6 February 2003

Karen M. Templeton-Somers, Ph.D.

Supervisory Health Science Administrator

Advisors and Consultants Staff

FDA, CDER, ORM

HFD-21, Room 1093

5630 Fishers Lane

Rockville, MD 20852-1734

RE: NDA 21-041 DepoCyt® Phase IV Commitments

Dear Dr. Somers:

As requested in your letter dated January 23, 2003, enclosed are 40
copies (and 2 electronic copies in Microsoft Word) of the background
package for the Oncologic Drugs Advisory Committee meeting scheduled
March 12-13, 2003. SkyePharma will be presenting and update on its Phase
IV commitments of NDA 21-041, DepoCyt (cytarabine liposome injection)
for the intrathecal treatment of lymphomatous meningitis.

As requested, both the paper and electronic copies have been marked
"AVAILABLE FOR PUBLIC DISCLOSURE IWTHOUT REDACTION" as described in the
Guidance for Industry "Disclosing Information Provided to Advisory
Committees in Connection with Open Advisory Committee Meetings Related
to the Testing or Approval of New Drugs and Convened by the Center for
Drug Evaluation and Research, Beginning on January 1, 2000."

Speakers and presenters from SkyePharma are as follows:

Gordon L. Schooley, Ph.D. Stephen B. Howell, M.D.

Senior Vice President Professor of Medicine

Global Clinical and Regulatory Affairs Director, Cancer Pharmacology
Program

SkyePharma Inc. University of California, San Diego

Please let me know if you require any further information in preparation
for the ODAC meeting.

Regards,

Gordon L. Schooley, Ph.D.

Sr. Vice President

Global Clinical and Regulatory Affairs

######## INFORMATION REGARDING ACCELERATED APPROVAL {#information-regarding-accelerated-approval .unnumbered}

**CLINICAL PHASE 4 COMMITMENTS**

######## General Information

######### Drug Name: DepoCyt^®^ (cytarabine liposome injection) {#drug-name-depocyt-cytarabine-liposome-injection .out2}

######### Indication: DepoCyt is indicated for the intrathecal treatment of lymphomatous meningitis. Neoplastic meningitis is an orphan indication with an estimated incidence of 1,200 cases/year. {#indication-depocyt-is-indicated-for-the-intrathecal-treatment-of-lymphomatous-meningitis.-neoplastic-meningitis-is-an-orphan-indication-with-an-estimated-incidence-of-1200-casesyear. .out2}

######### Accelerated Approval Date: April 1, 1999. DepoCyt was approved on the basis of a pivotal trial in 28 patients with lymphomatous meningitis supported by data from a Phase 1 trial (19 patients), two additional pharmacokinetic trials (11 and 13 patients), and a randomized prospective controlled trial (61 patients) and subsequent open-label trial (89 patients) in patients with solid tumor neoplastic meningitis.  {#accelerated-approval-date-april-1-1999.-depocyt-was-approved-on-the-basis-of-a-pivotal-trial-in-28-patients-with-lymphomatous-meningitis-supported-by-data-from-a-phase-1-trial-19-patients-two-additional-pharmacokinetic-trials-11-and-13-patients-and-a-randomized-prospective-controlled-trial-61-patients-and-subsequent-open-label-trial-89-patients-in-patients-with-solid-tumor-neoplastic-meningitis. .out2}

######## Description of Commitment including titles of individual studies {#description-of-commitment-including-titles-of-individual-studies .out1}

SkyePharma committed to conducting a Phase IV Post-Marketing study
(Protocol C0101-010) and a pharmacokinetic sub-study titled "A
randomized clinical study to determine the patient benefit and safety of
DepoCyt (Cytarabine Liposomal Injection) for the treatment of solid
tumor neoplastic and lymphomatous meningitis." These studies were to be
initiated within six (6) months. The original estimated dates for the
study timeline are as follows:

Start date: September 1999

Interim Analysis: 4^th^ Quarter 2001 (after 50% of events)

Enrollment Completion: September 2003

SkyPharma also estimated 6 months for final data analysis and 3 months
for study report completion.

The following amendments were made to the Protocol:

1.  The Pharmacokenetic study was in incorporated into the Phase IV
    Post-Marketing study (Protocol C0101-010).

2.  Protocol was subsequently categorized as a Phase III/IV study, so as
    to simultaneously pursue an indication in patients with solid tumor
    neoplastic meningitis. The title of the amended study is "A
    randomized phase III/IV clinical study to determine the patient
    benefit and safety of DepoCyt (cytarabine liposome injection) for
    the treatment of neoplastic meningitis".

3.  Sample size was changed from approximately 100 patients total to
    enroll patients until 75 patients with solid tumor neoplastic
    meningitis achieved the clinical endpoint of neurological
    progression or death. This is estimated to be a total of 110
    patients.

4.  The interim analysis was eliminated.

5.  Addition of European clinical study sites.

6.  Stratified randomization for North America vs. Europe.

######## Study Details {#study-details .out1}

########  {#section .out1 .unnumbered}

######### Essentials of Study Design {#essentials-of-study-design .out2}

#########  {#section-1 .out2 .unnumbered}

> **1. Summary of Study Sites**
>
> Forty-three (43) study sites are currently participating in the Phase
> III/IV trial. A summary of participating sites is in Appendix 1:

a.  18 study sites are currently participating in the U.S.

b.  2 study sites are currently participating in Canada

c.  24 study sites are currently participating in Europe

**2. Patient Population**

The trial is open to adult patients with lymphomatous or solid tumor
neoplastic meningitis documented within 21 days of randomization by
either:

a.  positive CSF cytology for lymphoma or solid tumor neoplasm **OR**

b.  characteristic signs and symptoms of neoplastic meningitis **PLUS**
    an MRI or CT scan indicating the presence of meningeal tumor.

**3. Endpoints**

The primary endpoint is progression-free survival defined as the time to
neurological progression or death.

**4. Treatment Schema**

Lymphoma patients are randomized (1:1) to DepoCyt or cytarabine. Solid
tumor patients are randomized (1:1) to DepoCyt or methotrexate.
Randomization is further stratified by region (U.S. vs. Europe).
Treatment consists of two phases: 6 Induction cycles (2 weeks per cycle)
and 4 Maintenance cycles (4 weeks per cycle). DepoCyt patients are
treated once at the beginning of each Induction cycle and once at the
beginning of each Maintenance cycle. Cytarabine and methotrexate
patients are treated twice per week during Induction and once per week
during Maintenance. At the completion of treatment, all patients are
followed monthly through 1 year after study entry and bi-monthly for the
following 12 months for neurological assessments.

**5. Efficacy and Safety Monitoring**

CSF cytology, laboratory assessments, and neurological assessments prior
to each treatment cycle. In addition, adverse events are monitored
through 30 days following the start of the patient's final treatment
cycle.

**6. Statistical Design**

The study is designed to have an 80% power of detecting a 50% reduction
in the rate at which solid tumor patients suffer neurological
progression. The estimated number of necessary events is 75. Accrual of
both solid tumor and lymphomatous meningitis patients will continue
until 75 solid tumor patients have suffered neurologic progression or
have died. Anticipated total accrual of patients with either
lymphomatous or solid tumor neoplastic meningitis is 110 based on the
observation that approximately two-thirds of the patients accrued to the
trial thus far have solid tumor neoplastic meningitis and one third
lymphomatous meningitis. An intent-to-treat (ITT) analysis will consider
all patients randomized and analyzed according to the drug of
randomization irrespective of whether or not they actually received the
drug to which they were assigned. Kaplan-Meier distributions will be
analyzed using the log-rank test for progression-free survival (time to
neurological progression or death).

######### Date of Initiation {#date-of-initiation .out2}

#########  {#section-2 .out2-text}

######### Identification of investigators began immediately after DepoCyt approval in April of 1999. The study was ready for patient accrual in October 1999. However, available supplies of DepoCyt were recalled in October 1999, and no drug was available for 18 months until FDA approved reintroduction to the market in March 2001. Trial preparation was reactivated immediately thereafter and the first patient was enrolled on 03 July 2001.  {#identification-of-investigators-began-immediately-after-depocyt-approval-in-april-of-1999.-the-study-was-ready-for-patient-accrual-in-october-1999.-however-available-supplies-of-depocyt-were-recalled-in-october-1999-and-no-drug-was-available-for-18-months-until-fda-approved-reintroduction-to-the-market-in-march-2001.-trial-preparation-was-reactivated-immediately-thereafter-and-the-first-patient-was-enrolled-on-03-july-2001. .out2-text}

#########  {#section-3 .out2-text}

######### Accrual {#accrual .out2}

#########  {#section-4 .out2-text}

######### As of 31 January 2003, 49 patients have been enrolled, 12 of which were enrolled with lymphomatous neoplastic meningitis.  {#as-of-31-january-2003-49-patients-have-been-enrolled-12-of-which-were-enrolled-with-lymphomatous-neoplastic-meningitis. .out2-text}

#########  {#section-5 .out2-text}

######### Enrollment status: {#enrollment-status .out2-text}

######### 2001: 16 patients {#patients .out2-text}

######### 2002: 27 patients {#patients-1 .out2-text}

######### 2003: 40 patients to be enrolled (6 patients were enrolled by 31 Jan 2003) {#patients-to-be-enrolled-6-patients-were-enrolled-by-31-jan-2003 .out2-text}

######### [2004: 27 patients to be enrolled]{.underline} {#patients-to-be-enrolled .out2-text}

######### Total: 110 patients {#total-110-patients .out2-text}

#########  {#section-6 .out2-text}

######### Estimated Timeline for Study Completion {#estimated-timeline-for-study-completion .out2}

#########  {#section-7 .out2-text}

######### The current enrollment rate is sufficient to meet SkyePharma's enrollment commitment by August 2004. {#the-current-enrollment-rate-is-sufficient-to-meet-skyepharmas-enrollment-commitment-by-august-2004. .out2-text}

#########  {#section-8 .out2-text}

######### Start date: March 2001 {#start-date-march-2001 .out2-text}

######### Interim analysis: Eliminated as per agreement with FDA {#interim-analysis-eliminated-as-per-agreement-with-fda .out2-text}

######### Enrollment Complete: August 2004 {#enrollment-complete-august-2004 .out2-text}

######### Last patient visit: Approximately March 2005 {#last-patient-visit-approximately-march-2005 .out2-text}

######### Report Completion: August 2005 -- approximately 6 months {#report-completion-august-2005-approximately-6-months .out2-text}

######### Following the last patient visit {#following-the-last-patient-visit .out2-text}

######### Total elapsed time: Approximately 4-1/2 years (identical to the  {#total-elapsed-time-approximately-4-12-years-identical-to-the .out2-text}

######### original commitment) {#original-commitment .out2-text}

#########  {#section-9 .out2-text}

######### Estimated Timeline for Submission of Study Results {#estimated-timeline-for-submission-of-study-results .out2}

#########  {#section-10 .out2-text}

######### The study calls for a two-year follow-up period following randomization. However, due to the severity of the disease under study, the likelihood of a patient failing to reach neurological progression or death within 6 months after receiving initial treatment is low. It is anticipated that the clinical database could be closed Q2 2005 should all participating patients reach the primary endpoint by March 2005. Should this occur, the study results would be available by the third quarter of 2005. This is approximately 4-1/2 years of elapsed time from the study start, which is same elapsed time as the original Phase IV commitment of March 1999. The final clinical study report could be submitted to FDA within one month following report completion. However, should one or more of the patients enrolled after the first quarter of 2003 have progression-free survival for two years following randomization, there could be a respective delay in the analysis of the data. For this reason, the proposed timeline to provide study results is between approximately Q3 2005 and Q1 2007.  {#the-study-calls-for-a-two-year-follow-up-period-following-randomization.-however-due-to-the-severity-of-the-disease-under-study-the-likelihood-of-a-patient-failing-to-reach-neurological-progression-or-death-within-6-months-after-receiving-initial-treatment-is-low.-it-is-anticipated-that-the-clinical-database-could-be-closed-q2-2005-should-all-participating-patients-reach-the-primary-endpoint-by-march-2005.-should-this-occur-the-study-results-would-be-available-by-the-third-quarter-of-2005.-this-is-approximately-4-12-years-of-elapsed-time-from-the-study-start-which-is-same-elapsed-time-as-the-original-phase-iv-commitment-of-march-1999.-the-final-clinical-study-report-could-be-submitted-to-fda-within-one-month-following-report-completion.-however-should-one-or-more-of-the-patients-enrolled-after-the-first-quarter-of-2003-have-progression-free-survival-for-two-years-following-randomization-there-could-be-a-respective-delay-in-the-analysis-of-the-data.-for-this-reason-the-proposed-timeline-to-provide-study-results-is-between-approximately-q3-2005-and-q1-2007. .out2-text}

#########  {#section-11 .out2-text}

######## Other Issues {#other-issues .out1}

########  {#section-12 .out1 .unnumbered}

######### Difficulties encountered in conduct/accrual/completion of trials {#difficulties-encountered-in-conductaccrualcompletion-of-trials .out2}

#########  {#section-13 .out2 .unnumbered}

**1. Changes in medical practice**

With the initial approval and commercial availability of DepoCyt for the
treatment of lymphomatous neoplastic meningitis in the United States and
Canada, there appears to have been a shift in the standard treatment of
patients inflicted with this disease. There is certainly interest among
clinicians to initiate DepoCyt treatment in patients with lymphomatous
neoplastic meningitis without enrolling them in this controlled,
randomized clinical trial. Considering that a lymphoma patient could be
randomized to ara-C in this trial, which requires 4 times more clinic
visits than if treated with DepoCyt, many of the U.S. investigators
queried to participate in this trial chose not to.

Similarly, as part of the consent process, patients are informed of the
treatment options that are available to them other than participating in
this controlled study. These options include off-study treatment with
commercially available DepoCyt without the patient having to worry about
being randomized to ara-C or methotrexate, both of which are
administered twice weekly.

Although both of these issues are potentially hindrances to study
enrollment, 18 U.S. institutions have been recruited and the rate of
enrollment in the U.S. appears to be in-line with enrollment in the
prior Phase III controlled studies. In addition, European sites were
recently added to the study, which should aid in completing the study
within the currently specified timelines since DepoCyt, although
approved in Europe for lymphomatous meningitis patients, is not yet
distributed by SkyePharma's. European licensee.

**2. Safety considerations**

The safety of the trial is continuously monitored and there have been no
reasons to believe that safety would adversely effect the study
completion timelines.

**3. Other: Product unavailable**

A recall of both lots distributed between April and October 1999 was
initiated when the free cytarabine content was found to be out of
specification during stability studies. These results were unexpected
and atypical of prior history with the product. SkyePharma conducted a
lengthy and rigorous investigation of possible sources of product
instability and discovered that the problem was caused by a slight
change in the composition of one of the lipids due to a minor change in
a single step of the manufacturing process used by the lipid supplier. A
comprehensive investigation report was submitted to FDA in July 2000
documenting the single cause for the recall and corrective and
preventive actions taken by the Sponsor. SkyePharma met with FDA in
September 2000 and when additional stability data became available, FDA
approved resumption of commercial distribution in March 2001. Thus,
DepoCyt was not available for conduct of the post-marketing trial for a
period of 18 months.

######### Other Applicant Concerns {#other-applicant-concerns .out2}

#########  {#section-14 .out2-text}

######### None  {#none .out2-text}

#########  {#section-15 .out2-text}

#########  {#section-16 .out2-text}

#########  {#section-17 .out2-text}

######### **APPENDIX 1** {#appendix-1 .out2-text}

#########  {#section-18 .out2-text}

#########  {#section-19 .out2-text}

#########  {#section-20 .out2-text}

#########  {#section-21 .out2-text}

######### **ACTIVE CENTERS**  {#active-centers .out2-text}

#########  {#section-22 .out2-text}

######### **PROTOCOL SKY010-010** {#protocol-sky010-010 .out2-text}

Appendix 1: Active Centers Protocol SKY0101-010

[**Investigator** **Center No. Institution** **City**
**Country**]{.underline}

William Shapiro MD 2 Barrow Neurological Phoenix USA

Institute

Pamela New MD 3 University of Texas San Antonio USA

Health Science Center

Pamela Khosla MD 5 Rush Cancer Institute Chicago USA

Surasak Phuphanich MD 6 H. Lee Moffitt Cancer Tampa USA

Center and Research Inst.

Eric Wong MD 9 Beth Israel Deaconess Boston USA

Medical Center

Benjamin Lawler MD 10 Marshfield Clinic Marshfield USA

Paul Moots MD 19 Vanderbuilt University Nashville USA

Medical Center

Kurt Jaeckle MD 23 Mayo Clinic Jacksonville USA

Deborah Blumenthal MD 27 Huntsman Cancer Institute Salt Lake City USA

Marc Chamberlain MD 28 USC Los Angeles USA

Subramanian Hariharan MD 29 JFK Neuroscience Institute Edison USA

Lynne Taylor MD 30 Virginia Mason Medical Seattle USA

Center

Lynn Ashby MD 36 Straub Clinic and Hospital Honolulu USA

Jeffrey Olson MD 37 Windship Cancer Institute Atlanta USA

David Irwin MD 38 Alta Bates Comprehensive Berkeley USA

Cancer Center

Thomas Coyle MD 39 SUNY Upstate Medical Syracuse USA

University

[**Investigator** **Center No. Institution** **City**
**Country**]{.underline}

George Marcoullis MD 40 Comprehensive Cancer Bronx USA

Center

David Linch MD 56 UCL London WC1E 6HX United Kingdon

A.Y. Rostom MD 50 The Royal Marsden Surrey, SM2 5PT United Kingdom

Hospital

Thomas A. Lister MD 51 St. Bartholomew\'s Hospital London EC1A 7BE
United Kingdom

Peter Johnson MD 53 Southampton General Southampton S016 6YD United
Kingdom

Hospital

David Spooner MD 57 Queen Elizabeth Hospital Birmingham B15 2TH United
Kingdom

Ann Hunter MD 63 Leicester Royal Infirmary Leicester LE1 5WW United
Kingdom

Kliniek

Simon M.G.J. Daenen MD 49 University Hospital 9713 GZ Groningen The
Netherlands

Albert Twijnstra MD 54 University Hospital of 6202 AZ Maastricht The
Netherlands

Maastricht

Christiana Sessa MD 45 Ospedale San Giovanni Bellinzona Switzerland

John Crown MD 58 St. Vincent\'s Hospital Dublin 4 Ireland

Simus O\'Reilly MD 64 Cork University Hosptial Wilton, Cork Ireland

Maccon Keane MD 65 University College Galway Ireland

Hospital

Brian Moulton MD 68 Irish Clinical Oncology Dublin 2 Ireland

Research Group

Dieter Hoelzer MD 52 Klinilum der J.W. 60590 Frankfurt Germany

Goethe-Universitat

Mathias Schmid MD 59 Unilkinilum Ulm D-89070 Ulm Germany

[**Investigator** **Center No.** **Institution** **City**
**Country**]{.underline}

Dirk Behringer MD 60 Universitatsklinikum-Freiburg D-79106 Freiburg
Germany

K. Hossfeld MD 61 Medizinische Universitatsklinik D-20246 Hamburg
Germany

Kurt Possinger MD 62 Charite University Hospital Mitte D-Berlin Germany

Jean-Louis Misset MD 43 Hopital Saint-Louis 75010 Paris France

Jean-Pierre Droz MD 44 Center Leon Berard Lyon France

Sopie Taillibert MD 46 Chu Pitie-Salpetriere Hospital Paris Cedex
F-75651 France

Jean-Luc Harousseau MD 47 Centre Hospitalier Universitaire 44093 Nantes
Cedex 1France

Bertrand Coiffier MD 48 Centre Hospitaliere F-69495 Pierre-Benite France

Rena Buckstein MD 22 Toronto Sunnybrook Toronto Canada

Regional Cancer Centre

David Eisenstat MD 34 CancerCare Manitoba Winnipeg Canada

Dominique Lossignol MD 41 Institut Jules Bordet Bruxelles B-1000 Belgium