other review(s)...on august 19, 2011, emd serono, inc. withdrew nda 022561. on october 11, 2017, the...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

022561Orig1s000

OTHER REVIEW(S)

Department of Health and Human Services Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research

Office of Medical Policy

PATIENT LABELING REVIEW

Date:

March 19, 2019

To:

Billy Dunn, MD Director Division of Neurology Products (DNP)

Through:

LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Marcia Williams, PhD Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP)

From:

Kelly Jackson, PharmD Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Domenic D’Alessandro, PharmD, MBA, CDE Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

Subject: Review of Patient Labeling: Medication Guide (MG)

Drug Name (established name):

MAVENCLAD (cladribine)

Dosage Form and Route:

tablets, for oral use

Application Type/Number:

NDA 022561

Applicant: Merck Serono, Inc.

Reference ID: 4405700Reference ID: 4413345

1 INTRODUCTION On May 31, 2018, Merck Serono, Inc., submitted for the Agency’s review an original 505(b)(1) New Drug Application (NDA) 022561 for MAVENCLAD (cladribine) tablets, for oral use. The Applicant is resubmitting the NDA 022561 for the oral formalution of cladribine (10mg tablets) for the proposed indication of the treatment of patients with relapsing form of multiple sclerosis (RMS). References are made to EMD Serono’s NDA dated May 27, 2010, the Complete Response (CR) letter received February 28, 2011, and the request for withdrawal of NDA 022561 on August 19, 2011. This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of Neurology Products (DNP) on October 12, 2018 and June 20, 2018, respectively, for DMPP and OPDP to review the Applicant’s proposed Medication Guide (MG) for MAVENCLAD (cladribine) tablets, for oral use.

2 MATERIAL REVIEWED

• Draft MAVENCLAD (cladribine) MG received on May 31, 2018, and received by DMPP and OPDP on March 6, 2019.

• Draft MAVENCLAD (cladribine) Prescribing Information (PI) received on May 31, 2018, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on March 6, 2019.

3 REVIEW METHODS

To enhance patient comprehension, materials should be written at a 6th to 8th grade reading level, and have a reading ease score of at least 60%. A reading ease score of 60% corresponds to an 8th grade reading level. Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in collaboration with the American Foundation for the Blind (AFB) published Guidelines for Prescription Labeling and Consumer Medication Information for People with Vision Loss. The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make medical information more accessible for patients with vision loss. In our collaborative review of the MG we:

• simplified wording and clarified concepts where possible

• ensured that the MG is consistent with the Prescribing Information (PI)

• removed unnecessary or redundant information

• ensured that the MG is free of promotional language or suggested revisions to ensure that it is free of promotional language

• ensured that the MG meets the Regulations as specified in 21 CFR 208.20


• ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006)

4 CONCLUSIONS

The MG is acceptable with our recommended changes. 5 RECOMMENDATIONS

• Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence.

• Our collaborative review of the MG is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the MG.

Please let us know if you have any questions.


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AMANPREET K SARAI03/19/2019 10:08:00 AM

MARCIA B WILLIAMS03/19/2019 10:09:34 AM

ALINE M MOUKHTARA03/19/2019 12:45:47 PMSigned for Domenic D’Alessandro

LASHAWN M GRIFFITHS03/19/2019 12:48:16 PM

Signature Page 1 of 1


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****Pre-decisional Agency Information**** Memorandum Date: March 15, 2019 To: Lawrence D. Rodichok, M.D., Clinical Reviewer

Division of Neurology Products (DNP) Sandra Folkendt, PharmD, Regulatory Project Manager, (DNP)

Tracy Peters, Associate Director for Labeling, (DNP) From: Domenic D’Alessandro, PharmD, MBA, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) CC: Aline Moukhtara, RN, MPH, Team Leader, OPDP Subject: OPDP Labeling Comments for MAVENCLAD® (cladribine) tablets, for oral

use NDA: 022561

In response to DNP consult request dated June 20, 2018, OPDP has reviewed the proposed product labeling (PI), Medication Guide, and carton and container labeling for the original NDA submission for MAVENCLAD® (cladribine) tablets, for oral use. PI: OPDP’s comments on the proposed labeling are based on the draft PI received by electronic mail from DNP (Sandra Folkendt) on March 6, 2019, and are provided below. Medication Guide: A combined OPDP and Division of Medical Policy Programs (DMPP) review will be completed, and comments on the proposed Medication Guide will be sent under separate cover.

Carton and Container Labeling: OPDP has reviewed the attached proposed carton and container labeling submitted by the Sponsor to the electronic document room on January 30, 2019, and we do not have any comments. Thank you for your consult. If you have any questions, please contact Domenic D’Alessandro at (301) 796-3316 or [email protected].

FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion

Reference ID: 4404782



DOMENIC G DALESSANDRO03/15/2019 05:42:25 PM



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MEMORANDUM REVIEW OF REVISED LABEL AND LABELING

Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM)

Office of Surveillance and Epidemiology (OSE)Center for Drug Evaluation and Research (CDER)

Date of This Memorandum: February 4, 2019

Requesting Office or Division: Division of Neurology Products (DNP)

Application Type and Number: NDA 022561

Product Name and Strength: Mavenclad (cladribine) tablets10 mg

Applicant/Sponsor Name: EMD Serono, Inc.

FDA Received Date: January 30, 2019

OSE RCM #: 2018-1352-2

DMEPA Safety Evaluator: Briana Rider, PharmD

DMEPA Team Leader: Lolita White, PharmD

1 PURPOSE OF MEMORANDUMDivision of Neurology Products (DNP) requested that we review the revised container labels and carton labeling for Mavenclad (Appendix A) to determine if they are acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling review.a

2 CONCLUSIONThe revised container labels and carton labeling for Mavenclad are acceptable from a medication error perspective. We have no further recommendations at this time.

a Rider B. Label and Labeling Review for Mavenclad (NDA 022561). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2018 DEC 12. RCM No.: 2018-1352-1.




BRIANA B RIDER02/04/2019 01:25:08 PM

LOLITA G WHITE02/04/2019 02:50:38 PM



1

LABEL, LABELING AND PACKAGING REVIEWDivision of Medication Error Prevention and Analysis (DMEPA)

Office of Medication Error Prevention and Risk Management (OMEPRM)Office of Surveillance and Epidemiology (OSE)

Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: November 1, 2018

Requesting Office or Division: Division of Neurology Products (DNP)

Application Type and Number: NDA 022561

Product Name and Strength: Mavenclad (cladribine) tablets10 mg

Product Type: Single Ingredient Product

Rx or OTC: Prescription

Applicant/Sponsor Name: EMD Serono, Inc.

FDA Received Date: May 31, 2018

OSE RCM #: 2018-1352

DMEPA Safety Evaluator: Briana Rider, PharmD

DMEPA Team Leader: Lolita White, PharmD


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1 REASON FOR REVIEW

This review evaluates the proposed labels and labeling and packaging for Mavenclad (cladribine) tablets for areas of vulnerability that could lead to medication errors. The Division of Neurology Products (DNP) requested this review as part of their evaluation of NDA 022561 for Mavenclad.

1.1 REGULATORY HISTORY

EMD Serono, Inc. submitted NDA 022561 on September 30, 2009. The Division of Neurology Products (DNP) subsequently sent a Refuse to File (RTF) communication to EMD Serono, Inc. on November 25, 2009.

On May 27, 2010, EMD Serono, Inc. resubmitted NDA 022561. However, on February 28, 2011, a Complete Response (CR) letter was issued. In the letter, the Agency notes that cladribine is effective as a treatment for patients with relapsing remitting multiple sclerosis; however, safety concerns associated with its use precluded its approval. Specifically, the presence of a disproportionate number of malignancies in cladribine-treated subjects represented an unacceptable safety risk.

On May 18, 2011, the Agency participated in an End of Review meeting during which the Sponsor obtained further clarification on the safety issues that resulted in the CR.

On August 19, 2011, EMD Serono, Inc. withdrew NDA 022561.

On October 11, 2017, the Agency participated in a Type C meeting to review the content and format of the Sponsor’s resubmission package. DMEPA was not consulted for this meeting.

EMD Serono, Inc. resubmitted NDA 022561 on May 31, 2018.

1.2 PRODUCT INFORMATION

The active ingredient, cladribine, a cytotoxic agent, was first approved by the FDA on February 26, 1993, as an injection formulation under the proprietary name, Leustatin, NDA 020229 (withdrawn FR effective 11/03/2016). In addition, the injection has three approved generic equivalents.

EMD Serono, Inc. is seeking approval of Mavenclad (cladribine) 10 mg tablets for the treatment of patients with relapsing forms of multiple sclerosis (MS). The recommended cumulative dose is 3.5 mg per kg body weight over 2 years, administered as 1 treatment course of 1.75 mg per kg body weight per year. Each treatment course consists of 2 treatment weeks,

. (See Appendix G for full dosing information)


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EMD Serono, Inc. proposes to supply Mavenclad in

2 MATERIALS REVIEWED

We considered the materials listed in Table 1 for this review. The Appendices provide the methods and results for each material reviewed.

Table 1. Materials Considered for this Label and Labeling Review

Material Reviewed Appendix Section (for Methods and Results)

Product Information/Prescribing Information A

Previous DMEPA Reviews B

Human Factors Study C – N/A

ISMP Newsletters D – N/A

FDA Adverse Event Reporting System (FAERS)* E – N/A

Other – Information Request F

Other – Dosing Information G

Labels and Labeling H

N/A=not applicable for this review*We do not typically search FAERS for our label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED

3.1 PACKAGE DESIGN

We considered whether a Human Factors (HF) validation study would be required to ensure the safe and effective use of the proposed packaging in the intended population. We find the use risks have been mitigated to a reasonably acceptable level and an HF validation study is not needed at this time.

a EMD Serono, Inc. proposes .


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We used the principles of human factors (HF) and Failure Mode and Effects Analysisb to analyze the steps involved in using the ’ child-resistant feature (e.g. use issues users may experience and the corresponding potential negative clinical consequences) in the intended user population.

We note the intended users, patients with relapsing forms of multiple sclerosis (MS), may have manual dexterity impairments that could affect their ability to remove their dose from the carton, as intended. The child-resistant feature requires users to 1) open the

. We note that the design of the child-resistant packaging could lead users to forcefully open the carton by tearing it, which would negate the child-resistant feature and pose risk of secondary exposure medication error. Our review of the carton labeling notes the user is instructed which, if followed, would minimize the risk of unintentional exposure. Furthermore, each carton contains one or two tablets, taken as a single daily dose. Therefore, by design, after the dose is taken there are no tablets remaining in the carton, thereby eliminating the risk of secondary exposure. Additionally, because each carton contains a single daily dose, there is no risk should the user be unable to close the carton.

To better inform our review on the acceptability of the packaging in the intended population, we submitted two information requests to the EMD Serono to clarify the use of this packaging in similar products and if any usability data exists for the use of this packaging in MS patients (see Appendix F). We reviewed the information submitted to support the safe and effective use of the product in the intended population and, based on the use-related risks of this product, in this particular case, we find EMD Serono’s justifications are reasonable.

Use issues associated with using the child-resistant feature could result in a delay in therapy. We consulted with the medical officer and, given the proposed dosing regimen, and that the product is not indicated for the acute treatment of MS symptoms, we do not believe that a delay in therapy would result in immediate harm to the patient.

For the aforementioned reasons, we find that a HF validation study is not needed at this time.

3.2 LABELS AND LABELING

Our review of the proposed Prescribing Information (PI) labeling, container labels, and carton labeling identified areas which may be improved to decrease risk of medication error.

Section 2.5 (Administration) of the full PI does not align with the carton labeling because it does not contain the important administration instruction

. The carton labeling and container labels do not indicate the intended expiration date

format and may pose risk of degraded drug medication administration errors.

b Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.


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As currently presented, the warning of ‘cytotoxic properties’ of this product is embedded within the special handling instructions and may be easily overlooked which poses risk of inappropriate handling medication errors.

The “Rx only” statement does not appear on the wallet container label as required by Section 503(b)(4)(A) of the Federal Food, Drug, and Cosmetic Act.

It is not immediately clear that the designated strength (10 mg) is per single unit (one tablet).

The statement does not appear in a prominent and conspicuous manner in accordance with

21 CFR 208.24(d). The 1-tablet and 2-tablet carton labeling is visually cluttered. Specifically, the principal

display panel contains non-critical information.

4 CONCLUSION & RECOMMENDATIONS

Based on our review of the Sponsor’s reply to our IR, the proposed dosage regimen, the intended uses, the package design in this population, and our heuristic and expert review of the product’s labels and labeling, we agree with EMD Serono that, in this particular case, the potential use-related risks have been mitigated to a reasonably acceptable level and an HF validation study to demonstrate safe and effective use is not needed at this time. However, we identified areas in the labels and labeling that are vulnerable to medication error and we recommend revisions to increase prominence of critical information and to ensure safe use and handling of the proposed product. We provide recommendations in section 4.1 and 4.2 and recommend their implementation prior to approval of this NDA application.

4.1 RECOMMENDATIONS FOR THE DIVISION

A. Prescribing Information (PI)1. Dosage and Administration Section

a. We note that the carton labeling states .

However, Section 2.5 (Administration) of the full PI does not contain this instruction.

4.2 RECOMMENDATIONS FOR EMD SERONO, INC.

We recommend the following be implemented prior to approval of this NDA:

A. General Comments (Container labels & Carton Labeling)


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B. Container Labels (Wallet)

C. Carton Labeling

c Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors. Food and Drug Administration. 2013. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM349009.pdf


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(See Draft Guidance: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors)


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APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED

APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION

Table 2 presents relevant product information for Mavenclad received on May 31, 2018 from EMD Serono, Inc.

Table 2. Relevant Product Information for Mavenclad

Initial Approval Date N/A

Active Ingredient Cladribine

Indication Treatment of patients with relapsing forms of multiple sclerosis (MS)

Route of Administration Oral

Dosage Form Tablet

Strength 10 mg

Dose and Frequency The recommended cumulative dose is 3.5 mg per kg body weight over 2 years, administered as 1 treatment course of 1.75 mg per kg per year. Each treatment course consists of 2 treatment weeks,

. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight.

How Supplied

Storage Store at controlled room temperature, 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C).

Container Closure Cladribine tablets are packaged in a blister which consists of an foil. The blister is

sealed in a child-resistant carton .


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APPENDIX B. PREVIOUS DMEPA REVIEWS

On July 20, 2018, we searched for previous DMEPA reviews relevant to this current review using the terms, cladribine AND NDA 022561. Our search identified one previous reviewd, and we considered our previous recommendations to see if they are applicable for this current review.

d Chan, I. Label and Labeling Review for (cladribine) NDA 022561. Silver Spring (MD): FDA, CDER, OSE, DMEPA (US)’ 2010 SEP 07. RCM No.: 2010-1241.


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APPENDIX F. INFORMATION REQUEST

F.1 AGENCY’S INFORMATION REQUEST #1 (ISSUED AUGUST 6, 2018)

SPONSOR’S RESPONSE TO INFORMATION REQUEST #1 (RECEIVED AUGUST 10, 2018)The response can be accessible in EDR via: \\cdsesub1\evsprod\nda022561\0063\m1\us\111-info-amend\response-to-ir-packaging.pdf


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F.2 AGENCY’S INFORMATION REQUEST #2 (ISSUED AUGUST 20, 2018)


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SPONSOR’S RESPONSE TO INFORMATION REQUEST #2 (RECEIVED AUGUST 28, 2018)The response can be accessible in EDR via: \\cdsesub1\evsprod\nda022561\0064\m1\us\111-info-amend\response-to-ir-packaging-follow-up-august-28-2018.pdf


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APPENDIX G. DOSING INFORMATION

The recommended cumulative dose is 3.5 mg per kg body weight over 2 years, administered as 1 treatment course of 1.75 mg per kg body weight per year. Each treatment course consists of 2 treatment weeks,

. Following completion of the two treatment courses, no further treatment is required in years 3 and 4.

Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (1 or 2 tablets) as a single daily dose, depending on body weight.

The recommended daily doses in each treatment week should be taken at intervals of 24 hours.


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BRIANA B RIDER11/01/2018

LOLITA G WHITE11/01/2018



M E M O R A N D U MDepartment of Health and Human Services

Food and Drug AdministrationCenter for Drug Evaluation and Research

Date: October 31, 2018

To: Billy Dunn, MD, DirectorDivision of Neurology Products

Through: Dominic Chiapperino, PhD, DirectorSilvia N. Calderon PhD, Senior PharmacologistControlled Substance Staff

From: Jovita Randall-Thompson PhD, PharmacologistControlled Substance Staff

Subject: NDA 22561, Cladribine tablets (Mavenclad)Indication: For the treatment of relapsing forms of multiple sclerosis (MS) Dosages: 10 mg tablets, cumulative dose of 3.5 mg/kg body weight over 2 years administered as 1 treatment course of 1.75 mg/kg per yearSponsor: EMD Serono

Materials reviewed: NDA 22561, for filing purposesIND 74634, CSS Review, DARRTS, J. Randall-Thompson, August 15, 2018

I. BackgroundThis memorandum is in response to a consult request dated June 20, 2018, from the Division of Neurology Products (DNP) pertaining to the fileability of NDA 22561, cladribine tablets, and is being submitted in lieu of a filing checklist.

Pursuant to Section 505(b)(l) of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314, EMD Serono, Inc. is resubmitting NDA 22,561, for cladribine tablets proposed for patients with relapsing forms of multiple sclerosis (MS) . The NDA received a Complete Response letter from FDA, issued on February 28, 2011. The Complete Response was based on safety concerns of high and disproportionate incidence of malignancies in cladribine-treated subjects.

Cladribine is a synthetic chlorinated nucleoside analogue of the naturally occurring nucleoside deoxyadenosine. Cladribine is the active pharmacological ingredient of the drug Leustatin (NDA 20229, approved February 26, 1993, Janssen Pharmaceuticals INC.), formulated as an injectable solution for the indication of hairy cell leukemia (HCL). The drug was discontinued by Janssen, but not for safety or efficacy reasons, and it is available as a generic medication and marketed in other countries.


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NDA 22561, Cladribine tablets (Mavenclad) 2 of 2

II. Conclusions

1. There is no need to further evaluate the potential for abuse of cladribine, based on the following:a. Binding assays performed by the Sponsor revealed that cladribine selectively binds to

several adenosine receptor subtypes and phosphodiesterases of which when activated or inhibited do not directly cause any meaningful abuse-related effects.

b. Cladribine (0, 5, or 10 mg/kg) administered intravenously did not alter centrally-mediated responses in the rat when an Irwin test conducted by the Sponsor examined the general responses elicited by cladribine.

c. When administered orally to healthy volunteers in Phase 1 studies, centrally-mediated adverse events (AEs) associated with cladribine tablets were limited and have included headache, dizziness, insomnia, and anxiety.

d. In summary, the mechanism of actions, general nonclinical responses, and associated CNS-related adverse events (AEs) shown with cladribine did not present a signal of abuse potential (see CSS Review, DARRTS J. Randall-Thompson, August 15, 2018).

III. Recommendations to the Division

Based on the lack of an abuse signal found with cladribine, we believe that CSS need not be involved in the review of this NDA. Consequently, CSS will not submit a filing checklist or further review for NDA 22561.

Additionally, the label for Leustatin, the injectable formulation of cladribine mentioned above, does not include a Section 9, Drug Abuse and Dependence. Therefore, as is the case with Leustatin, Section 9 should not be included in the label for cladribine tablets.

CSS recommends that the Division contact CSS if the DNP review team identifies any abuse-related concerns associated with the drug through the course of their review of this NDA.



JOVITA F RANDALL-THOMPSON10/31/2018

SILVIA N CALDERON10/31/2018

DOMINIC CHIAPPERINO10/31/2018



****Pre-decisional Agency Information****

Memorandum Date: 3/1/11 To: Hamet Toure, Regulatory Project Manager Division of Neurology Products (DNP) From: Quynh-Van Tran, Regulatory Review Officer

Division of Drug Marketing, Advertising, and Communications (DDMAC)

Subject: NDA 022561 DDMAC labeling Comments for (cladribine) tablets We acknowledge receipt of your June 17, 2010, consult request for the proposed product labeling for (cladribine) tablets, NDA 022561. DDMAC notes that a Complete Response letter was issued on February 28, 2011 and final labeling negotiation was not initiated during the current review cycle. Therefore, DDMAC will provide comments regarding labeling for this application during a subsequent review cycle. DDMAC requests that DNP submit a new consult request during the subsequent review cycle. Thank you for the opportunity to comment on these proposed materials. If you have any questions, please contact Quynh-Van Tran at 301-796-0185.

FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Division of Drug Marketing, Advertising, and Communications


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QUYNH-VAN TRAN03/01/2011


M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

______________________________________________________________________________________________________________________________

CLINICAL INSPECTION SUMMARY

DATE: December 1, 2010 TO: Hamet Toure, Regulatory Health Project Manager

Jody Green, M.D., Medical Officer Division of Neurology Products

THROUGH: Tejashri Purohit-Sheth, M.D. Branch Chief

Good Clinical Practice Branch II Division of Scientific Investigations

FROM: Antoine El-Hage, Ph.D. Regulatory Pharmacologist Good Clinical Practice Branch II Division of Scientific Investigations SUBJECT: Evaluation of Clinical Inspections NDA: 22-561 APPLICANT: EMD Serono, Inc. DRUG: Cladribine NME: No. THERAPEUTIC CLASSIFICATION: Priority Review INDICATION: Treatment of patients with relapsing forms of multiple sclerosis CONSULTATION REQUEST DATE: June 28, 2010 DIVISION ACTION GOAL DATE: November 28, 2010 PDUFA DATE: November 28, 2010 I. BACKGROUND: The sponsor, EMD Serono Inc, submitted a New Drug Application for the approval of the use of oral Cladribine in subjects with relapsing-remitting multiple sclerosis (RRMS). Cladribine, a chlorinated purine nucleoside analog, is approved in the U.S. under the trade name Leustatin



Clinical Inspection Summary/NDA 22-561

(Ortho Biotech) for the treatment of hairy cell leukemia and in more than 30 countries worldwide for the treatment of hairy cell leukemia and chronic lymphocytic leukemia. Multiple Sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) and one of the most common causes of neurological disability in young adults. The exact cause of MS is unknown, although an autoimmune process has been implicated. There are currently several approved drugs that are effective in the treatment of MS. However, currently, no oral medication is approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Cladribine injection (1mg/mL) is currently indicated for the treatment of lymphoid malignancies including, in many countries, hairy cell leukemia and, in some countries, chronic lymphocytic leukemia. An oral formulation of cladribine was recently developed that is anticipated to deliver comparable exposure to the doses administered parenterally in previous MS studies. The development of an oral formulation as a disease modifying treatment for MS would fulfill a currently unmet medical need. EMD Serono, Inc. initially submitted NDA 22-561 on September 30, 2009, which included two pivotal studies in support of the application: CLARITY and Scripps C study. However, the initial application was not filed because of concerns regarding data reliability of the Scripps C study as well as issues with datasets from the CLARITY study. The data reliability concerns for the Scripps C study originated from a 1999 FDA inspection of this study conducted in support of a previously filed application: . Scripps C was a single center study which enrolled 52 subjects and was conducted by Dr. Beutler, the principal investigator. The inspectional findings raised significant concerns as to data reliability and integrity. The regulatory file revealed that was withdrawn in 1999 after the previous sponsor received a Warning Letter from the Agency and DSI recommended to the review division that data from the Scripps- C trial not be used in support of the application. The results of the 1999 FDA inspection were considered critical to the filing decision for NDA 22-561. As a result, the Agency submitted an RTF to the applicant on November 25, 2009. On December 18, 2009, EMD Serono submitted a request to the Agency for a meeting to discuss its plan in addressing the deficiencies that were outlined in the RTF letter. On January 26, 2010, a meeting was held between the Agency and EMD Serono to discuss the issues detailed in the RTF letter. At that meeting, the sponsor was informed that an independent third party audit of all subject records (n=52) for the Scripps- C study with 100% source document verification of all data documented in the case report forms (CRFs) for all enrolled subjects will be needed. The sponsor agreed to a third party audit that was conducted by and the results were submitted to the Agency. Review of the third party audits did not support reliability of the Scripps C study. A summary of DSI’s review of this third party audit can be found in Appendix 1. Subsequently, on May 27, 2010 EMD Serono, Inc. resubmitted NDA 22-561 and again included the results of both the CLARITY Study and the Scripps C Study. However, based on DSI’s review of the third party audits, it was recommended that the data from the Scripps C study not be used in support of the pending application as they are not considered reliable. The review division concurred with the recommendation and decided to use only the CLARITY study in support of the pending application.



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CLARITY, therefore, became the sole pivotal study in support of the resubmission. CLARITY (Study 25643) is entitled: “A Phase III, Randomized, Double-Blind, Three-arm, Placebo-Controlled, Multicenter Study to Evaluate the efficacy and safety of oral Cladribine in Subjects with relapsing-remitting Multiple Sclerosis (RRMS).” In this study, female and male subjects over 18 years of age who were diagnosed with RRMS were assigned to receive:

• Cladribine tablets 3.5 mg/kg (administered p.o. as 0.875 mg/kg/course for two courses plus placebo p.o. for two courses during the first 48 weeks and 0.875 mg/kg course for two courses during the second 48 weeks), or

• Cladribine tablets 5.25 mg/kg (administered p.o. as 0.875 mg/kg course for four courses during the first 48 weeks and 0.875 mg/kg for two courses during the second 48 weeks), or

• Matching placebo (administered p.o. for four courses during the first 48 weeks and two courses during the second 48 weeks).

The primary objective of Study 25643 was to evaluate the efficacy of cladribine versus placebo in the reduction of qualifying relapse rate during 96 weeks of treatment in subjects with RRMS. The secondary objectives were: 1) to assess the effect of cladribine on progression of disability in subjects with RRMS, 2) to assess the effect of cladribine in reducing lesion activity compared to placebo as measured by MRI in subjects with RRMS, and 3) to assess the safety of cladribine in subjects with RRMS. The review division requested inspection of six clinical investigators for the CLARITY study (Protocol Study 25643) as data from the protocol is considered essential to the approval process. Five foreign clinical investigators and one domestic investigator were chosen for inspection of the protocol. These sites were targeted for inspection due to: 1) enrollment of a relatively large number of subjects, 2) relatively large efficacy shown in both relapse rate and EDSS change at the sites, and 3) these sites demonstrating significant primary efficacy results pertinent to decision-making. EMD Serono, Inc. is the Sponsor of this application. II. RESULTS (by protocol/site): Name of CI, site # and location

Protocol and # of subjects

Inspection Dates

Final Classification

Stoyan Bojinov, M.D. Medical University Pleven I-st Base Dept. of Neurology 8A, G.Kochev Blvd. 5800 Pleven, Bulgaria Site# 13

Protocol# 25643 Number of subjects listed 23

9/13-17/10 Pending Preliminary: VAI




Name of CI, site # and location

Protocol and # of subjects

Inspection Dates

Final Classification

Jelena Drulovic, M.D. Clinical Center Serbia Institute of Neurology Dr. Subotica 6 11000 Belgrade Serbia and Montenegro Site# 106

Protocol # 25643 Number of subjects listed 31


Tetanya Nehrych, M.D. Lviv Regional Central Hospital 6Nekrasova Street Lviv 79010, Ukraine Site# 128

Protocol #25643 Number of subjects listed 26


Petr Kanovsky, M.D. Faculty Hospital, Olomouc Neurological Dept. I.P.Pavlova 13 Olmouc 77520 Czech Republic Epileptology Dept. Frunze Str.103-A Kiev 04080, Ukraine Site# 181

Protocol #25643 Number of subjects listed 40


Steve Glyman, M.D. Nevada neurological Consultants University of Nevada School of Medicine 1707 W Charleston Avenue Las vegas NV 89102 Site# 165

Protocol #25643 Number of subjects 7

9/22-10/8/10

Pending Preliminary :VAI

Leonid Zaslavsky, M.D. State Institution of Public Health“leningrad regional Clinical Hospital“ 45-47, lunacharskogo Prospect St-Petersburg 194291 Sites# 104

Protocol# 25643 Number of subjects listed 21

10/11-15/10 Pending Preliminary: NAI




Key to Classifications NAI = No deviations VAI = Deviation(s) from regulations OAI = Significant deviations for regulations. Data unreliable. Pending = Preliminary classification based on e-mail communication from the field; EIR has not been received from the field and complete review of EIR is pending.

Note: Observations noted below for all sites are based on an e-mail communication from the field; EIR has not been received from the field and complete review of the EIR is pending. An inspection summary addendum will be generated if conclusions change upon receipt and review of the EIR. Protocol Study 25643 1. Stoyan Bojinov, M.D.

Pleven, Bulgaria

a. What Was Inspected: At this site, a total of 24 subjects were screened, one subject was reported as screen failure (did not meet inclusion criteria but signed consent). Twenty three (23) subjects were randomized and 20 subjects completed the study. There were no deaths and no under-reporting of adverse events. Review of Informed Consent Documents for all records reviewed, verified that subjects signed prior to enrollment.

A review of the medical records/source documents was conducted. The medical records for all subjects were reviewed in depth, including drug accountability records, vital signs, laboratory test results, IRB records, use of concomitant medications; source documents were compared to case report forms and to data listings, to include primary efficacy endpoints and adverse events. b. General observations/commentary: At the conclusion of the inspection, a 2 item Form FDA 483 was issued to Dr. Bojinov. The medical records reviewed disclosed minor protocol violations and errors in recording the kit number for certain subjects. The clinical investigator acknowledged the inspectional findings in a written response dated September 30, 2010, in which he promised to exercise more care in the future. Specifically, our investigation found the following: Protocol Violations: According to the protocol, “The same individual should remain as the Evaluating Physician for each subject, except when exceptional circumstances make this impossible. Whenever these exceptional circumstances occur, the situation must be clearly documented and reported to the sponsor, CRA, or monitor”. The change from the initial/original evaluating Physicians were not reported to the sponsor for Subjects

although subsequent changes were reported as protocol deviations.



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Record keeping violations:

• Subject# drug accountability forms showed kit B063995 was issued on July 27, 2005. The actual kit number is B06399.

• Subject drug accountability forms showed kit R806224 was issued on August 1, 2005. The actual kit number is B006224.

• Subject drug accountability forms showed kit R044833 was issued on May 28, 2007. The actual kit number is R044837.

Reviewer’s comments: Although the above errors were identified, evaluation of other study records document that the subjects received the correct test article to which they were randomized. Therefore, these errors in inaccurate recordkeeping are unlikely to impact data reliability.

c. Assessment of Data Integrity: Although regulatory violations were noted, the findings are unlikely to affect data integrity as they appear to be isolated occurrences and not systemic in nature. However, the review division may choose to consider the findings as outlined above with respect to protocol violations in their assessment of efficacy or safety. The remaining data generated from Dr. Bojinov’s site are considered reliable and appear acceptable in support of the application.

2. Jelena Drulovic, M.D.

Sebia and Montenegro Belgrade

a. What Was Inspected: At this site, a total of 34 subjects were screened and three (3) subjects were reported as screen failures. Two subjects were discontinued and the reasons were documented. Thirty one (31) subjects were randomized and completed the study. There were no deaths and no under-reporting of adverse events. Review of the Informed Consent Documents, for all subjects reviewed, verified that subjects signed consent forms prior to enrollment. The medical records/source data for subjects were reviewed in depth, including drug accountability records, vital signs, laboratory results, IRB records, prior and current medications, inclusion/exclusion criteria, and source documents were compared to data listings for primary efficacy endpoints and adverse events. b. General Observations/Commentary: At the conclusion of the inspection, a one item Form FDA 483 was issued to Dr. Drulovic. Our investigation found protocol violations and discrepancies in the number of visual scores due to transcription errors as follows. Protocol Violations: 1. According to the protocol, “The same individual should remain as the Evaluating

Physician for each subject, except when exceptional circumstances make this impossible. Whenever these exceptional circumstances occur, the situation must be



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clearly documented and reported to the sponsor, CRA, or monitor”. The first 10 subjects reviewed found that their evaluating physicians changed from the pre-study neurological exam. The changes and the reasons were not reported to the sponsor or the CRO.

2. In addition, “a complete pre-study evaluation is to be performed within 28 days prior

to Study Day 1”. Five subjects were enrolled who exceeded the 28 day allowance between screening and Study Day1.

• Subject had 35 days which is greater than 28 days allowed by the

protocol. • Subject had 35 days which is greater than 28 days allowed by the




protocol. Recordkeeping Violations: 1. Our investigation found discrepancies in the neurological exam between the source

document and what was recorded on the eCRF for Subject . The functional score for visual on the source document recorded 3 while the eCRF recorded 2; the Expanded Status Score on the source document recorded 4 while the eCRF recorded 3.

2. The informed consent for protocol amendment 6 was approved by the IRB/EC on

November 13, 2006. The site was notified on January 5, 2007. Subject was seen in the clinic on January 8, 2007, but did not sign the amended consent until February 14, 2007.

The medical records/source document reviewed disclosed no adverse findings that would reflect negatively on the reliability of the data. With the exception of items noted above, the records reviewed were found to be in order and verifiable and the data generated by this site appear acceptable in support of the respective indication. There were no known limitations to this inspection. The clinical investigator acknowledged the inspectional findings in a written response dated October 7, 2010. I find her response reasonable and acceptable.

c. Assessment of Data Integrity Although regulatory violations were noted, the findings are not likely to affect data integrity. However, the review division may choose to consider the isolated discrepancies and the protocol deviations noted above in their assessment of safety or



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efficacy. The data from Dr. Druovic’s site are considered reliable and appear acceptable in support of the pending application.

3. Tetanya Nehrych, M.D.

Lviv 79010, Ukraine

a. What Was Inspected: At this site, a total of 29 subjects were screened, 3 subjects were reported as screen failures (MRI not confirming MS), 26 subjects were randomized into the study, one subject was terminated (relocated), and 25 subjects completed the study. Review of the Informed Consent Documents, for all subjects records reviewed, verified that all subjects signed consent forms prior to enrollment. The medical records/source documents for all subjects were reviewed in depth, including drug accountability records, vital signs, IRB files, laboratory test results, inclusion/exclusion criteria use of concomitant medications; source documents for subjects were compared to case report forms and data listings, to include primary efficacy endpoints and adverse events and no discrepancies were noted. No inaccurate reporting of relapses was found. b. General Observations/Commentary: At the conclusion of the inspection, a two item Form FDA 483 was issued to Dr. Nehrych. Our investigation found protocol deviations and inadequate drug accountability records. Protocol Violations: The protocol required that subjects record the dose and the time of treatment administration in the subject diaries. The investigation revealed that “the number of tablets taken” was pre-completed by the physician in the subject diaries at the time the treatments were dispensed. The clinical investigator stated that this was done at the request of the subjects to make it easier for them to identify the amount of investigational product to be dosed. The subjects recorded the dates and times the tablets were taken. Reviewer comment: Based on preliminary communication from the field, there doesn’t appear to be any reason to question the accuracy of compliance documentation as the subjects did record the dates and times that they actually took the tablets.

Recordkeeping Violations:

There was no documentation to indicate that the investigational products received were maintained under controlled temperature conditions (monitoring device to record temperature control while in transit) during transport to the site.

Reviewer Comment: The reviewing records did not indicate whether or not a temperature monitoring device was included with the incoming shipment, and did not include the results of any temperature monitoring of the shipments in transit. Per the protocol, the investigational product was required to be stored at room temperature. According to the protocol and per discussion with the review division CMC TL, the IP




must be stored at room temperature below 25 degrees centigrade and should not be stored below the minimum storage temperature of 4 degrees centigrade. The test product is stable for 36 months. No additional information was provided in the protocol regarding monitoring temperature during transit. Given that the product was shipped at room temperature and given the excursionary range provided, it is unlikely that this finding would impact data reliability.

The clinical investigator acknowledged the inspectional findings in a written response dated September 23, 2010, in which he stated that corrective measures will be instituted and promised to exercise more care in his future studies. I find his response acceptable. The medical records reviewed disclosed no adverse findings that would reflect negatively on the reliability of the data. In general, the records reviewed were found to be in order and the data verifiable. There were no known limitations to this inspection. c. Assessment of Data Integrity: Although regulatory violations were noted, the findings are unlikely to affect data integrity. No inaccurate reporting of relapse and no under-reporting of adverse events were found. Assuming that the stability of the investigational drug was not impacted and that the subjects received non-degraded tablets, the data generated from Dr. Nehrych’s site are considered reliable and appear acceptable in support of the application.

4. Petr Kanovsky, M.D. Kiev, Ukraine

a. What was Inspected: At this site, a total of 54 subjects were screened, 14 subjects were reported as screen failures, 40 subjects were randomized and 35 subjects completed the study. Five (5) subjects withdrew from the study and the reasons were documented. Review of Informed Consent Documents, for all subjects reviewed, verified that all subjects signed consent forms prior to enrollment.

The medical records/source data for 21 subjects were reviewed in depth, including drug accountability records, vital signs, laboratory results, diary cards, IRB files, prior and current medications, inclusion/exclusion criteria, the use of concomitant medications; source documents for 21 selected subjects were compared to case report forms and to data listings for primary efficacy endpoint and adverse events.

b. General Observations/Commentary: At the conclusion of the inspection, a two item Form FDA 483 was issued to Dr. Kanovsky. Our investigation found protocol deviations and inadequate record keeping violations.

Protocol Violations: According to the protocol (relapse evaluation) required that in instances where a relapse has occurred, the “treating physician” review the entire set of available information and determine whether the relapse meets the protocol definition of a




“qualifying” relapse. For all relapses that occurred during this study, the “treating physician” failed to document the performance of the protocol-required review of relapse data. In addition, the treating physician’s assessment as to whether the relapses met the protocol definition of “qualifying” or “non-qualifying” was not documented. Relapse assessment results were recorded in the eCRF by someone other than the “treating physician”. Reviewer's Comments: DSI reviewer discussed this with the review division medical officer who stated that although qualifying was the primary endpoint, qualifying and non-qualifying were secondary endpoints and both won statistically. Hence an incorrect designation of qualifying and non-qualifying has no significant impact. Since the “treating physician” is a subinvestigator there is no problem with performing the relapse assessments. Recordkeeping Violations: At this, the “qualifying/non-qualifying” status of relapses for two subjects was incorrectly reported to the sponsor in the eCRFs.

• Subject suffered a “qualifying” relapse from . Although initially the relapse was correctly recorded in the eCRF as

“qualifying”, following query by the manager a study physician changed the relapse evaluation to the incorrect status of “non-qualifying.” In addition, the results of post-relapse neurological evaluation were not reported to the sponsor.

• Subject suffered a “qualifying” relapse starting . Although

initially this relapse was recorded in the eCRF as “qualifying” following query by the manger a study physician changed the relapse evaluation in the eCRF to the incorrect status of “non-qualifying”. In addition, the results of the post-relapse neurological evaluation were not recorded in the eCRF and subsequently not reported to the sponsor.

The clinical investigator acknowledged the observations noted above in a written response dated September 23, 2010.

The medical records reviewed disclosed no other adverse findings that would negatively on the reliability of the data. With the exception of the items noted above, the records reviewed were found to be organized and the data verifiable. There were no known limitations to this inspection. I find his response acceptable.

c. Assessment of Data Integrity: Although regulatory violations were noted, the

findings are considered isolated in nature and/or unlikely to significantly impact data reliability. The data from Dr. Kanovsky’s site are considered reliable and appear acceptable in support of the pending application.



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5. Leonid Zaslavsky St. Petersburg, Russian Federation

a. What was Inspected: At this site, a total of 29 subjects were screened, 8 subjects were reported as screen failures. Twenty one (21) subjects were randomized and all completed the study. There were no deaths and no under-reporting of adverse events. Review of Informed Consent Documents for all records reviewed, verified that subjects signed prior to enrollment.

A review of the medical records/source documents was conducted. The medical records for all 21 subjects were reviewed in depth, including drug accountability records, vital signs, laboratory test results, IRB records, use of concomitant medications; source documents were compared to case report forms and to data listings, to include primary efficacy endpoints and adverse events. No Form FDA 483 was issued. b. General Observations/Commentary: The medical documents reviewed disclosed no adverse findings that would reflect negatively on the reliability of the data. In general, the records reviewed were found to be organized and the data verifiable. There were no known limitations to the inspection.

c. Assessment of Data Integrity: The data from Dr. Zaslavsky’s site are considered reliable and appear acceptable in generated appear to be acceptable in support of the pending application.

6. Steve Glyman, M.D. Las Vegas, Nevada

a. What was Inspected: At this site, a total of 12 subjects were screened and five subjects were reported as screen failures. Seven (7) subjects were enrolled and 4 subjects completed the study. There were no deaths and no under-reporting of adverse events. Review of the Informed consent Documents, for all subjects reviewed, verified that subjects signed consent forma prior to enrollment.

A review of the medical records/source documents was conducted. The medical records for 6 subjects were reviewed in depth, including drug accountability records, vital signs, laboratory test results, IRB records, use of concomitant medications; source documents were compared to case report forms and to data listings, to include primary efficacy endpoints and adverse events. b. General Observations/Comments: At the conclusion of the inspection, a three item Form FDA 483 was issued to Dr. Glyman. Our investigation found protocol deviations and inadequate record keeping.




Protocol Violations: 1. According to the protocol, patients who have used natalizumab should be excluded

from the study. Subject received two injections of natalizumab and was randomized into the study. The subject was followed for safety, subsequently considered ineligible and was withdrawn from the study.

2. According to the protocol, patients can be included in the study if they are clinically stable and not have had a relapse within 28 days prior to Study Day#1; and the protocol requires “confirmation of inclusion/exclusion criteria” on Study Day #1. Subject had symptoms of relapse beginning on and was randomized on 10/11/10.

3. According to the protocol, a suspected relapse will be evaluated using the EDSS

assessment, and that assessment must be completed prior to treating the patient for the relapse.

• Subject experienced symptoms of relapse on . The subject was prescribed a higher dose of Klonopin on that day. The relapse was designated as “non-qualifying” in the absence of EDSS assessment. EDSS was not performed as required by the protocol.

• Subject experienced symptoms of relapse which began on . The Evaluating Physician made an assessment of the patient and Medrol was prescribed and began taking Medrol on . The relapse was designated as “non-qualifying” in the absence of EDSS assessment. EDSS was not performed as required by the protocol. In addition, the week 16 medical records dated this patient had symptoms of relapse for the past week. Decadron was prescribed and the patient started the Decadron the next day. There was no indication the patient refrained form taking the Decadron prior to the EDSS assessment.

4. According to the protocol, “A complete Pre-study Evaluation is to be performed

within 28 days prior to Study Day1”. Subjects had their pre-study physical exams, EDSS, and laboratory evaluation greater than the 28 days required by the protocol. In addition, certain protocol evaluations were not performed at certain visits/weeks for Subjects .

5. According to the protocol, the neurological exams and the MRIs should be

conducted on the same day, but a three day window is permissible. Subjects’ neurological exams and MRIs did not occur within the three days of the

specified schedule. Reviewer Comment: These delays took place prior to the subjects receiving the study drug and therefore, may not impact data integrity. The site informed the IRB and the sponsor and was informed not to re-screen. Because of the unforeseen circumstances,(MRI scheduling) every attempt was taken by the site to ensure the well being of study subjects. The delay was beyond the control of the site. Although regulatory violations were identified, these protocol violations are unlikely to affect



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data integrity due to a small number of subjects involved. The review division should consider the impact if any the findings noted above from the clinical investigator site have on the pending application in their assessment of efficacy and safety. Record Keeping Violations:

• Subject Cerebellar Functional System Score showed an EDSS score of 3. However, the corresponding case report form listed a score of “0”. In addition, the EDSS score dated 4/2/08 showed a score of “1”, however, the case report form listed as score of “3”.

• Subject had a functional system score for bowel/bladder functions of “2”; the corresponding case report listed the bowel/bladder score of “1”. In addition, this subject had a Kurtzke Functional System Score of “1” for the cerebral function. The corresponding case report form showed a score of “1a” instead of “1b”.

• Subject had a Kurtzke Functional Systems Score of ‘1” for the cerebral function. The corresponding case report form showed a score of “1a” instead of “1b”.

• Subject took Levaquin 750 mg daily from . The corresponding case report form listed Levaquin 750 mg twice per day taken by the subject during the same period.

• A memo to file stated that subject was not seen by the Treating Physician during week 9 on . However, two updated consent forms were signed by the designated Evaluating Physician on 12/27/06.

The clinical investigator acknowledged the inspectional findings in a written response dated October 25, 2010, in which he stated that all possible corrective and preventive measures will be taken to avoid such deviations from occurring in future studies. c. Assessment of Data Integrity: Although regulatory violations were noted, the findings are unlikely to affect data integrity due to a small number of subjects involved. However, the review division may choose to consider the findings above with respect to protocol violations in their assessment of efficacy or safety.

III. OVERALL ASSESSMENT OF FINDINGS AND GENERAL RECOMMENDATIONS Six clinical investigator sites, one domestic and five foreign sites were inspected in support of this application. The inspections of Drs. Bojinov, Drulovic, Nehryeh, Kanovsky, Zaslavsky and Glyman revealed no significant problems that would adversely impact data acceptability. Except for the noted observations at the selected sites, overall the data submitted from these sites are acceptable in support of the pending application.



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Note: Observations noted above for all inspections are based on an e-mail communication from the field; EIR has not been received from the field and complete review of the EIR is pending. An inspection summary addendum will be generated if conclusions change upon receipt and review of the EIR. {See appended electronic signature page}

Antoine El-Hage, Ph.D. Regulatory Pharmacologist Good Clinical Practice Branch II Division of Scientific Investigations

CONCURRENCE: {See appended electronic signature page}

Tejashri Purohit-Sheth, M.D. Branch Chief Good Clinical Practice Branch II Division of Scientific Investigations



4 Pages have been Withheld In Full as B4(CCI/TS) Immediately Following this Page


ANTOINE N EL HAGE12/01/2010

TEJASHRI S PUROHIT-SHETH12/01/2010



Department of Health and Human Services Food and Drug Administration

Center for Drug Evaluation and Research Office of Surveillance and Epidemiology

DEFER COMMENT MEMO

Date: November 4, 2010 To: Russell Katz, M.D., Director Division of Neurology Products (DNP) Through: Claudia Karwoski, Pharm.D., Director Division of Risk Management From: Scientific Lead, Risk Management Analyst (RMA) Reema Jain, Pharm.D., M.P.H., DRISK Team Leader, Kendra Worthy, Pharm.D., DRISK DRISK Review Team

Mary Dempsey, Risk Management Program Coordinator (DRISK)

Jodi Duckhorn, M.A., Assessment Team Leader Laurie Kelley, Safety Regulatory Project Manager (OSE)

Sharon Mills, BSN, RN, CCRP, Senior Patient Labeling Reviewer (DRISK)

Subject: Defer Comment on the proposed REMS/ Patient Labeling Drug Name (Established Name): (cladribine) Application Type/Number: Priority review/NDA 22-561 Applicant/Sponsor: Merck Serono S.A. OSE RCM #: 2010-1242

1Reference ID: 2859877


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This document is to defer comment on the proposed risk evaluation and mitigation strategy (REMS) and Medication Guide fo (cladribine).

On October 28, 2010, the Division of Neurology Products (DNP) requested that the Division of Risk Management (DRISK) review the proposed risk evaluation and mitigation strategy (REMS) and Medication Guide for (cladribine) submitted with the New Drug Application (NDA) 22-561 for the proposed treatment of relapsing forms of multiple sclerosis .

A Complete Response letter will be issued by the review division because of the product’s risk for malignancy in patients with multiple sclerosis. Therefore, DRISK defers comment on the sponsor’s REMS proposal and patient labeling at this time.

A final discussion on the appropriate risk management strategy will be undertaken after the sponsor submits a satisfactory response to the Complete Response letter.

Please send DRISK a new consult request at such time. This memo serves to close the existing consult request for (cladribine) oral tablets under NDA 22-561.

Please notify DRISK if you have any questions.



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REEMA JAIN11/04/2010

CLAUDIA B KARWOSKI11/04/2010concur



Department of Health and Human Services

Public Health Service Food and Drug Administration

Center for Drug Evaluation and Research Office of Surveillance and Epidemiology

Date: September 7, 2010

Application Type/Number:

NDA 022561

To: Russell Katz, M.D., Director Division of Neurology Products

Through: Melina Griffis, RPh, Team Leader Carol Holquist, RPh, Director Division of Medication Error Prevention and Analysis (DMEPA)

From: Irene Z. Chan, Pharm.D., BCPS, Safety Evaluator Division of Medication Error Prevention and Analysis (DMEPA)

Subject: Label and Labeling Review

Drug Name(s): (Cladribine) Tablets, 10 mg

Applicant/Sponsor: EMD Serono

OSE RCM #: 2010-1241

*** This document contains proprietary and confidential information that should not be released to the public.***


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CONTENTS 1 INTRODUCTION................................................................................................................... 1

1.1 Regulatory History......................................................................................................... 1 1.2 Product Information ....................................................................................................... 1

2 METHODS AND MATERIALS ............................................................................................ 2 2.1 FDA Adverse Event Reporting System (AERS) Database............................................ 2 2.2 Labels and Labeling....................................................................................................... 3

3 RESULTS AND DISCUSSION.............................................................................................. 3 3.1 FDA Adverse Event Reporting System (AERS) Database............................................ 3 3.2 Labels and Labeling....................................................................................................... 3

4 CONCLUSIONS AND RECOMMENDATIONS.................................................................. 4 4.1 Comments to the Division.............................................................................................. 4 4.2 Comments to the Applicant............................................................................................ 6

APPENDICES..................................................................................................................................9


1

1 INTRODUCTION This review summarizes the Division of Medication Error Prevention and Analysis’ (DMEPA) evaluation of the proposed labels and labeling for for areas of vulnerability that can lead to medication errors. We provide recommendations in Section 4 that aim at reducing the risk of medication errors with regard to the proposed product labels and labeling.

1.1 REGULATORY HISTORY EMD Serono submitted an original New Drug Application on September 29, 2009. The Division of Neurology Products (DNP) subsequently sent a Refuse to File communication to EMD Serono on November 25, 2009. On May 27, 2010, EMD Serono resubmitted the New Drug Application, including revised labels and labeling, for the Food and Drug Administration (FDA) to review.

The active ingredient, cladribine, was first approved by the FDA on February 26, 1993, as an injection formulation under the proprietary name, Leustatin (NDA 20-229), manufactured by Ortho Biotech. In addition, the injection has two approved generic equivalents.

1.2 PRODUCT INFORMATION is the proposed proprietary name for cladribine tablets. The Applicant is seeking approval for

the treatment of relapsing forms of multiple sclerosis. The strength proposed for marketing authorization is 10 mg.

The recommended dose is based on patient weight with a maximum cumulative dose of 3.5 mg/kg . Product therapy is administered in treatment courses. One treatment course is in

length . Treatment consists of four courses over a span of two cycles (see Table 1).

A treatment course is initiated with 1 or 2 tablets by mouth each day for the first 4 or 5 days of the course. During the remaining days of the course, the patient does not take any medication. A second treatment course is administered, and then the patient is off medication for the next

. This completes the first cycle.

The third and fourth treatment courses are administered as described above. After the fourth treatment course is administered, the patient is off medication for the next . This completes the of therapy. Additional treatment courses beyond after treatment initiation have not yet been evaluated.

Cladribine is a cytotoxic agent. Proper precautions should be taken when handling and disposing of this medication.

EMD Serono proposes supplying in pre-packaged blisters in tablet holders that provide the exact number of tablets required for a treatment course (see Table 2).

.


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2

Table 1: Total number of tablets administered during each treatment course based on patient weight

Weight Range Number of 10 mg Tablets Per Treatment Course

First Cycle Second Cycle

Kg Course 1 Course 2 Course 3 Course 4

40* to 49 4 4 4 4

50 to 59 5 5 5 5

60 to 69 6 6 6 6

70 to 79 7 7 7 7

80 to 89 8 7 8 7

90 to 99 9 8 9 8

100 to 109 10 9 10 9

110 and above 10 10 10 10

* The use of in patients weighing less than 40 kg has not been investigated.

2 METHODS AND MATERIALS The Division of Medication Error Prevention and Analysis (DMEPA) evaluated the proposed blister labels, carton labeling, tablet holder labeling, package design, insert labeling, and medication guide for

Tablets 10 mg to identify areas of vulnerability that can lead to medication errors. We also searched the FDA Adverse Event Reporting System (AERS) Database to determine if any medication errors due to labels and labeling have occurred with the existing marketed product, Leustatin.

2.1 FDA ADVERSE EVENT REPORTING SYSTEM (AERS) DATABASE Cladribine is a currently marketed in an injectable form under the proprietary name Leustatin and is also available as a generic formulation; therefore, DMEPA conducted a search of the FDA Adverse Event Reporting System (AERS) database on July 27, 2010, to identify medication errors involving Cladribine


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or Leustatin.

The MedRA High Level Group Terms (HLGT) “Medication Errors” and “Product Quality Issues” were search criteria for Reactions. The search criteria for Products included the active ingredients “cladribine,” the trade name “Leustatin,” and verbatim substances “Leustat%” and “Cladrib%.” No date limitations were set.

The reports were manually reviewed to determine if a medication error occurred. Duplicate reports were combined into cases. The cases that described a medication error were categorized by type of error. We reviewed the cases within each category to identify factors that contributed to the medication errors. If a root cause was associated with the labels or labeling of the product, the case was considered applicable to this review. Those reports that did not describe a medication error, or did not describe an error applicable to this review, were excluded from further analysis.

2.2 LABELS AND LABELING Using Failure Mode and Effects Analysis (FMEA), the Division of Medication Error Prevention and Analysis (DMEPA) evaluated the labels and labeling submitted as part of the May 27, 2010 resubmission (see Appendices A, B, and C). We also reviewed the package prototype submitted by the Applicant. 3 RESULTS AND DISCUSSION The label and labeling risk assessment indicates the presentation of information on the proposed labels and labeling introduces vulnerability to confusion that can lead to medication errors. During our review of the proposed labels and labeling, we considered the relevant AERS cases identified during our search.

3.1 FDA ADVERSE EVENT REPORTING SYSTEM (AERS) DATABASE The AERS search conducted on July 27, 2010, yielded 13 cases. Of these, we excluded 11 from further evaluation for the reasons presented in Appendix E. The remaining 2 cases are discussed below, and corresponding ISR numbers can be found in Appendix F.

The first case reported a potential for medication error between Leustatin and Doxorubicin by GensiaSicor. The reporter noted that the product packagings of these two products are similar due to the boxes being white with green accent printing. No actual medication error was reported.

The second case was an improper dose error where a patient received a 10-fold overdose of Cladribine. The reporter noted that the error was possibly due to confusion with the drug packaging; however, no additional details were provided.

EMD Serono proposes supplying in pre-packaged blisters in tablet holders that provide the exact number of tablets required for a treatment course. It is not likely that a prepackaged tablet holder can be confused with Doxorubicin injection. Additionally, because only the exact number of tablets required for a treatment course with directions of how many tablets to take each day will be packaged in the tablet holders, the likelihood of 10-fold overdose is also decreased.

3.2 LABELS AND LABELING It was determined that the labels and labeling need improvement in the following areas: Increased prominence of the proprietary name, established name, and strength presentation, the trade dress, colors chosen for the net quantity differentiation, the graphic embedded into the proprietary name presentation, dosage and administration directions, and removal of trailing zeros in the insert labeling. Our recommendations are further explained in Section 4.


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4 CONCLUSIONS AND RECOMMENDATIONS Our evaluation of the proposed labels and labeling noted areas of needed improvement in order to minimize the potential for medication errors. We provide recommendations on the insert labeling in Section 4.1 Comments to the Division. We request the recommendations for the tablet holder labeling, carton labeling, blister label, and package design in Section 4.2 be communicated to the Applicant prior to approval. Please copy the Division of Medication Error Prevention and Analysis on any communication to the Applicant with regard to this review. If you have further questions or need clarifications on this review, please contact the OSE Regulatory Project Manager, Laurie Kelley, at 301-796-5068. 4.1 COMMENTS TO THE DIVISION

A. GENERAL COMMENTS

1. The Applicant has utilized trailing zeros within the insert labeling. Trailing zeros can lead to 10-fold errors in dosing. DMEPA recommends removing all trailing zeros with the exception of when it is required to demonstrate the level of precision of the value being reported, such as for laboratory results, imaging studies that report size of lesions, or catheter/tube sizes.

B. HIGHLIGHTS OF PRESCRIBING INFORMATION

1. Dosage and Administration Subsection

a) As currently presented, the dosage and administration of this product is unclear. We recommend revising the bullets for clarity, such as the following:

C. FULL PRESCRIBING INFORMATION

1. Section 2 - Dosage and Administration

a) As currently presented, the dosage and administration of this product is unclear. We recommend revising Section 2.1 for clarity.


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After consultation with DRISK, we recommend the following language be considered:

b) Due to the complexity of the dosing directions, we recommend adding a diagram

immediately after the general dosing instructions, such as the following:

c) Currently the dosing tables and other dosage information are presented in Section 2.3 and are separated from 2.1 . These two sections

should be kept together. We recommend moving the current Section 2.2 up to Section 2.1. Move the current Section 2.1

down to Section 2.2. d) Weights should be based on the metric system (e.g. kg) for safety and to avoid confusion

in calculating patient doses. We recommend keeping the column containing patient weight in kilograms (kg) and removing the column with patient weight in pounds (lb).


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e) DMEPA is concerned that providers may overlook the fact that the number of tablets may vary from one treatment course to another . We recommend bolding the statement

f) As currently presented, the following statement under Section 2.4

Consider revising this statement to read as follows: …the patient must take the missed dose in place of the next scheduled dose, then resume treatment and extend the number of days in that treatment course. In addition, the heading for this section does not seem appropriate considering its content. Consider revising the heading to read Missed Doses

2. Section 5 – Warnings and Precautions

Under Section 5.9 we note that EMD Serono intends . We defer to DRISK and OND to determine whether this drug requires

a risk evaluation and mitigation strategy (REMS). If it is determined that a REMS with elements to assure safe use (ETASU) is necessary for , we recommend including adequate dispensing instructions to communicate the requirements of the REMS.

3. Section 16 – How Supplied/Storage and Handling

Under section 16.2 we feel that the current statement regarding proper handling and disposal of this drug needs to be strengthened, similar to that of chemotherapeutic agents. We recommend a statement indicating is a cytotoxic agent be included in this section of labeling. Additionally, we recommend revising the last paragraph to read as follows: Patients and caregivers should follow procedures for proper handling and disposal of drugs that require special precautions. Several guidelines on this subject have been published. Any unused product or waste material should be disposed of in accordance with local requirements.

D. MEDICATION GUIDE

1. consider adding the following statement: Depending on your weight, the number of tablets you take may vary from one treatment course to the next.

2. There are currently no instructions regarding proper disposal of . Consider adding

the following statement: Contact your pharmacist for instructions on proper disposal of unused tablets and the tablet holder.

3. Based on recommendations to the Applicant (see section 4.2, comment C2), we recommend

removal 4.2 COMMENTS TO THE APPLICANT

A. CARTON LABELING AND TABLET HOLDER LABELING (all quantities)


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B. CARTON LABELING (all quantities)

C. BLISTER LABEL (all quantities)


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D. TABLET HOLDER LABELING (all quantities)

E. PACKAGING DESIGN (all quantities)


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ApplicationType/Number

SubmissionType/Number Submitter Name Product Name

-------------------- -------------------- -------------------- ------------------------------------------NDA-22561 ORIG-1 EMD SERONO INC CLADRIBINE


IRENE Z CHAN09/07/2010

MELINA N GRIFFIS09/07/2010

CAROL A HOLQUIST09/07/2010
