. Consensus guidelines have been established by the CFF in order to limit the

maximum daily dose; the guidelines recommend that PEP doses not exceed 10,000 lipase

units/kg/day or 2,500 lipase units/kg/meal.

1,2,3

(See also Section 8 and Appendix 1.)

2.2 Regulatory History

2.2.1 Pancreatic Enzyme Products

Approved PEPs: Only two PEPs have been approved under NDA to date:

(1) Cotazym (NDA 20-580): approved in 1996; not currently marketed

(2) Creon (NDA 20-725): approved in April 2009

Thus, there is only one approved PEP, Creon, that is currently commercially available in the

US.

Other PEPs: Other than Creon, PEPs currently available have not undergone formal

evaluation under NDAs for efficacy or safety. PEPs have been available since prior to the

Federal Food, Drug, and Cosmetic Act of 1938; most PEPs have been available since before

Drug Efficacy Study Implementation (DESI; pre-1962).

Federal Register Notices: Over the past many years, the FDA has published a number of

notices in the Federal Register (FR) with the aim of requiring all marketed PEPs to have

undergone the NDA application and review process. This is largely to address variations in

formulation, dosage, and manufacturing processes, both between different PEPs and within

individual PEP brands. Recent FR notices for PEPs are summarized in the table below; a

more complete history is provided in the review by Dr. Anne Pariser dated June 16, 2008.

Borowitz DS, Baker RD, Stallings V. Consensus Report on Nutrition for Pediatric Patients with Cystic

Fibrosis. J Pediatric Gastroenterology and Nutrition. 2002 Sep; 35: 246-259.

Borowitz, DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic

fibrosis in the context of fibrosing colonopathy, J Pediatrics 1995; 127: 681-684.

FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing

colonopathy in children with cystic fibrosis. NEJM 1997; 336: 1283-1289.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

Table 1. Recent Federal Register Notices for Pancreatic Enzyme Products

Year Federal Register Notices

April 1995 Notice of Final Rule: All PEPs must obtain FDA approval under NDA in order to

remain on the market.

April 2004 Notice of Requirement for NDA Approval: All PEPs must obtain NDA approval

within the next four years (deadline April 28, 2008)

October 2007 Notice of Extension: FDA would use enforcement discretion for the PEPs. In order

to continue marketing their products, manufacturers must have:

 open IND by April 28, 2008,

 NDA submitted by April 28, 2009, and

 approved NDA by April 28, 2010.

Above is summarized from Anne Pariser’s CDTL review dated June 16, 2008.

PEP Guidance: It should also be noted that the draft PEP guidance was published in 2004,

and the final PEP Guidance was published in 2006 (Guidance for Industry: Exocrine

Pancreatic Insufficiency Drug Products – Submitting NDAs).

REMS for Creon: A Risk Evaluation and Mitigation System (REMS) was implemented for

Creon for two reasons:

(1) Risk of Fibrosing Colonopathy: To address the concern that the risk of FC may be

increased with high dose exposure to PEPs, a Medication Guide that informs patients of

the risk of FC is part of the REMS for Creon. (See also Section 2.1 and Appendix 1.)

(2) Risk of Transmission of Viral Disease to Patients: There is a concern that because Creon

and other PEPS are porcine-derived products, there may be a risk of porcine viruses

being transmitted to humans although no such case has been documented, and there are

procedures in place to minimize this risk (e.g., certificates of health of animals,

acceptance criteria, viral load testing, viral inactivation studies, and surveillance for

animal diseases). This was also the subject of an Anti-Viral Advisory Committee that

took place on December 2, 2008 for Creon; the Committee generally agreed that

physicians and patients should be informed of the theoretical risk of viral transmission

but the overall risk/benefit profile should not be considered unfavorable so as to preclude

patients from receiving the drug.

4,5

To address the concern about the theoretical risk of

viral transmission, a Medication Guide that informs patients of the theoretical risk of viral

transmission is part of the REMS for Creon. (See also Drug Product and Drug Substance

Reviews.)

Antiviral Drugs Advisory Committee (December 2, 2008);

<http://www.fda.gov/ohrms/dockets/ac/cder08 html#AntiviralDrugs>

Ku, Joanna. CDTL Review of NDA 20-725, April 30, 2009.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

2.2.2 Regulatory History of Zenpep

The table below summarizes the regulatory activity of Zenpep for EPI; a more complete

summary of the period before the Approvable Action is provided in the review by Dr. Anne

Pariser dated June 16, 2008.

Table 2. Pertinent Regulatory History of Zenpep

Date Action

November 2005 Original IND submission

January 2007 Fast Track Designation

December 2007 NDA 22-210 submitted for Zenpep

June 2008 Approvable Action

July 2008

Meeting with the Sponsor to discuss items in the Division’s Approvable Letter

December 2008*

Class II Resubmission – Complete Response to Approvable Letter

*Response to Approvable Letter submitted in September 2008 deemed incomplete due to Item #5 (Nordmark DMF) deficiency

History prior to approvable action summarized from Anne Pariser’s CDTL review dated June 16, 2008.

Review documents from the previous review cycle that were relied on by this reviewer are

the following:

¾ Cross Discipline Team Leader Review by Anne Pariser, dated June 16, 2008

¾ Clinical Review by Marjorie Dannis, dated June 15, 2008

¾ Statistical Review by Freda Cooner, dated June 9, 2008

Correspondence from the previous review cycle that was cited by this reviewer consisted of

the following:

¾ Approvable Letter sent to Eurand Pharmaceuticals, Inc. dated June 16, 2008

¾ Letter sent to Nordmark Arzneimittel GmbH & Company, KG dated June 13, 2008

(Master File #7090)

2.3 Current Submission

The NDA resubmission was dated December 22, 2008, and it was received on December 23,

2008. It was classified as a six-month resubmission with a PDUFA deadline of June 23,

2009; because of a major amendment received on June 15, 2009, the PDUFA date was

extended to September 23, 2009.

It should be noted that during the current review cycle, information became available that the

Applicant was continuing to market another pancrelipase product “in association with IND

70,563 and NDA 22-210.” Complete safety information was required to be submitted for the

unbranded pancrelipase product; this was received on June 15, 2009 and constituted a major

amendment that led to the three-month extension of the PDUFA date. (See Clinical Review

of Safety Update by Marjorie Dannis.)

No Advisory Committee meeting was convened to discuss this application.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

The relevant review disciplines for this review cycle have all written review documents. The

primary review documents relied upon for the current review cycle are the following:

¾ Clinical Review of Safety Update by Marjorie Dannis, dated August 12, 2009

¾ Clinical Pharmacology Review by Tien-Mien Chen, dated August 17, 2009

¾ DTP Reviews of CMC by Howard Anderson:

 Drug Product Review, dated August 18, 2009

 Drug Substance Review (review of DMF), dated August 18, 2009

¾ DMEPA Reviews by Deveonne Hamilton-Stokes:

 Proprietary Name Review, dated July 30, 2009

 Labeling Review, dated May 5, 2009

 Proprietary Name Review, dated March 6, 2009

¾ DRISK Reviews:

 Proposed REMS Review by Jessica Diaz, dated July 22, 2009

 Patient Labeling and Medication Guide Review by Robin Duer, dated July 19, 2009

¾ DTP Carton and Container Label Review by Kimberly Rains, dated June 5, 2009

¾ DDMAC Labeling Review by Shefali Doshi, dated June 15, 2009

¾ SEALD Labeling Review by Jeanne Delasko, dated June 11, 2009

The reviews should be consulted for more specific details of the application. The reader is

also referred to the CDTL Review dated June 16, 2008, for the initial review cycle, as well as

to the primary review documents from that cycle.

This memorandum summarizes selected information from the review documents, with

primary emphasis on the issues to be resolved in the current review cycle.

3. CMC

The reader is referred to the CDTL Review by Anne Pariser dated June 16, 2008, and the

Drug Product and Drug Safety Reviews by Howard Anderson dated August 18, 2009 for

complete information.

Overview of Drug Substance (DS): The DS is manufactured by Nordmark, the Drug Master

File (DMF) holder (DMF #7090); the DMF has been cross referenced by Eurand in NDA 22-

210. DS is derived from porcine pancreas glands harvested from pigs raised for consumption

as food. The glands then undergo a

The resulting pancrelipase DS is to be used

for manufacture of DP.

Overview of Virology: Given the source of the material, the possibility of contamination of

the starting material with viruses relevant to swine has to be considered. The viruses known

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

to be present in swine include enveloped, non-enveloped, and emerging viruses listed and

considered in detail in the virology review.

The viral clearance studies include the

selection of model viruses for viral clearance and validation.

Overview of Drug Product (DP): The DP is manufactured by Eurand in a process that entails

Zenpep capsules contain 5,000, 10,000, 15,000 and 20,000 USP units (U)

lipase. The 10,000, 15,000, and 20,000 U capsules contain identical pancrelipase formulated

beads; the 10,000, 15,000, and 20,000 U capsules contain enteric-coated cylindrical mini-

tablets having a diameter of mm and a thickness of 2.2 mm. The 5,000 U capsule beads

(“small coated beads”) are prepared with approximately dose proportional pancrelipase

excipients; the 5,000 U capsules contain slightly smaller mini-tablets having a diameter of

mm and a thickness of mm. The smaller size beads in the 5,000 U strength capsules

offer the potential advantage of administration to young children by sprinkling the beads

onto food. Stability studies with small beads mixed in foods (e.g., applesauce, pudding)

support the use of various foods to administer the small beads (stability for up to 60

minutes). (See Section 5 Clinical Pharmacology.)

Packaging: The capsules are packaged in amber glass bottles. Each bottle contains a

desiccant package. Zenpep is presented in four strengths, based on the lipase activity

content: 5,000, 10,000, 15,000, and 20,000 USP units.

3.1 Initial Review Cycle

In the initial review cycle, the Drug Product review and Drug Substance review was

conducted by Howard Anderson, the Virology review was conducted by Ennan Guan, and

the Microbiology review was conducted by Stephen Langille. Each of these reviews was

summarized in the CDTL review by Anne Pariser. (Please refer to the CDTL review, and

each of the individual reviews for more information.)

An Approvable (AE) action was recommended from the Drug Substance, Virology, and Drug

Product reviews; an Approval (AP) action was recommended from the Microbiology

Review.

The deficiencies identified by the Virology, Drug Substance, and Drug Product Reviewers

are summarized below.

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

Viral DS Issues

The overall assessment of the virology reviewer was that although the manufacturing process

may provide for an acceptable capacity for viral inactivation of enveloped viruses and

inadequate viral inactivation for non-enveloped viruses, without additional data (e.g., assay

validation characteristics), the results are not assured. Infectivity testing by cell-based assays

for non-enveloped viruses was also performed. Using these assays, Nordmark showed that

negative infectivity results were observed for all viruses tested, except for PPV, PCV1, and

PCV2. HEV was not detected, but DTP did not feel the results of this test were reliable.

DTP’s assessment of Nordmark’s routine viral testing plan, which plans to routinely test for a

limited number of viruses (PPV, HEV and PEV9) was that the plan is inadequate, and did not

sufficiently address risk. DTP recommended that the testing plan include routine testing of all

viruses thought to have the capacity to infect humans, to routinely test infectivity of PCV 1

and 2, and to address risk mitigation for emerging viruses, animal disease surveillance, and

sanitizing procedures for equipment.

Deficiency items for viral issues that were sent to Nordmark were related to (see final

wording of Items #1 to #5 in letter to Nordmark in Appendix 2): (1) risk mitigation for

adventitious agents; (2) viral inactivation studies; (3) validation of PCR tests; (4) validation

of viral infectivity assays; and (5) specifications for adventitious agents.

Non-Viral DS Issues

The DS reviewer noted that characterization of the enzymes contained in the DS, including

assays for amylase, lipase, protease (e.g., for a number of individual proteases, such as

was performed. Detailed descriptions and

validation reports for the analytical methods and enzyme assays used also were provided.

The overall findings of the DS reviewer were that there were a number of deficiencies

identified for the DS, including deficiencies in DS manufacturing and controls.

Deficiency items for non-viral DS issues that were sent to Nordmark were related to (see

final wording of Items #6 to #18 in letter to Nordmark in Appendix 2): (6) USP lipase,

amylase, and protease reference standards; (7) specification for total starting gland weight;

(8) plans to re-examine the production process; (9) rejected batches may not be reworked or

reprocessed; (10) (11) release specifications; (12)

HPLC assay validation; (13) specification for water content for release testing: (14)

specification for DS release; (15) demonstration of predicted lipase activity; (16) olive oil

qualification; (17) DS label; and (18) storage conditions and expiration date.

DP Issues

The DP reviewer noted that characterization of physicochemical and biological properties of

lipase, protease, and amylase activities have been carried out on clinical trial lots of DS and

DP. Validation of analytical methods has been provided, and in general, validation is

acceptable and data are presented to support that enzyme reactions are linear with respect to

time and specific activity is measured. Spiking DS with excipients demonstrate that

excipients do not affect the performance of enzyme activity assays; however, further

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

information is required for the lipase assay. Stability data to support 18 months of product

storage are also provided. The overall findings of the DP reviewer were that there were a

number of deficiencies identified for the manufacture of DP.

CMC deficiencies in the AE letter were related to (see final AE Letter wording in Appendix

3): (1) process validation; (2) enteric coating; (3) stability data; (4) storage conditions; (5)

drug substance (separate letter with 18 items sent to the DMF holder; included viral issues);

(6) olive oil qualification; (7) drug product acceptance criteria; (8) RP-HPLC assay

validation; (9) qualification of the reference standard; and (10) USP lipase reference standard

used.

3.2 Current Review Cycle

In the current review cycle, both the reviews of Drug Product and Drug Substance were

conducted by Howard Anderson. (The reader is referred to the Drug Substance Review

dated August 18, 2009, and the Drug Product Review dated August 18, 2009, for complete

information.)

A review by the Microbiology discipline was not conducted during the current cycle because

the microbiology reviewer recommended an Approval Action in the first cycle. A separate

review by the Virology discipline was not conducted in the current review cycle; virology

issues are included in the review of Drug Substance.

Viral DS Issues

The DS reviewer noted that deficiencies exist, but do not preclude approval of the application

since these can be addressed as postmarketing commitments (PMC’s). (See Drug Substance

Review by Howard Anderson for complete information.)

A summary of Items #1 to #5 in the letter to Nordmark, and a summary of the DS reviewer’s

assessment of the adequacy of the manufacturer’s response is presented below.

(1) Risk mitigation plan for adventitious agents. Each of the parts of this item was

adequately addressed: (a) The plan for disease surveillance includes a provision that

thus allowing sufficient time to prevent the

release of potentially contaminated glands. (b)

(d) It was confirmed that the porcine

glands are generally not considered food items, but are derived from animals fit for

human consumption. (e) The manufacturer stated that according to EU regulations,

imported animals from Canada or the US must be accompanied by a health certificate

(documenting that the animals remained in the territory since birth or at least three

months before slaughter), and importation of living pigs is restricted to a limited number

of countries (Canada, Switzerland, Chile, Iceland, and New Zealand); the manufacturer

also noted that importation of living pigs for slaughtering is not a common event. The

response was deemed adequate by the DS reviewer. The DS reviewer noted that on

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

inspection, Nordmark indicated that Eurand specifies that pancreatic glands be obtained

only from swine raised in the US or Canada. (f) Details of the gland qualification

program were provided, and were deemed adequate by the DS reviewer.

(2) Viral inactivation studies. Each of the parts of this item was adequately addressed: (a)

The manufacturer provided results of viral inactivation studies using two independent

experiments as requested. (b) The manufacturer was requested to demonstrate consistent

results from FCV (Feline Calcivirus) clearance studies; FCV is a model of Hepatitis E

Virus (HEV), and HEV is of concern since it is a porcine virus that has been shown to

infect humans. The manufacturing process does not demonstrate an ability to remove

FCV; thus there is a potential risk that product could be contaminated with HEV.

However, because Nordmark implemented a PCR method to test for HEV and will reject

lots if HEV is present, the response is acceptable. (c) The DS reviewer determined that

there were appropriate controls to account for the potential cytotoxic effect of the PEP

test article on cells and the potential interference of the PEP test article on the ability to

detect virus. (d) The manufacturer demonstrated that the viral inactivation observed could

(e) The manufacturer described the procedures used for

the evaluation of the

(3) Validation Characteristics of PCR tests. A PMC is recommended; the DS reviewer

recommends that Nordmark should increase the sensitivity of the viral PCR assays for

DS release testing as a PMC. The DS reviewer notes that critical validation parameters

(e.g., sensitivity, linearity, precision, and recovery) of the PCR tests to detect EMCV,

HEV, PEV9, Reo1/3, Rota A, Flu A, VSV-IND, and VSV-NJ genome equivalents were

provided. The DS reviewer further notes that the infectious assay sensitivity is equivalent

to that of Creon manufactured by Solvay.

(4) Validation of Viral Infectivity Assays. This item has been adequately addressed. The DS

reviewer notes that critical validation parameters (e.g., specificity, robustness, limit of

detection) were provided for infectious assays for PPV and PCV2.

(5) Specifications for Adventitious Agents. Four PMC’s are recommended; the DS reviewer

determined that four parts of this item (a, b, d, and e) were not adequately addressed, but

did not preclude approval since each could be addressed as a PMC: (a) The DS reviewer

determined that PPV specification could be a PMC, and recommended that PCV2

specification also be included with that PMC. (b) Regarding the revised viral testing plan

that includes monitoring for EMCV, Reovirus, and Rotavirus, a validated PCR method

will be used to test for each of these viruses; however, the DS reviewer recommends that

improvement of assay sensitivity be done as a PMC. (d) Regarding specification for

infectious PCV 1 and PCV 2, an assay for PCV1 infectivity is not available, but an assay

for PCV2 infectivity was recently validated; the DS reviewer recommends that

development of an assay for PCV1 infectivity, and establishing specification for the PCV

2 assay be done as PMC’s. (e) Regarding specification for enveloped viruses, Nordmark

has developed a genome equivalent assay for the VSV and Influenza virus for routine

testing of each lot; the DS reviewer recommends that as a PMC, Nordmark monitor the

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

incoming glands to estimate the potential starting levels for the enveloped viruses. The

DS reviewer determined that the remaining part (c) of this item was adequately

addressed: (c) Because PPV genome equivalents measurements are not correlated with

infectivity, the manufacturer eliminated this measurement.

Non-Viral DS Issues

The DS reviewer noted that a deficiency exists, but it does not preclude approval of the

application since it can be addressed as a PMC. (See Drug Substance Review by Howard

Anderson for complete information.)

A summary of Items #6 to #18 in the letter to Nordmark, and a summary of the DS

reviewer’s assessment of the adequacy of the manufacturer’s response is presented below.

(6) USP lipase, amylase, and protease reference standards. Each of the parts of this item

was adequately addressed: (a) Regarding development of an internal reference standard

that reflects the commercial manufacturing process, a lipase assay internal reference

standard was created using the Nordmark manufacturing process; it will be used to

qualify future USP lipase standards. The DS reviewer determined that the changes

made to the reference standard qualification represent an improvement and are

acceptable. (b) Regarding the qualification program, the identity acceptance criteria for

number of peaks and peak area has been tightened and is consistent with the acceptance

criteria used for lot release. (c) Details of storage conditions and expiration dating for

reference standards were provided.

(7) Starting gland weight: Specification for total starting gland weight used for each

manufacturing run was provided, and the response is adequate.

(8) Plans to re-examine the production process: The data in the DMF update supports the

consistency of the Nordmark pancrelipase manufacturing process; thus, the response to

this request is adequate.

(9)

(10)

(11)

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

(12) HPLC assay validation: Regarding the request to determine how much protein is

retained on the column as part of the RP-HPLC assay validation, the manufacturer

clarified that most of the pancrelipase material is not retained on the column thus

supporting the use of this test method for identity and impurity analysis.

(13) Specification for water content for release testing: The manufacturer was requested to

establish a specification for water content for DS release and stability testing. The

response is adequate as the current test method provides an accurate measurement of

water content in the active pharmaceutical ingredient (API).

(14)

(15) Demonstration of predicted lipase activity

The response is adequate as Nordmark has performed the requested characterization

studies to demonstrate that lipase-inhibitory compounds are not present in the API.

(16) Olive oil qualification: The manufacturer was requested to provide sufficient

information to evaluate qualification results for olive oil testing, and to establish

specifications for critical olive oil components. The response is adequate as the

requested details of the qualification program have now been included in the DMF and

are identical to the European Pharmacopoeia.

(17) DS label: A PMC is recommended. The manufacturer was requested to provide a copy

of the pancrelipase drug substance label. The label was provided, but there was no

expiration date on the DS label; the DS reviewer recommends that this be addressed as

a PMC.

(18) Storage conditions and expiration date: The manufacturer was requested to clarify the

storage conditions and expiration date, and how it will be ensured that the DS is

transported under appropriate conditions. Data were provided to support stability when

subjected to freeze thaw conditions and when stored at 40

C/75% RH for 6 months.

Data were also provided to support storage of the DS at 25

C/60% RH for three years.

On the April 2009, cGMP inspection of the Nordmark facility the company informed

the DS reviewer that Eurand is responsible for ensuring that the pancrelipase is shipped

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

under appropriate conditions. The DS reviewer concluded that the response is

adequate.

DP Issues

The DP reviewer noted that a deficiency exists, but it does not preclude approval of the

application since it can be addressed as a PMC. (See Drug Product Review by Howard

Anderson for complete information.)

A summary of Items #1 to #10 in the AE letter to Eurand, and a summary of the DP

reviewer’s assessment of the adequacy of the Applicant’s response is presented below.

(1) Process validation: The Applicant was requested to provide a summary of the process

validation program. The response is adequate as the validation data support the

Applicant’s claim that production of the drug product at commercial scale is validated.

(2) Enteric coating:

Thus, concerns regarding this coating have been

adequately addressed.

(3) Stability data: The Applicant has submitted stability data to support the proposed expiry

of 30 months. Thus, the response is adequate.

(4) Storage conditions: Data was submitted to support temperature excursions that may

occur during transport and storage. The Applicant’s proposed labeling language was

deemed acceptable by the DP reviewer: “Exposure of the product to excessive heat

should be avoided. Brief exposure to temperatures up to 35

C (95

F) does not

adversely affect the product.”

(5) Drug substance: The Nordmark DMF contained deficiencies; a separate letter was sent

to Nordmark. This is discussed in the Viral DS Issues and Non-Viral DS Issues

sections above.

(6) Olive oil qualification: The Applicant was requested to provide information to evaluate

qualification results for olive oil testing, and to establish specifications for critical olive

oil components. This was adequately addressed.

(7) Drug product acceptance criteria: A PMC is recommended. The DP reviewer

determined that one part of this item was not adequately addressed, but did not preclude

approval since it could be addressed as a PMC: (a) The DP reviewer noted that

acceptance criteria for protease and amylase activity have been tightened slightly, but

should be further adjusted and tightened as part of a PMC. The DP reviewer

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

determined that the remaining parts of this item were adequately addressed: (b)

specifications for drug product peaks in the RP-HPLC assay; (c) release specification

for phthalic acid for each of the dosage strength formulations; (d) acceptance criteria

for determining content uniformity; and (e) specification for water content in the

product.

(8) RP-HPLC assay validation: The Applicant has adequately addressed the concern that

material might be excessively retained on the column.

(9) Qualification of the reference standard: The DP reviewer determined that the reference

standard has an appropriate qualification program, and is manufactured by a process

identical to that of the commercial product; thus, this request has been adequately

addressed.

(10) USP lipase reference standard used: A particular batch had two different lipase specific

activities depending on the reference standard used; the Applicant was requested to

develop and implement a method to ensure accurate and consistent lipase activity for

the reference standard. The DP reviewer determined that Eurand has adequately

responded to this request. The DP reviewer noted that at the present time an assay to

more accurately determine lipase activity is being developed, and acknowledged that to

develop this assay will require more time and is a challenge faced by the entire

pancrelipase industry.

3.3 Final Recommendation

An Approval Action is the final recommendation by CMC.

The DP Review states the following: “The data submitted in this application support the

conclusion that the manufacture of pancrelipase is controlled, and leads to a product that is

consistent and potent. The conditions used in manufacturing have been validated, and a

consistent product is produced by the process. It is recommended that this product be

approved for human use (under conditions specified in the package insert).”

The DP Review also notes the following: “Although some lots of pancrelipase have been

shown to contain infectious porcine parvovirus (PPV), the risk that PPV can cross species

and transmit diseases to humans is minimal, and is outweighed by the clinical benefit

provided by pancrelipase.”

The DP and DS Reviews note that there are deficiencies identified in the NDA and in the

DMF but these do not preclude approval of this application since these can be addressed as

PMC’s. The PMC’s concern the drug substance label, improving viral detection assays and

surveillance strategies during manufacturing of the drug substance, and tightening acceptance

criteria for the drug product amylase and protease potency assays. (See Section 13.6

Postmarketing Commitments of this review.)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

4. Nonclinical Pharmacology/Toxicology

4.1 Initial Review Cycle

Nonclinical pharmacology/toxicology data were reviewed by the Nonclinical

Pharmacology/Toxicology reviewer, Ke Zhang, and summarized in the CDTL review by

Anne Pariser. (Please refer to each of those reviews for more information.)

Per the Exocrine Pancreatic Insufficiency Drug Products Guidance

, given the long history of

clinical use with the PEPs, the performance of new animal pharmacology studies with the

active ingredient (pancrelipase) is not needed to support the Zenpep clinical development

program. However, toxicology studies are needed if the excipients in the Zenpep DP are not

classified as GRAS, and the toxicology program for the excipients should supply data from

long-term studies in both rodent and non-rodent mammalian species, plus standard

reproductive toxicity and genotoxicity information. Consistent with the Guidance, no new

pharmacology or toxicology studies were conducted with Zenpep and no new non-clinical

studies were submitted in the NDA submission. The non-clinical information provided by

the Applicant in the submission was from the published literature for the excipients in the

clinical formulation of Zenpep.

Dr. Zhang notes that the Applicant also submitted an IND (70,563) with Zenpep on

November 11, 2005, and based on the pharmacology review of this IND, all excipients in the

clinical formulation of Zenpep are present in FDA-approved oral drug products. The

estimated daily intake of these excipients is less than the amounts present in the FDA-

approved products except for three excipients: hypromellose phthalate

, triethyl citrate and hypromellose

if 25 capsules are consumed daily. These excipients are present in higher

amounts than the allowable levels in the FDA-approved products for a single-dose, which are

hypromellose phthalate 302 mg, triethyl citrate 20 mg, and hypromellose 480 mg.

The Applicant did not provide the maximum daily allowable levels for these excipients in the

original NDA submission. The Division requested in the 74-day letter to the Applicant (in

the initial review cycle) that the maximum daily allowable levels in the FDA-approved

products for hypromellose phthalate, triethyl citrate, and hypromellose be provided, and that

the Applicant justify the safety of these excipients by published literature or by supporting

toxicology studies. The requested information was provided, and was deemed acceptable by

Dr. Zhang (see Appendix 4).

Dr. Zhang’s overall conclusion from the non-clinical review of the information submitted in

the NDA was that approval of the Zenpep NDA is recommended. Dr. Zhang additionally

recommended that the proposed labeling be revised to include the following:

• Wording in the Pregnancy section be revised to: Category C. “Animal reproduction

studies have not been conducted with Zentase. It is not known whether Zentase capsules

U.S. Department of Health and Human Services, Food and Drug Administration. Center for Drug Evaluation and

Research (CDER). “Guidance for Industry. Exocrine Pancreatic Insufficiency Drug Products—Submitting NDAs.”

<http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071651.pdf>

April 2006.

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

can cause fetal harm when administered to a pregnant woman or can affect reproduction

capacity. Zentase capsules should be given to a pregnant woman only if clearly

needed.”

• In the Carcinogenesis, Mutagenesis and Impairment of Fertility section, the paragraph

referring to should be removed.

Since Zenpep was not recommended for Approval during the initial review cycle, the

proposed labeling changes above were not negotiated with the Applicant.

4.2 Current Review Cycle

There were no new nonclinical pharmacology/toxicology data in the resubmission, and no

additional review of nonclinical data was performed in this review cycle.

The recommendations for labeling revisions from the previous cycle were negotiated with the

Applicant during the current review cycle. The labeling revisions included changes to the

Pregnancy section and the Carcinogenesis, Mutagenesis and Impairment of Fertility section.

4.3 Final Recommendation

An Approval Action is the final recommendation by the Nonclinical Pharmacology/

Toxicology discipline.

5. Clinical Pharmacology/Biopharmaceutics

5.1 Initial Review Cycle

Clinical pharmacology data were reviewed by the Clinical Pharmacology reviewer, Tien-

Mien Chen, and summarized in the CDTL review by Anne Pariser. (Please refer to each of

those reviews for more information.)

The studies reviewed by Dr. Chen and his conclusions are described below:

• In vivo intubation study (PR-001; BA study): This was a randomized open-label single-

treatment crossover study that evaluated the bioavailability of Zenpep in patients with

chronic pancreatitis (CP) and EPI in gastric and duodenal aspirates under fed conditions.

A single fixed dose of 75,000 USP lipase units (about 1,100 U/kg) was administered. The

study was not deemed to be acceptable due to questions about the reliability of the data,

unclear methodology for total lipase recovery from duodenal aspirations, small size of the

study and high variability of the results, enrollment of patients with high baseline lipase

levels, and the lack of a specific assay method for exogenous pancreatic lipase.

• In vitro stability study (Stability study): This study was performed to evaluate the

influence of the contact of different common types of baby foods on “gastroresistance” of

Zenpep capsules. The study was conducted using the contents of 5,000 U capsules, since

this strength is specifically intended for administration to infants and young children, and

is likely to be administered after mixing in soft foods. The results from this study showed

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

acceptable stability data for Zenpep content when mixed with ten types of food (pH<5.0)

for 60 minutes, such as commercial preparations of applesauce, bananas, pears, pudding,

or yogurt. It was noted that the in vitro stability data for two of the three batches of

Zenpep capsules provided in this NDA were identical, and it was not clear if there were

errors in the dataset. An information request for clarification sent to the Applicant had not

been responded to by the end of the review cycle.

Dr. Chen stated that the concern with the in vitro stability data is an Approvability issue and

was included as Item #11 in the Approvable Letter (see Appendix 3). The other comments

regarding the BA study were not deemed to be Approvability issues, and could be conveyed

to the Applicant in a separate letter.

5.2 Current Review Cycle

The reader is referred to the Clinical Pharmacology Review by Tien-Mien Chen dated

August 17, 2009, for complete information.

The studies reviewed by Dr. Chen and his conclusions are described below:

• In vivo intubation study (PR-001; BA study): After the submission of the original NDA

on 12/14/07, the sponsor continued to enroll patients to study PR-001. The amended

study report was submitted on 01/09/09, which included a total of 11 evaluable patients

as judged by the sponsor. However, two of the 11 patients had negative values in the

recovery of lipase due to high endogenous lipase levels and should have been excluded

and another two patients had low duodenal pH (<4.0) during the food only study period

which might impact the results. Furthermore, it is uncertain that the same endogenous

lipase levels would occur in the two treatment periods (Ensure Plus with and without

Zenpep), raising the question whether Ensure Plus only can serve as a reliable control for

estimation of Zenpep bioavailability. Therefore, the study results cannot be properly

interpreted. However, as stated before, the bioavailability study is not a required study

for the NDA approval.

• In vitro stability study (Stability study): The Applicant has corrected the errors and has

adequately addressed Item #11 in the Approvable Letter.

5.3 Final Recommendation

An Approval Action is the final recommendation by the Clinical Pharmacology discipline.

6. Clinical Microbiology

Clinical Microbiology considerations do not apply to this application because Zenpep is not

an antimicrobial agent.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

7. Clinical/Statistical- Efficacy

7.1 Initial Review Cycle

The reader is referred to the CDTL Review by Anne Pariser dated June 16, 2008, the Clinical

Review by Marjorie Dannis dated June 15, 2008, and the Statistical Review by Freda Cooner

dated June 9, 2008, for complete information.

The Applicant conducted a single pivotal study (EUR-1008-M) that demonstrated

improvement in fat absorption with Zenpep treatment over placebo. In addition, the

Applicant conducted a supportive study (EUR-1009-M). See table below.

Table 3. Pivotal Study and Supportive Study

Study Study No. No.

Sites

No. Pts

Enrolled Design Primary Endpoint

Pivotal

Study EUR-1008-M 12 34

Randomized,

multicenter, double-

blind, placebo-

controlled, 2-

treatment, crossover

study

To compare the % coefficient of fat

absorption* (%CFA) during oral

administration of Zenpep or

placebo in CF patients with EPI,

ages seven to adult

Supportive

Study EUR-1009-M 10 19

Multicenter, non-

randomized, open-

label, multiple-dose,

single-treatment

study

To compare the responder rate and

fecal fat excretion in CF patients

with EPI before (while on prior

PEP) and after administration of

Zenpep in CF patients with EPI,

ages one to six years

* %CFA= {[Fat intake (g/day) – Fat excretion (g/day)] / Fat intake (g/day)} X 100

* %CFA is determined from a 72-hour stool collection while the patient is consuming a high-fat diet

Table above is modified form Page 15 of Clinical Review by Marjorie Dannis.

In the pivotal study (EUR-1008-M), 34 patients ages seven to 23 years (mean age 15.5 years)

were randomized to receive Zenpep or matching placebo for six to seven days of treatment,

followed by crossover to the alternate treatment for an additional six to seven days. The

mean dose during the controlled treatment periods ranged from a mean dose of 3,900 lipase

units per kilogram per day to 5,700 lipase units per kilogram per day. The mean CFA for

patients during placebo treatment was 63%, and during Zenpep treatment was 88%. The

mean difference in CFA on Zenpep as compared to placebo was 25%, which was a

statistically significant difference (p<0.001; 95% CI [-32,-19]). See table below.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

Table 4. ANOVA Model Results of CFA (%) [Study EUR-1008-M]

Zenpep (N=32) Placebo (N=31)

Mean (SEM) 88.3 (1.4) 62.7 (3.4)

SD 7.9 19.1

Median 89.8 65.8

Min, Max 62.9, 98.7 28.7, 95.5

LS means (SEM) 88.3 (2.6) 62.8 (2.66)

Difference between Zenpep and Placebo -25.5

95% CI (-31.7, -19.3)

p value <0.001

Table above is modified from Page 25 of the CDTL Review by Anne Pariser.

In the supportive study (EUR-1009-M), 19 patients, ages 1.2 to 6.4 years (mean age 3.9

years) were transitioned to Zenpep from their usual PEP treatment without a wash-out period.

After a 4-14 days screening period on the current PEP, patients received Zenpep at

individually titrated doses ranging between 2,300 and 10,000 lipase units per kg body weight

per day, with a mean of approximately 5,000 lipase units per kg body weight per day for 14

days. The results show that for the cut-point of fecal fat <30% selected by the Applicant as

defining patients without steatorrhea, at Screening 14 of 19 patients had a fecal fat <30%, at

Visit 3 13 of 19 patients had a fecal fat <30%, and at End-of-Study 13 of 18 patients had a

fecal fat <30%, and throughout the study, 16 of 19 patients had a fecal fat <30% at one or

more study visits. Thus, the majority of patients were without steatorrhea during the study,

whether on their usual PEP treatment or after transition to treatment with Zenpep.

There is no previous clinical experience with the formulation of Zenpep that was studied in

the pivotal and supportive studies; however, there is considerable clinical experience with

similar formulations of porcine-derived PEPs.

7.2 Current Review Cycle

No additional efficacy data was submitted in the current review cycle.

7.3 Final Recommendation

An Approval Action is the final recommendation from a Clinical/Statistical Efficacy

standpoint.

8. Safety

The reader is referred to the CDTL Review by Anne Pariser dated June 16, 2008, the Clinical

Review by Marjorie Dannis dated June 15, 2008, and the Clinical Review of Safety Update

by Marjorie Dannis, dated August 12, 2009 for complete information.

There is extensive clinical experience with porcine-derived PEPs in patients, as these have

been in clinical use since prior to 1938. The AE profile of PEPs has been well described in

the clinical literature; the long-term safety experience has demonstrated that the PEPs are

relatively safe.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

The PEP Guidance states that it is not necessary to conduct long-term safety evaluations of

PEPs in support of PEP NDAs; this is largely because of the long and extensive safety

experience with PEPs. The PEP Guidance however does state that a short-term safety

evaluation is required during the clinical efficacy studies. Since PEPs act locally in the

gastrointestinal tract and are not absorbed, the Guidance further recommends that the safety

variables assessed should focus predominantly on the monitoring of clinical signs and

symptoms during these clinical trials.

A key exception to the relative safety of PEPS is fibrosing colonopathy (FC):

¾ Fibrosing Colonopathy: FC is a rare but serious condition that may result in colonic

stricture. Most of the cases of FC have been reported in younger children with CF.

Although the etiology of FC is not known with certainty, FC has been associated with

high dose exposure to PEPs. Consensus guidelines have been established by the Cystic

Fibrosis Foundation (CFF) in order to limit the maximum daily dose; the guidelines

recommend that PEP doses not exceed 10,000 lipase units/kg/day or 2,500 lipase

units/kg/meal.

7,8,9

(See also Appendix 1.) Continued monitoring for fibrosing

colonopathy that is associated with PEP use is likely to best be performed through global

safety surveillance.

Other safety concerns with PEPs are described in the literature, and include the following:

¾ Hyperuricemia/Hyperuricosuria: Hyperuricemia/hyperuricosuria is thought to occur due

to aborption in the gastrointestinal tract of porcine purines; this is particularly of concern

in patients with renal impairment, gout or hyperuricemia.

¾ Hypersensitivity: Hypersensitivity reactions including skin reactions (e.g., pruritus,

urticaria) and respiratory reactions (e.g., dyspnea, wheezing) are thought to occur due to

inhalation of the PEP powder that may occur when the capsules are opened.

¾ Irritation to Oral Mucosa: Disruption of the protective enteric coating, and early release

of the enzymes may lead to the irritation of the oral mucosa as well as loss of enzyme

activity.

The theoretical risk of viral transmission is summarized below:

¾ Theoretical Risk of Viral Transmission: There is a concern that because PEPS are

porcine-derived products, there may be a risk of porcine viruses being transmitted to

humans although no such case has been documented, and there are procedures in place to

minimize this risk (e.g., certificates of health of animals, acceptance criteria, viral load

Borowitz DS, Baker RD, Stallings V. Consensus Report on Nutrition for Pediatric Patients with Cystic

Fibrosis. J Pediatric Gastroenterology and Nutrition. 2002 Sep; 35: 246-259.

Borowitz, DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic

fibrosis in the context of fibrosing colonopathy, J Pediatrics 1995; 127: 681-684.

FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing

colonopathy in children with cystic fibrosis. NEJM 1997; 336: 1283-1289.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

testing, viral inactivation studies, and surveillance for animal diseases). This was also the

subject of an Anti-Viral Advisory Committee that took place on December 2, 2008 for

Creon; the Committee generally agreed that physicians and patients should be informed

of the theoretical risk of viral transmission but the overall risk/benefit profile should not

be considered unfavorable so as to preclude patients from receiving the drug.

10,11

(See

also Section 2.2.1 of this review, and the Drug Product and Drug Substance Reviews.)

8.1 Initial Review Cycle

The reader is referred to the CDTL Review by Anne Pariser dated June 16, 2008, and the

Clinical Review by Marjorie Dannis dated June 15, 2008, for complete information.

In the initial review cycle (which included data from the 120-day safety update to March 30,

2008), the AE profile of Zenpep as described in the individual studies was consistent with the

currently described AE profile of PEPs in the medical literature. In general, AEs tended to

reflect underlying disease, and were most commonly reported in the gastrointestinal (GI) and

respiratory systems. There were no new or noteworthy AEs noted during the initial cycle of

safety review.

8.2 Current Review Cycle

The reader is referred to the Clinical Review of Safety Update by Marjorie Dannis, dated

August 12, 2009 for complete information.

The safety update (to March 30, 2008) had already been reviewed in the previous review

cycle.

During the current review cycle, information became available that the Applicant was

continuing to market a pancrelipase product “in association with IND 70,563 and NDA 22-

210.” Complete safety information was required to be submitted for the unbranded

pancrelipase product; this was received on June 15, 2009.

Dr. Dannis concluded in the Safety Update Review that the limited safety information

submitted appears to be consistent with the known adverse event profile of PEPs. Dr. Dannis

notes that the total US sales of the unbranded pancrelipase product during the reporting

period (January 1, 1999 through June 1, 2009) was almost capsules; patient

exposure to the unbranded pancrelipase product was estimated to be between approximately

911,000 and 2,250,000 patient treatment-months. Overall, 15 case reports of adverse events

were received; 2 of these reports were serious spontaneous reports (one hospitalization and

one pancreatic growth), while 13 of the case reports were non-serious (predominantly

gastrointestinal signs and symptoms and/or lack of efficacy) spontaneous reports. The most

frequently reported adverse events were lack of efficacy (8), followed by diarrhea (4) and

flatulence (2). The remaining cited adverse events were single occurrences.

Antiviral Drugs Advisory Committee (December 2, 2008);

<http://www.fda.gov/ohrms/dockets/ac/cder08 html#AntiviralDrugs>

Ku, Joanna. CDTL Review of NDA 20-725, April 30, 2009.

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

8.3 Final Recommendation

An Approval Action is the final recommendation from a Safety standpoint.

9. Advisory Committee Meeting

This application was not presented to an Advisory Committee.

10. Pediatrics

The application was presented to the Pediatric Research Committee (PeRC) on May 6, 2009;

there were also additional clarifications and discussion with the Division subsequent to the

meeting. The committee recommended the following with the corresponding rationale:

(1) Waiver ages 0-1 month: Necessary studies are impossible or impracticable because

patients are usually not diagnosed before the age of 1 month, so there would not be

enough eligible patients in this age range to study.

(2) Deferral from age >1 month - 12 months: Development of an age-appropriate formulation

is needed.

(3) Completed for ages >12 months - 17 years: Each of the PEPs was unapproved prior to

being submitted under NDA; thus, existing labels for the PEPS not submitted under NDA

are not viewed as valid. One body of evidence (a range of study types using all

formulations of the pancreatic enzymes) was used to create class labeling. As this is new

labeling for each of the PEPs, and because the labels did not previously exist, the studies

needed to fulfill PREA are considered as having been completed.

The clinical review team including this reviewer is in agreement with these

recommendations.

It should be noted that the deferral for patients age > 1 month to 12 months does not require

additional studies; rather, the deferral for this age category is for the development of an age-

appropriate formulation (i.e., a capsule containing 2,000 to 4,000 lipase units). Such a

formulation will allow for dosing to the youngest, lowest weight pediatric patients, including

infants less than 12 months of age who will be administered 2,000 to 4,000 lipase units per

120 mL of formula or per breast-feeding.

In addition, it should be noted that published literature data with PEPs in general, not data

with the particular formulation (i.e., Zenpep) is used to establish that pediatric studies for

ages > 12 months to 17 years have been completed.

A related point that deserves mention is that there is no “extrapolation” of efficacy data from

one age category to another. Rather, the extensive data from studies in the published

literature with a variety of PEP formulations across pediatric age groups constitutes evidence

of efficacy for PEPs in the pediatric population; evidence of efficacy for the particular

formulation (i.e., Zenpep) comes from the randomized double-blind placebo-controlled

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

cross-over study using that formulation (i.e., EUR-1008-M) regardless of whether it was

conducted in a pediatric population, an adult population, or a population that included both

adult and pediatric patients. In effect, EUR-1008-M can be considered to be a “bridging

study” to the existing body of evidence from the literature for a range of pancreatic enzyme

formulations.

The above recommendations are generally consistent with those for Creon. In particular, the

approval letter for Creon reflects a waiver for patients ages 0 to 1 month, and a deferral for

patients age > 1 month to 12 months (for the purpose of the development of an age-

appropriate formulation); it also includes a statement that no additional pediatric studies are

needed.

11. Other Relevant Regulatory Issues

11.1 Lack of QT Evaluation

There was no thorough QT assessment for this product and the clinical studies did not

incorporate collection of ECG data. Zenpep is not systemically absorbed.

11.2 Division of Scientific Investigations (DSI) audits

Initial Review Cycle

In the initial review cycle, site inspections of two clinical sites and the central laboratory

were performed by the Division of Scientific Investigations (DSI) as part of the review of

this NDA submission. The sites inspected were part of the pivotal study EUR-1008-M. That

information is provided in the Clinical Inspection Summary memorandum by Khairy Malek,

M.D., and summarized in the CDTL review by Anne Pariser (see each of those documents

for more detailed information). The site inspections are summarized in the table below.

Table 5. Overview of two sites inspected (Study EUR-1008-M)

Site No. Investigator / Location No. patients enrolled Primary Endpoint Results

Site 105

Steven Boas, M.D.,

Glenview, IL

Six Not available at clinical site (obtained at

Mayo Central Laboratory*)

Site 103

David Schaeffer, M.D.,

Jacksonville, FL

Four Not available at clinical site (obtained at

Mayo Central Laboratory*)

* Inspection of the lab was limited to comparing the lab results for the primary endpoint obtained at the two

clinical sites (103 and 105) with the data reported to the FDA.

Information in the table above is taken from the CTDL review by Anne Pariser.

Review of the data showed that the data in the lab records were the same as the data reported

to the FDA. The overall assessment of the inspector from the inspection of the two clinical

sites and the Mayo Central Laboratory was that the data are reliable and can be used in

support of the NDA.

Current Review Cycle

No additional site inspections were requested in the current review cycle.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

11.3 Drug Shortage

Currently, Creon is the only PEP that is available on the market that has undergone the NDA

review process. There are other PEPs on the market that have not undergone the NDA

review process, but these will not be able to be marketed after April 28, 2010; as per the FR

Notice (see Section 2.2.1), all PEPs must have an open IND by April 28, 2008, an NDA

submitted by April 28, 2009, and an approved NDA by April 28, 2010. Thus, the approval of

Zenpep may help to prevent a drug shortage from developing in the near future (i.e., by April

28, 2010; the time that all marketed PEPs must have an approved NDA).

12. Labeling

12.1 Proprietary name

Initial Review Cycle:

In the initial review cycle, the name “Zentase” was submitted. A review of the trade name

“Zentase” was performed by Deveonne Hamilton-Stokes in the Division of Medication

Errors Prevention (DMEP), Office of Surveillance and Epidemiology (OSE); that review is

summarized in the CDTL review by Anne Pariser. Please see each of those reviews for more

detailed information.

DMEP considered the proposed trade name “Zentase” unacceptable (under 21 CFR

201.10(c)(5)) based on the orthographic similarity of the name and potential for confusion

with two other marketed products Pentasa and Zantac.

A letter was sent to the Applicant during the review cycle (dated March 28, 2008) notifying

the Applicant that the proposed trade name “Zentase” was unacceptable and requesting

submission of two alternative trade names. The Applicant subsequently proposed two new

names “ZenPep” and “Zenase;” the review of those names was still under review at the time

of writing of the CDTL Review of the previous review cycle by Anne Pariser.

Current Review Cycle:

In the current review cycle, the Division of Medication Error Prevention and Analysis

(DMEPA) concluded that the proprietary name of “Zenpep” was acceptable. Please see

DMEPA Proprietary Name Reviews (dated March 6, 2009 and July 30, 2009) by Deveonne

Hamilton-Stokes for complete information.

In the March 6, 2009 Proprietary Name Review, the reviewer concluded that based on the

Proprietary Name Risk Assessment findings, the proposed name, Zenpep, is not

vulnerable to name confusion that could lead to medication errors.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

In the July 30, 2009 Proprietary Name Review, the reviewer conducted a re-assessment of

the proprietary name in response to a notification that NDA 22-210 may be approved within

90 days. The reviewer noted that since the March 6, 2009 review, none of Zenpep’s product

characteristics have changed. The reviewer added that during this re-review one new name

(Zipsor) was identified for its similarity to Zenpep. The reviewer concluded that the results of

the Failure Mode Effects Analysis found that the proposed name, Zenpep, is not vulnerable

to name confusion that could lead to medication errors with Zipsor.

12.2 Division of Drug Marketing, Advertising, and Communications

(DDMAC) Comments

The Division of Drug Marketing, Advertising and Communications (DDMAC) found the

name acceptable from a promotional perspective; an e-mail stating this was sent from Nina

Ton, Safety Regulatory Project Manager OSE/DDMAC on February 17, 2009. This is also

documented in the Tradename review by Deveonne Hamilton-Stokes dated July 30, 2009.

12.3 Physician Labeling / Medication Guide / Carton and Container

Labeling

The Applicant was requested to revise the label and medication guide to be consistent with

the corresponding sections for the other drug in the class that was recently approved, Creon.

In addition to these revisions, additional revisions were negotiated with the Applicant. Many

of these revisions are based on recommendations from the DMEPA Labeling Review, the

DRISK Proposed REMS Review, the DRISK Patient Labeling and Medication Guide

Review, the DTP Carton and Container Label Review, the DDMAC Labeling Review, and

the SEALD Labeling Review. The reader is referred to each of these reviews for complete

information.

The most notable revisions are summarized below:

Physician Labeling:

¾ Administration (Section 2.2 of Label): A statement that capsule contents may be

sprinkled on small amounts of acidic soft food with a pH of ≤ 4.5 was included in this

section based on the results of the in vitro study. Commercially available preparations of

bananas, pears, and applesauce were stated as examples of foods that had a pH of ≤ 4.5

because these particular foods were studied in the in vitro study, and these foods from

different manufacturers were consistently shown to have the pH stated.

¾ Adverse Reactions – Clinical Trials Experience (Section 6.1 of Label): A description of

the adverse reactions in the open-label single-arm study (Study EUR-1009M) which

included patients between the age of 1 and 6 years was included in addition to the

summary of adverse reactions in the double-blind placebo-controlled trial (EUR-1008M)

which included patients between the age of 7 and 23 years.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

¾ Use in Specific Populations – Pediatric Use (Section 8.4 of Label): A brief description of

the results of the open-label single-arm study (Study EUR-1009M) which included

patients between the age of 1 and 6 years was included

¾ Overdosage (Section 10 of Label): Information about one 10-year old patient who was

administered a dose of greater than 10,000 lipase units/kg/day was included.

¾ Clinical Studies (Section 14 of Label): The results of EUR-1009M which included

patients between the age of 1 and 6 years were included in addition to the results of the

double-blind placebo-controlled trial (EUR-1008M) which included patients between the

age of 7 and 23 years.

¾ How Supplied/Storage and Handling (Section 16 of Label): The DP reviewer revised

Section 16 based on data submitted by the Applicant to support temperature excursions

that may occur during transport and storage. The following is stated in this section of the

label:

”Avoid excessive heat. Store at room temperature (68-77°F; 20-25°C), brief

excursions permitted to 15-40°C (59-104°F).”

Medication Guide:

¾ Giving ZENPEP to infants: In order to communicate in more patient-friendly language

the statement in the Administration section (Section 2.2 of the label) about foods that the

contents of the capsules may be sprinkled on (i.e., small amounts of acidic soft food with

a pH of ≤ 4.5 such as commercially available preparations of bananas, pears, and

applesauce), the following is stated in this section of the Medication Guide:

“Open the capsules and sprinkle the contents on a small amount of applesauce,

pureed bananas or pears. These foods should be the kind found in baby food jars

that you buy at the store, or other food recommended by your doctor.”

Carton and Container Labeling:

¾ Unit of Use: The capsules are packaged in bottles containing 100 capsules or 500

capsules; each bottle contains one desiccant. Because of the concern that capsules may

be dispensed without a desiccant, the carton and container labeling was revised to

indicate that the container is a unit of use container; the statement “Pharmacist: Dispense

in original container” was added to the carton and container labeling. This is intended to

communicate to the pharmacist that a specific quantity of the drug product (i.e., the 100

or 500 capsule bottle) is intended to be dispensed without further modification.

(b) (4)

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

13. Recommendations/Risk Benefit Assessment

13.1 Recommended Regulatory Action

All the primary review disciplines recommended the product for approval. This Reviewer

concurs with the approval recommendation.

13.2 Risk Benefit Assessment

The risk and benefit characteristics appear similar to those of already marketed PEPs for

treatment of EPI. The product has a favorable risk/benefit profile.

13.3 Recommendation for Postmarketing Risk Evaluation and Mitigation

Strategy Requirements (REMS)

A REMS is recommended with the goal of informing patients about the following serious

risks associated with the use of Zenpep:

• The risk of fibrosing colonopathy

• The theoretical risk of transmission of porcine viral disease.

The REMS element is the following:

• Medication Guide

It should be noted that the REMS for Zenpep will not include a Communication Plan, or an

Implementation System.

The timetable for submission of assessments will be:

• 1st Assessment: (March 23, 2011) 18 months after NDA approval

• 2nd Assessment: (September 23, 2012) 3 years after NDA approval

• 3rd Assessment: (September 23, 2016) 7 years after NDA approval

A notable item of the REMS for Zenpep is the following:

Unit of Use: The REMS specifies that Zenpep is available in unit of use bottles. The

capsules are packaged in bottles containing 100 capsules or 500 capsules; each bottle

contains one desiccant. Because of the concern that capsules may be dispensed without a

desiccant, the REMS includes a statement that the container is a unit of use container.

This is intended to communicate that a specific quantity of the drug product (i.e., the 100

or 500 capsule bottle) is intended to be dispensed without further modification.

13.4 Recommendation for Postmarketing Required Pediatric Studies

Development of an age appropriate formulation under PREA is recommended, with the

following language for the Approval Letter:

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

REQUIRED PEDIATRIC ASSESSMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications

for new active ingredients, new indications, new dosage forms, new dosing regimens,

or new routes of administration are required to contain an assessment of the safety

and effectiveness of the product for the claimed indication(s) in pediatric patients

unless this requirement is waived, deferred, or inapplicable.

We are waiving the pediatric study requirement for ages birth to 1 month because

necessary studies are impossible or highly impracticable. This is because patients are

not usually diagnosed before the age of 1 month, so there would not be enough

eligible patients in this age range to study.

We note that you have fulfilled the pediatric study requirement for ages 1 year to 18

years for this application. The pediatric requirement for 1 month to 1 year is not

fulfilled due to the lack of an age appropriate formulation.

We are deferring submission of an age appropriate formulation. The status must be

reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the

Federal Food, Drug, and Cosmetic Act. This requirement is listed below.

1. Deferred requirement for development of an age appropriate formulation for

Zenpep (pancrelipase) Delayed-Release Capsules: Develop an age appropriate

formulation to allow for dosing to the youngest, lowest weight pediatric patients,

including infants less than 12 months of age who will be administered 2,000 to

4,000 lipase units per 120 mL of formula or per breast-feeding. Submit a

supplement for an age appropriate formulation by December 31, 2010.

Submit final reports to this NDA. For administrative purposes, all submissions

related to this pediatric postmarketing requirement must be clearly designated

“Required Pediatric Assessments”.

13.5 Recommendation for other Postmarketing Study Requirements

(PMRs)

PMR studies are recommended, with the following language for the Approval Letter:

Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA

to require holders of approved drug and biological product applications to conduct

postmarketing studies and clinical trials for certain purposes, if FDA makes certain

findings required by the statute (section 505(o)(3)(A)).

We have determined that an analysis of spontaneous postmarketing adverse events

reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess the

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

known serious risk of fibrosing colonopathy and the unexpected serious risk of

transmission of viral disease to patients.

Furthermore, the new pharmacovigilance system that FDA is required to establish

under section 505(k)(3) of the FDCA has not yet been established and is not sufficient

to assess these serious risks.

Therefore, based on appropriate scientific data, FDA has determined that you are

required to conduct the following studies:

1. A 10 year, observational study to prospectively evaluate the incidence of fibrosing

colonopathy in patients with cystic fibrosis treated with Zenpep (pancrelipase)

Delayed-Release Capsules in the US and to assess potential risk factors for the

event.

The timetable you submitted on August 19, 2009 states that you will conduct this

study according to the following timetable:

Final Protocol Submission: by July 15, 2010

Study Completion Date: by July 1, 2022

Final Report Submission: by December 31, 2022

2. A 10 year, observational study to prospectively evaluate the risk of transmission

of selected porcine viruses in patients taking Zenpep (pancrelipase) Delayed-

Release Capsules.

The timetable you submitted on August 19, 2009 states that you will conduct this

study according to the following timetable:

Final Protocol Submission: by July 15, 2010

Study Completion Date: by July 1, 2022

Final Report Submission: by December 31, 2022

13.6 Recommendation for Postmarketing Study Commitments (PMCs)

The postmarketing commitments below are recommended:

NDA 22-210 Postmarketing Commitments

(1) Re-evaluate the acceptance criteria for the protease and amylase assays after more

experience is gained with the manufacturing process. After 50 drug product lots are

manufactured, specifications will be reevaluated and adjusted to reflect manufacturing

history and capability.

Final Report Submission: by September 2011

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

DMF 7090 Postmarketing Commitments

(1) Develop and validate an infectious assay for PCV1.

Final Report Submission: by December 2010

(2) Establish lot release specifications for PCV1 for the drug substance.

Final Report Submission: by June 2011

(3) Establish lot release specifications for PPV and PCV2 for the drug substance.

Final Report Submission: by December 2009

(4) Perform additional monitoring of enveloped viral load entering the manufacturing

process. The control program will include the selection of human pathogenic enveloped

viruses for monitoring by qPCR together with an appropriate control strategy.

Final Report Submission: by June 2011

(5) Improve the sensitivity of the qPCR assays used for drug substance release testing in

order to provide adequate assurance that released drug substance will not contain EMCV,

HEV, PEV-9, Reo1/3, Rota, Influenza, VSV-IND, and VSV-NJ viruses. Revise the

assays, and submit assay validation data, together with acceptance criteria.

Final Report Submission: by December 2010

(6) Assess the risk to product quality associated with hokovirus, and submit a control

strategy for mitigating the risk to product quality.

Final Report Submission: by December 2009

(7) Improve the animal surveillance program and the risk assessment evaluation for source

animals to capture new and emerging viral adventitious agents. The proposed program

will include an example using Ebola virus, recently described in pigs from the

Philippines, to illustrate how these programs will be implemented.

Final Report Submission: by December 2009

(8) Assign an expiration date to the pancrelipase drug substance label used for production of

the Zenpep product. An expiration date will be included on the drug substance label by

December 2009.

13.7 Recommended Comments to Applicant

None.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

APPENDIX 1

The CFF Dosing Guidelines (from Borowitz et al., 1995

) are provided below:

Borowitz et al. 2002

states:

Fitzsimmons et al. 1997

states:

Borowitz, DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic

fibrosis in the context of fibrosing colonopathy, J Pediatrics 1995; 127: 681-684.

Borowitz DS, Baker RD, Stallings V. Consensus Report on Nutrition for Pediatric Patients with Cystic

Fibrosis. J Pediatric Gastroenterology and Nutrition. 2002 Sep; 35: 246-259.

FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing

colonopathy in children with cystic fibrosis. NEJM 1997; 336: 1283-1289.

CDTL Memo for NDA 22-210 ● Zenpep (pancrelipase) ● Exocrine Pancreatic Insufficiency ● Eurand

Linked Applications Submission

Type/Number Sponsor Name Drug Name / Subject

-------------------- -------------------- -------------------- ------------------------------------------

NDA 22210 ORIG 1 EURAND

PHARMACEUTICA

LS LTD

ZENTASE

NDA 22210 ORIG 1 EURAND

PHARMACEUTICA

LS LTD

ZENTASE

---------------------------------------------------------------------------------------------------------

This is a representation of an electronic record that was signed

electronically and this page is the manifestation of the electronic

signature.

---------------------------------------------------------------------------------------------------------

/s/

----------------------------------------------------

ANIL K RAJPAL

08/21/2009

MD7090 022210s000crossr

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