DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ANTIVIRAL DRUGS ADVISORY COMMITTEE
IMMUNOSUPPRESSIVE DRUGS SUBCOMMITTEE MEETING
NDA 21-083 Rapamune (sirolimus) Oral Solution
Cyclosporine Withdrawal Maintenance Regimen
Thursday, January 24, 2002
Holiday Inn Gaithersburg
Two Montgomery Village Avenue
Janet A. Englund, M.D., Chairperson
Tara P. Turner, Pharm.D., Executive Secretary
Victor DeGruttola, Sc.D.
Darrell Abernethy, M.D., Ph.D.
Hugh Auchincloss, Jr., M.D. (CBER
Steven Ebert, Pharm D. (Consumer
Lynt B. Johnson, M.D.
William G. Lawrence, J.D. (CBER
Ron Shapiro, M.D.
Mannikam Suthanthiran, M.D.
Lawrence Hunsicker, M.D.
Roslyn B. Mannon, M.D.
Renata Albrecht, M.D.
Marc Cavaille-Coll, M.D., Ph.D.
Mark Goldberger, M.D., M.P.H.
Rosemary Tiernan, M.D., M.P.H.
C O N T E N T S
Call to Order and Opening Remarks
Janet Englund, M.D. 4
Conflict of Interest Statement
Tara P. Turner, Pharm.D. 6
FDA Introductory Remarks
Renata Albrecht, M.D. 9
Sponsor Presentation, Wyeth-Ayerst Research
Introduction: Randall B. Brenner, M.S. 12
Overview: John F. Neylan, M.D. 18
Design of Clinical Studies: John F. Neylan, M.D. 25
Efficacy Review: John F. Neylan, M.D. 33
Safety Review: John F. Neylan, M.D. 49
Pharmacokinetics: James Zimmerman, Ph.D. 70
James Zimmerman, Ph.D. --
Therapeutic Drug Monitoring:
James Zimmerman, Ph.D. --
Concluding Remarks: John F. Neylan, M.D. 87
Rosemary Tiernan, M.D., M.P.H. 114
Open Public Hearing
Alan Wilkinson, M.D., F.R.C.P. 167
Charge to the Subcommittee 185
Subcommittee Discussion and Vote 188
1 P R O C E E D I N G S
2 CALL TO ORDER
3 DR. ENGLUND: Good morning, everyone.
4 Welcome to the Subcommittee for Immunosuppressants
5 Meeting of the Antiviral Drugs Advisory Committee
6 group. I hope you are all in the right place here.
7 My name is Janet Englund. I am the Acting
8 Chairperson for this session. I am from the
9 University of Chicago and am a member of the
10 Antiviral Drugs Advisory Committee. We are very
11 grateful to have such knowledgeable guests and
12 voting members here to help us with the discussion
14 At this point in time, I think what we can
15 do is ask everyone at the table to introduce
16 themselves, their name and their affiliation.
17 Perhaps, if we could start at the very back, to my
19 DR. MANNON: I am Dr. Roslyn Mannon. I am
20 the transplant nephrologist at NIH and I am the
21 Medical Director of Transplantation at the NIDDK
22 Organ Transplant Program where we do kidney,
23 kidney-pancreas, pancreas transplants and, for the
24 past year and a half, have had extensive use in
1 DR. HUNSICKER: Larry Hunsicker from the
2 University of Iowa. I am a transplant nephrologist
3 also. I am a clinical trialist. I think that
5 MR. LAWRENCE: William Lawrence. I am an
6 attorney. I am Director of Patient Affairs for the
7 United Network for Organ Sharing. I am a liver
8 recipient of some fourteen years.
9 DR. AUCHINCLOSS: My name is Hugh
10 Auchincloss. I am a transplant surgeon at Harvard.
11 DR. ABERNETHY: Darrell Abernethy,
12 National Institute on Aging. I am a clinical
14 DR. DeGRUTTOLA: Victor DeGruttola,
15 statistician at Harvard School of Public Health.
16 DR. TURNER: Tara Turner, Executive
17 Secretary for the Committee.
18 DR. EBERT: Steven Ebert. I am an
19 infectious diseases pharmacist at Meriter Hospital
20 and Professor of Pharmacy at the University of
22 DR. SUTHANTHIRAN: Mannikam Suthanthiran.
23 I am Chief of Transplantation Medicine at New York
24 Hospital, Cornell Medical Center.
25 DR. SHAPIRO: I am Ron Shapiro. I am
1 Director of Renal Transplantation at the Thomas E.
2 Stassel Transplantation Institute at the
3 University of Pittsburgh.
4 DR. TIERNAN: Rosemary Tiernan, medical
5 reviewer, FDA.
6 DR. CAVAILLE-COLL: Marc Cavaille-Coll,
7 medical team leader, Division of Special Pathogen
8 and Immunologic Drug Products, FDA.
9 DR. ALBRECHT: I am Renata Albrecht,
10 Acting Director, Division of Special Pathogen and
11 Immunologic Drug Products.
12 DR. ENGLUND: Thank you. Welcome,
13 everyone. I would like now to have Tara Turner,
14 the Executive Secretary, read the conflict of
15 interest statement.
16 Conflict of Interest Statement
17 DR. TURNER: Thank you. The following
18 announcement addresses the issue of conflict of
19 interest with regard to this meeting and is made a
20 part of the record to preclude even the appearance
21 of such at this meeting.
22 Based on the submitted agenda for the
23 meeting and all financial interests reported by the
24 committee participants, it has been determined that
25 all interests in firms regulated by the Center for
1 Drug Evaluation and Research which have been
2 reported by the participants present no potential
3 for an appearance of a conflict of interest at this
4 meeting with the following exceptions.
5 Dr. Ron Shapiro has been granted waivers
6 under 18 USC 208(b)(3) and 21 USC 355(n)(4)
7 amendment of Section 505 of the Food and Drug
8 Administration Modernization Act for his lectures
9 supported by a competitor on unrelated matters. He
10 receives more than $10,000 a year.
11 Dr. Janet Englund has been granted a
12 waiver under 18 USC 208(b)(3) for her consulting
13 for a competitor on unrelated matters. She
14 receives less than $10,000 a year.
15 Dr. Lawrence Hunsicker has been granted
16 limited waivers allowing his participation without
17 voting privileges under 18 USC 208(b)(3) and 21 USC
18 355(n)(4) amendment of Section 505 of the Food and
19 Drug Modernization Act for three grants and
20 contracts to his employer. The first is a grant
21 from the federal government and a competitor
22 involving competing products funded for less than
23 $100,000 per year. The second is a contract from a
24 competitor involving competing products and the
25 product at issue. However, Dr. Hunsicker is
1 unaware of the details of this contract. The third
2 is a grant from the federal government involving
3 competing products which receives funding greater
4 than $300,000 per year.
5 A copy of these waiver statements may be
6 obtained by submitting a written request to the
7 agency's Freedom of Information Office, Room 12A30,
8 of the Parklawn Building. In the event that the
9 discussions involve any other products or firms not
10 already on the agenda for which an FDA participant
11 has a financial interest, the participants are
12 aware of the need to exclude themselves from such
13 involvement and their exclusion will be noted for
14 the record.
15 With respect to all other participants, we
16 ask, in the interest of fairness, that they
17 address any current or previous financial
18 involvement with any firm whose products they may
19 wish to comment upon.
20 Thank you.
21 DR. ENGLUND: Thank you. I think we have
22 Dr. Johnson here with us, if you want to introduce
24 DR. JOHNSON: I apologize for the
25 tardiness. Sometimes, it is hard when you have a
1 meeting that is at home. I am Lynt Johnson. I am
2 the Director of Transplantation at Georgetown
3 University Medical Center here in Washington, D.C.
4 DR. ENGLUND: Thank you. Glad you're
6 At this point, I would like Dr. Renata
7 Albrecht, who is Acting Director of the Division of
8 Special Pathogens and Immunological Drug Products
9 at the FDA, to give us some opening remarks.
10 FDA Introductory Remarks
11 DR. ALBRECHT: Thank you, Dr. Englund. On
12 behalf of the Division, I would like to extend a
13 welcome to you, Dr. Englund, to the members of the
14 committee, our distinguished guests and
15 representatives from Wyeth-Ayerst. We very much
16 appreciate your being here today to discuss a new
17 Rapamune regimen in the management of patients with
18 renal transplants.
19 Specifically, this is the first time the
20 agency and the committee has been asked to consider
21 a regimen, a maintenance regimen, in which
22 cyclosporine is withdrawn as the Rapamune dose is
23 increased to target blood levels.
24 Many of you will recall the original
25 application for Rapamune was brought before this
1 subcommittee in the summer of 1999 and resulted in
2 the approval of Rapamune, the 2 milligram dose, in
3 combination with cyclosporine and steroids for
4 maintenance. Results were also presented for the 5
5 milligram dose which was interpreted as showing
6 similar efficacy and increased toxicity.
7 One of the noteworthy findings from those
8 original studies was the reduction in
9 glomerular-filtration rate noted in the Rapamune,
10 cyclosporine and corticosteroid arm relative to the
11 other arm. This raised questions about long-term
12 consequences of the regimen and also prompted the
13 agency to ask the sponsor to conduct some phase IV
15 Now the company has submitted to us a
16 supplemental application containing studies in
17 which many patients were randomized to the
18 cyclosporine-withdrawal arm and had the Rapamune
19 doses increased. Questions that arise are whether
20 the cyclosporine withdrawal may have affected
21 efficacy either favorably or unfavorably.
22 The other questions are regarding safety.
23 Are there changes in the safety profile. Has the
24 GFR been preserved? Are there other new toxicities
25 that may be introduced with this new regimen?
1 These are some of the questions that we will be
2 asking you to deliberate during the course of this
4 Finally, I would like to express our
5 appreciation to Wyeth for putting forth a great
6 effort in planning in bringing forth this
7 application to the committee for discussion. I
8 would also like to recognize some of my colleagues,
9 Dr. Marc Cavaille-Coll, Rosemary Tiernan, Karen
10 Higgins and Cheryl Dixon for the intense effort
11 they have put forth into this project.
12 In the first part of the morning, Wyeth
13 will present a number of talks on the clinical and
14 pharmacokinetic findings from their studies. This
15 will be followed by a presentation by Dr. Rosemary
16 Tiernan. Finally, as I mentioned, we do have a
17 number of questions that we would like the
18 committee to deliberate and give us guidance on
19 this application and on issues relative to
20 clinical-study endpoints.
21 With that, thank you and I will return it
22 to you, Dr. Englund.
23 DR. ENGLUND: Thank you. At this point, I
24 think I would like to introduce Randall Brenner
25 from Wyeth-Ayerst Research to start your
2 Sponsor Presentation--Wyeth-Ayerst Research
4 DR. BRENNER: Good morning, everyone.
6 I am Randy Brenner from the Regulatory
7 Affairs Department at Wyeth-Ayerst. On behalf of
8 our organization, we are pleased to have this
9 opportunity today to review the data supporting our
10 supplemental NDA for the cyclosporine elimination
11 indication for Rapamune for use in renal-transplant
14 Our presentation today has the following
15 agenda. Upon completion of my brief introductory
16 remarks, Dr. John Neylan will discuss the need for
17 a calcineurin-inhibitor-free immunosuppressive
18 regimen in renal-transplant patients. He will
19 review in detail the designs of our pivotal-study
20 Protocol 310 and a supportive phase II study
21 Protocol 212 and provide a review of the collective
22 efficacy and safety data from these studies.
23 Following Dr. Neylan, Dr. James Zimmerman
24 will review the pharmacokinetics of Rapamune in
25 concentration-controlled trials and therapeutic
1 drug monitoring in this patient population.
2 For a conclusion, Dr. Neylan will return
3 and summarize the results presented today and
4 address any questions you may have.
6 The oral solution formulation of Rapamune
7 was first approved in the United States in
8 September of 1999. This application received a
9 priority review from FDA and was presented to this
10 advisory committee in July of 1999.
11 The approved package insert recommends
12 fixed dosing of this product in combination with
13 cyclosporine. Specifically, a 6 milligram loading
14 dose followed by a 2 milligram fixed daily dose is
15 recommended for most patients. A 5 milligram dose
16 has also been approved.
17 Immediately following approval of the oral
18 solution formulation, an application requesting
19 approval of a tablet formulation was submitted to
20 FDA. The 1 milligram tablet, which was approved in
21 August of 2000, provided significant advantages
22 over the oral solution in terms of patient
23 convenience while not compromising safety or
1 The original advisory committee
2 presentation was supported by two phase II pivotal
3 studies, Protocols 301 and 302. These studies
4 demonstrated that, when used in combination with
5 cyclosporine, patients receiving fixed doses of
6 Rapamune had significantly lower rates of acute
7 rejection at less than 18 percent while maintaining
8 excellent patient and graft survival at greater
9 than 95 and 90 percent respectively.
10 As such, this committee voted unanimously
11 that this product was safe and efficacious. One of
12 the more important issues discussed in detail was
13 the unexpected impact of the Rapamune-cyclosporine
14 combination on renal function. As a result, this
15 committee and the FDA recommended that Wyeth
16 further evaluate this finding.
17 We were optimistic that we could
18 demonstrate that the observed renal effects in
19 Protocols 301 and 302 were due to the exacerbation
20 of cyclosporine toxicity and were not directly
21 related to Rapamune.
23 To demonstrate this, we looked at the
24 information we knew from our phase III pivotal
25 studies, Protocols 310 and 302, which used fixed
1 dosing of Rapamune in combination with
2 cyclosporine. We also looked at information we
3 knew from additional phase II studies which used
4 Rapamune as base therapy demonstrating a favorably
5 safety profile with significant improvements in
6 renal function.
7 This was further supported by animal data
8 demonstrating Rapamune to be nonnephrotoxic and an
9 effective immunosuppressive agent when evaluated
10 alone. Rapamune's inherent absence of
11 nephrotoxicity is what makes a
12 calcineurin-inhibitor-free regimen with this
13 product potentially so beneficial to
14 renal-transplant patients.
15 As a result, we designed the current
16 registration studies, Protocols 212 and 310. These
17 studies evaluated the currently approved
18 combination of Rapamune plus cyclosporine versus a
19 group of patients that had cyclosporine eliminated
20 from the immunosuppressive regimen two or three
21 months after transplantation.
22 Additional details regarding the designs
23 of these studies will be presented by Dr. Neylan in
24 the design portion of this presentation.
1 Protocols 212 and 310, the studies in the
2 current application, demonstrate equivalent
3 efficacy with excellent patient and graft survival
4 with an improvement in safety specifically in
5 regard to renal function and blood pressure.
6 Importantly, despite a difference in the number of
7 acute-rejection episodes immediately following
8 cyclosporine elimination, by month 12, there were
9 similar rates of acute-rejection episodes in both
11 Dr. Neylan will relate the impact of acute
12 rejection immediately following cyclosporine
13 elimination as it relates to severity, long-term
14 patient and graft survival and the impact on renal
17 The application currently under review and
18 in front of this committee today seeks approval of
19 an indication that will allow for the elimination
20 of cyclosporine from the immunosuppressive regimen.
21 The Rapamune dosing for this new indication
22 recommends fixed dosing for the initial
23 post-transplant period.
24 At the time of cyclosporine withdrawal, at
25 two to four months post-transplantation, Rapamune
1 dosing will be based on trough concentration levels
2 within a recommended range. As this new dosing
3 will require patient dosing utilizing trough
4 concentration levels, therapeutic drug monitoring
5 will now be required.
6 Dr. Zimmerman will discuss therapeutic
7 drug monitoring in detail during his presentation.
9 As a reminder, Rapamune is currently
10 indicated in use in combination with cyclosporine.
11 The currently approved indication is provided here.
12 Rapamune is indicated for the prophylaxis of organ
13 rejection in patients receiving rental transplants.
14 It is recommended that Rapamune be used in a
15 regimen with cyclosporine and corticosteroids.
16 You will see today that the results of
17 Studies 212 and 310 provide physicians with an
18 alternate dosing regimen for Rapamune which
19 provides acceptable immunosuppressive while
20 preserving renal function. As such, we seek
21 approval of an indication provided here in which
22 Rapamune is indicated for the prophylaxis of organ
23 rejection in patients receiving renal transplants.
24 It is recommended that Rapamune be used initially
25 in a regimen with cyclosporine and corticosteroids.
1 Cyclosporine withdrawal should be considered two to
2 four months after transplantation.
3 This concludes my introduction. I would
4 now like to introduce Dr. John Neylan, the Vice
5 President of Clinical Research and Development for
8 DR. NEYLAN: Thank you Randy, and good
11 As Mr. Brenner told you, Rapamune was
12 recommended for approval by this committee in 1999
13 in combination with cyclosporine for the prevention
14 of rejection in renal-transplant patients. The
15 registration of this product has provided new
16 opportunities to advance immunosuppressive therapy
17 and improve patient outcomes.
18 We are here today to provide additional
19 data which will allow transplant physicians new
20 opportunities to build upon this success, improve
21 graft function and potentially extend the life of
22 transplant kidneys.
24 While the addition of new drugs has
25 decreased the incidence of acute rejection and
1 improved graft survival in the short term,
2 long-term outcomes remains suboptimal. Indeed,
3 most patients must continue to expect that their
4 transplants will fail within a decade.
5 In most cases, this graft failure will be
6 secondary to a deterioration, progressive over
7 time, in renal function.
9 Calcineurin inhibition, while providing
10 effective immunosuppressive, has long been
11 associated with time and dosage-dependent
12 toxicities that may lead to chronic allograft
13 nephropathy. This nephrotoxic injury has been
14 reported in up to 65 percent of renal, liver, heart
15 and bone-marrow transplant recipients and has been
16 directly implicated in causing end-stage renal
17 disease in up to 10 percent of nonrenal solid-organ
19 It is not surprising, then, that, since
20 1983 and the introduction of cyclosporine,
21 clinicians have continued in their quest to
22 eliminate nephrotoxicity. Our goal today is to
23 provide data to convince you that patients will
24 benefit from withdrawal of cyclosporine and
25 maintenance therapy with Rapamune. That is the
1 single objective of the current studies.
3 Rapamune, through its distinct biologic
4 activity and non nephrotoxic profile, offers the
5 opportunity to provide a new cornerstone to
6 immunosuppressive regimens. Although many of you
7 are familiar with the mechanism of action, I will
8 briefly review it now.
10 Rapamune is a novel drug, neither a
11 calcineurin inhibitor nor an antimetabolite. It
12 has a unique cellular target, mTOR, the mammalian
13 target of rapamycin. mTOR is a protein kinase
14 which is critical for cell-cycle progression and
15 cell proliferation. Rapamune blocks mTOR. This
16 action blocks cytokine-mediated cell proliferation
17 in T-cells, B-cells and mesenchymal cells including
18 smooth-muscle cells.
20 All known therapeutic effects of Rapamune
21 result from inhibition of mTOR. Critical pathways
22 affected by Rapamune include the following. One,
23 activation of translation for specific messenger
24 RNAs coding for cell-cycle proteins. Two,
25 activation of cyclin-dependent kinases required for
1 coordinated DNA synthesis. Three, synthesis of
2 specific ribosomal proteins required for cell-cycle
4 The interaction of Rapamune with mTOR is
5 specific and it is reversible and, importantly,
6 Rapamune is not cytotoxic. In summary, the
7 biologic activity of Rapamune as an inhibitor of
8 cell-cycle progression is consistent with both the
9 immunosuppressive and antiproliferative effects of
10 the molecule.
12 Next, we will review the data supporting
13 the design of the current registration trials.
14 This includes the utility and outcome seen when
15 Rapamune is administered with cyclosporine to
16 renal-transplant recipients. In addition, data
17 will be presented from clinical studies in which
18 Rapamune was utilized as a prophylactic agent in
19 renal-transplant patients.
20 Finally, data will be presented in which
21 Rapamune was utilized as primary therapy for
22 recalcitrant psoriasis.
24 In two phase III blinded trials comprising
25 some 1300 patients, Rapamune at 2 milligrams per
1 day or 5 milligrams per day was coadministered with
2 cyclosporine and corticosteroids and compared with
3 either placebo or azathioprine controls.
4 The Rapamune treatment groups proved to
5 have low rates of acute rejection and twelve-month
6 patient and graft survival was excellent. However,
7 an unanticipated finding in the unblinding of these
8 studies was the somewhat higher mean serum
9 creatinines in the Rapamune-treated patients.
10 Data from other trials with Rapamune had
11 suggested that the drug was not inherently
12 nephrotoxic. Thus, the change in renal function in
13 these studies was considered to be secondary to an
14 exacerbation of cyclosporine toxicity and not
15 directly related to Rapamune.
17 The absence of nephrotoxicity is supported
18 by data obtained from two phase II trials in which
19 Rapamune was utilized as primary therapy in the
20 absence of cyclosporine. In one trial, study 207,
21 patients were randomized to receive either Rapamune
22 or cyclosporine in combination with azathioprine
23 and corticosteroids.
24 In the second trial, study 210, patients
25 received either Rapamune or cyclosporine with
1 concomitant mycophenolate mofetil and
4 Pooled data from these studies
5 demonstrated that Rapamune and cyclosporine had
6 similar benefits in the prevention of acute
7 rejection and two-year patient and graft survival
8 but were associated with very different effects on
9 renal function.
10 Shown here are statistically significant
11 improvements in both creatinine and calculated
12 glomerular filtration rates in the Rapamune-treated
13 patients. These improvements were seen early and
14 were sustained over 24 months of follow up.
16 In psoriatic patients, Rapamune as
17 monotherapy similarly demonstrated no adverse
18 effects on renal function. Patients with
19 recalcitrant psoriasis were administered Rapamune
20 monotherapy at doses of 1, 3 and 5 milligrams per
21 meter squared per day and compared with
22 placebo-treated patients. There were no
23 differences seen in mean serum creatinines
24 following twelve weeks of therapy in any of the
25 treatment groups even when Rapamune was
1 administered at doses as high as 10 milligrams per
4 In summary, when Rapamune was administered
5 in two phase III trials with concomitant
6 cyclosporine treatment, low rates of acute
7 rejection but higher serum-creatinine
8 concentrations were observed compared to control
9 therapies. When Rapamune was administered to
10 renal-transplant patients as primary therapy for up
11 to 24 months in doses ranging from 6 to 9
12 milligrams per day, these patients enjoyed similar
13 patient and graft survival but had lower serum
14 creatinines and higher glomerular-filtration rates
15 compared to cyclosporine-treated patients.
16 Rapamune administered as monotherapy to
17 patients with recalcitrant psoriasis at doses of up
18 to 10 milligrams per day had no adverse impact upon
19 renal function. These collective data demonstrated
20 the clinical utility of Rapamune in a variety of
21 settings. While the combination of Rapamune plus
22 cyclosporine resulted in improved rejection
23 outcomes, the changes in renal function were in
24 clear contrast to studies in which Rapamune was
25 used without concomitant cyclosporine.
1 Design of Clinical Studies
2 DR. NEYLAN: These collective observations
3 led us to conduct trials of Rapamune-based therapy
4 to test the benefit of cyclosporine elimination.
6 We worked closely with over 60
7 investigators worldwide to develop studies that
8 would test the hypothesis that Rapamune-based
9 therapy could replace long-term cyclosporine-based
12 Since the introduction of cyclosporine,
13 numerous trials have been conducted to examine
14 whether this agent could be safely withdrawn from
15 long-term maintenance regimens. Many such studies
16 were based on a classic elimination strategy in
17 which immunosuppression was maximized early on for
18 its potential benefits in the prophylaxis of acute
19 rejection with subsequent elimination of
20 cyclosporine in the maintenance phase to decrease
21 long-term toxicity.
23 Studies 310 and 212 were modeled after
24 designs tested in previous elimination trials.
25 Specifically, all of the patients were treated for
1 the first two to three months with a regimen
2 consisting of Rapamune plus cyclosporine and
3 corticosteroids to maximize freedom from rejection
4 during this period of greatest immunologic risk.
6 As we previously demonstrated in two large
7 pivotal trials, Rapamune, in combination with
8 cyclosporine, provides one of the lowest rates of
9 acute rejection in this early post-operative period
10 when compared with other immunosuppressive
12 Following the period of initial risk,
13 patients in the control groups continue to receive
14 combination therapy with cyclosporine while
15 patients in the treatment arms had cyclosporine
16 withdrawn from regimen and concentration-control
17 Rapamune continued during the maintenance phase.
18 The comparison of these regimens allowed us to
19 examine the incidence of acute rejection when
20 cyclosporine was withdrawn and to identify
21 differences in the safety profiles following the
22 elimination of cyclosporine.
23 The pivotal phase III trial in this
24 application is study 310. It is supported with
25 data from Study 212, a smaller phase II trial.
1 Both trials were open label, controlled, randomized
2 and multicenter. Study 310 was conducted in 57
3 centers in Australia, Canada and Europe and
4 included a total of 525 patients.
5 These patients were either primary or
6 secondary recipients of renal allografts and
7 received donor organs from either cadaveric or
8 HLA-mismatched living donors. Randomization in
9 this trial occurred at Month 3.
10 In Study 212 conducted in 17 centers in
11 the U.S. and Europe, 246 patients were enrolled.
12 These patients were recipients of primary renal
13 allografts from cadaveric donors with randomization
14 occurring Days 2 through 7 following
15 transplantation. It is important to note that, in
16 both studies, all centers were required to follow
17 the patients for the full duration of the study for
18 the occurrence of acute rejection, graft survival,
19 patient survival and serious adverse events even if
20 these patients discontinued study medication.
22 The primary endpoints of the two studies
23 differed. study 310 was powered for equivalent
24 graft survival at one year while study 212 was
25 powered to demonstrate a significant difference in
1 renal function in a population of patients who
2 remained rejection free and on therapy at six
3 months following transplantation. For those
4 studies, multiple secondary endpoints were
7 For study 310, major secondary endpoints
8 included patient survival, the incidence of
9 biopsy-confirmed acute rejection, renal function,
10 efficacy failure and treatment failure. For study
11 212, major secondary endpoints included patient and
12 graft survival, the incidence of biopsy-confirmed
13 acute rejection, renal function beyond six months
14 and treatment failure.
16 Exclusion criteria for randomization were
17 slightly different for the two studies. In study
18 310, all enrolled patients went on to randomization
19 at month 3 with the following exceptions. Patients
20 were excluded from randomization if they had a
21 Banff grade III acute rejection or vascular
22 rejection during the preceding four weeks.
23 Patients were excluded if they were
24 dialysis-dependent at the time of randomization or
25 had a serum creatinine in excess of 4.5 milligrams
1 per deciliter. Finally, patients were excluded if,
2 in the opinion of the study investigator, they had
3 the inadequate renal function to continue in the
5 For study 212, all enrolled patients were
6 randomized at days 2 through 7 with the following
7 exceptions. Patients were not randomized if, in
8 the opinion of the investigator, they had
9 inadequate renal function within the first 48 hours
10 following transplantation or had ongoing acute
11 tubular necrosis or delayed graft function
12 persisting at day 7 post transplant.
14 In total, studies 310 and 212 included 771
15 patients. Of the 525 patients enrolled in study
16 310, 215 were randomized to the Rapamune plus
17 cyclosporine group and 215 were randomized to the
18 Rapamune group. 95 patients were not eligible for
19 randomization. In study 212, 246 patients were
20 enrolled and 97 were randomized to the cyclosporine
21 plus Rapamune group and 100 were randomly assigned
22 to the Rapamune group. 49 patients were not
23 eligible for randomization. However, in study 212,
24 the nonrandomized patients were permitted to
25 receive Rapamune at a dose of up to 5 milligrams
1 per day along with cyclosporine. These patients
2 continued to have follow up through month 12.
3 Note the color scheme used in this slide
4 and throughout the remainder of the presentation.
5 The Rapamune plus cyclosporine group is shown in
6 red and the Rapamune group is depicted in purple.
8 In study 310, a total of 525 patients were
9 enrolled and were administered a regimen consisting
10 of a single loading dose of 6 milligrams of
11 Rapamune followed by a fixed dose of 2 milligrams
12 per day. Cyclosporine was coadministered to
13 maintain trough concentrations of 200 to 400
14 nanograms per ml for the first month followed by a
15 gradual reduction through month 3.
16 At month 3, patients were randomly
17 assigned to one of two treatment groups. 215
18 patients were randomly assigned to the Rapamune
19 plus cyclosporine group. Patients in this group
20 continued to receive fixed doses of Rapamune at 2
21 milligrams per day. Cyclosporine was gradually
22 tapered for the specified ranges for the duration
23 of the study period.
24 215 patients were also randomly assigned
25 to the Rapamune group. This group of patients
1 received doses of Rapamune to maintain a sirolimus
2 trough concentration range of 20 to 30 nanograms
3 per ml from the time of randomization through the
4 end of month 12. Thereafter, sirolimus trough
5 concentrations remained at 15 to 25 nanograms per
6 ml for the duration of the study.
7 After randomization, patients had the dose
8 of cyclosporine tapered by 25 percent per week and
9 cyclosporine was to be completely eliminated from
10 the regimen within four weeks time. Patients in
11 both randomized groups received standard tapering
12 doses of corticosteroids.
14 In study 212, 246 patients were randomly
15 assigned to one of the two treatment groups. 97
16 were randomly assigned to the Rapamune plus
17 cyclosporine group. Patients in this group were
18 administered a regimen consisting of a single
19 loading dose of Rapamune followed by a fixed dose
20 of 2 milligrams per day.
21 Cyclosporine was coadministered to
22 maintain trough concentration ranges of 200 to 400
23 nanograms per milligram for the first month and was
24 gradually tapered to the specified ranges for the
25 duration of the treatment period. 100 patients
1 were assigned to the Rapamune group. The patients
2 in this group were administered a regimen
3 consisting of fixed doses of Rapamune at 20
4 milligrams daily for the first three days followed
5 by 10 milligrams daily through day 10.
6 Thereafter, sirolimus trough
7 concentrations were maintained at a target range of
8 10 to 20 nanograms per milligram for the duration
9 of the study period. Patients also continued to
10 receive reduced doses of cyclosporine for the first
11 month after randomization at a concentration range
12 of 100 to 175 nanograms per milligram and were then
13 tapered down to 100 to 150 nanograms per milligram
14 through month 2.
15 The dose of cyclosporine was further
16 tapered by 25 percent per week and cyclosporine was
17 to be completely eliminated from the regimen by the
18 end of month 3. The patients in this study also
19 received standard tapering doses of
22 It is important to note that the efficacy
23 and safety data from studies 310 and 212 were
24 deliberately not integrated. The designs of the
25 two studies, while similar, were distinct in
1 several important features. Time of randomization
2 differed. Study 310 allowed us to maximize the
3 opportunity to compare like patients at the onset
4 of cyclosporine withdrawal.
5 Different target sirolimus and
6 cyclosporine trough concentrations were also
7 utilized in the two studies. Complete safety and
8 efficacy data through 12 months will be presented
9 for both studies. For study 310, cumulative safety
10 data are presented for all patients through
11 month 15 with limited data being available through
12 month 24.
13 Efficacy Review
15 DR. NEYLAN: The efficacy comparisons in
16 each study will be now be reviewed.i
18 This slide shows the similar distribution
19 of key demographic variables among patients
20 enrolled in study 310. Comparing the features of
21 all enrolled patients to that of the randomized
22 groups shows only a slightly higher rate of delayed
23 graft function, shown here.
24 The groups were otherwise well matched for
25 gender, ethnic origin, age, receipt of a first or
1 second allograft, ischemia time and degree of HLA
2 mismatch. When compared to the UNOS database, the
3 race disparity is obvious.
4 But other features are similar including
5 rates of delayed graft function in the study groups
6 that were slightly greater than that of the U.S.
7 renal transplant population. Though not shown on
8 this slide, there were also no differences observed
9 in donor characteristics including donor source,
10 ethnic origin or age.
12 The intent-to-treat analysis of the
13 primary efficacy endpoint for study 310, graft
14 survival at twelve months, is shown here with a 95
15 percent confidence interval of the differences in
16 rates. The twelve-month graft survival was
17 equivalent and excellent in both groups. Rates
18 were high in excess of 95 percent in both cohorts.
19 There were similar rates of physical and
20 functional graft loss as well as graft loss
21 secondary to patient death. Note also that there
22 was 100 percent follow up for patients in both
23 randomized groups.
25 Similarly, patient survival in the
1 intent-to-treat population was equivalent at twelve
2 months following transplantation. The survival
3 rate exceeded 97 percent in both groups.
5 This Kaplan-Meier plot shows the incidence
6 of first-biopsy-confirmed acute-rejection episodes
7 in study 310. In the prerandomization period,
8 before month 3, there were similar rates of acute
9 rejection for all enrolled patients. For month 3
10 through 12, there was an incremental increase in
11 rejection frequency in the Rapamune arm. The
12 combined incidence of acute rejection over the
13 first twelve months was not statistically different
14 for both randomized groups, 13.5 percent for the
15 Rapamune plus cyclosporine group compared with 20
16 percent for the Rapamune group.
18 How does the acute-rejection rate compare
19 with other registration trials? The initial
20 therapy provided low acute-rejection rates which
21 meet the standards for immunosuppressive therapy
22 for today's transplant recipient. Specifically,
23 the use of Rapamune in combination with
24 cyclosporine was associated with the rejection rate
25 of only 12 percent for the entire enrolled
1 population of 525 patients.
2 These rejection rates compare favorably
3 with recently published registration trials.
5 At twelve months, acute-rejection rates in
6 all enrolled patients, not just those randomized to
7 the two treatment arms, were again equal to or
8 better than recently published registration trials
9 in which calcineurin inhibitors were included and
10 maintained in the regimen.
12 Following month 3 and the onset of
13 cyclosporine elimination, the incremental increase
14 in first biopsy-confirmed rejection was modest at
15 9.8 percent but was significantly higher than the
16 rejection rate in the control arm at 4.2 percent.
17 Even though the rejection rates were low,
18 an important question to ask is whether outcomes
19 for those patients who had rejection episodes were
20 worse than would be expected. Importantly, for
21 patients experiencing rejection in either treatment
22 arm, there was a single death in the Rapamune plus
23 cyclosporine group and no deaths in the Rapamune
25 Additionally, there was only one graft
1 loss in each group.
3 The histologic severity of acute-rejection
4 episodes was similar in the two groups. The
5 majority of these episodes were mild and no patient
6 experienced an episode of severe acute rejection
7 following cyclosporine elimination. The use of
8 antibody therapy to treat acute rejection was also
9 similar and was utilized in only two patients.
11 Another important variable in assessing
12 the impact of acute rejection is the potential
13 effect on subsequent graft function. This analysis
14 compares the change in glomerular-filtration rate
15 from baseline to twelve months in randomized
16 patients who subsequently did or did not experience
17 an acute-rejection episode.
18 On the left, patients without acute
19 rejection had experienced a change in renal
20 function at twelve months consistent with the study
21 as a whole. Specifically, function improved in
22 patients in the Rapamune arm while it worsened for
23 patients maintained in the Rapamune plus
24 cyclosporine group.
25 On the right are depicted patients with
1 acute rejections after month 3. As might be
2 expected, the GFR at twelve months was numerically
3 lower for patients in either group who had
4 experienced an episode of acute rejection.
5 However, the GFR for rejectors in the Rapamune
6 group remained stable through twelve months. This
7 stability suggests that the adverse impact of acute
8 rejection upon renal function appeared to be
9 lessened with the elimination of cyclosporine.
11 The combination of Rapamune plus
12 cyclosporine in the first three months following
13 transplantation maintained very low rejection rates
14 which were equal to or better than those observed
15 in recent registration trials. The incremental
16 increase in acute rejection following cyclosporine
17 elimination was statistically higher in the
18 Rapamune group with an absolute difference of 6
20 This compares favorably with previous
21 trials in which rates of rejection following
22 elimination are equal to or greater than those
23 observed in study 310. Episodes of rejection
24 attending cyclosporine elimination were generally
25 mild and clinically manageable. Importantly, there
1 were no episodes of severe rejection and only one
2 graft loss was reported in the Rapamune group.
3 In addition, at twelve months, there were
4 similar rates of acute rejection in the randomized
5 groups. As expected, at twelve months, the mean
6 GFRs in the rejectors were lower than those in the
7 nonrejectors. But, importantly, there was no
8 penalty in patients in whom cyclosporine was
11 Comparable rates of efficacy failure were
12 demonstrated. These composite rates at twelve
13 months following transplantation were primarily due
14 to the occurrence of acute rejections with very few
15 graft losses or patient deaths.
17 Treatment failure for study 310 was
18 defined as the first occurrence of rejection, graft
19 loss, death or discontinuation of study medication.
20 The overall treatment failure at twelve months was
21 significantly higher with patients randomized to
22 the Rapamune group. This was primarily due to the
23 numerically higher rates of acute rejection and for
24 discontinuations within the group.
25 On review of the clinical dataset, the
1 difference in the rate of treatment failure was no
2 longer statistically significant.
3 Now let's examine what many would consider
4 to be the most important efficacy endpoint in a
5 study of cyclosporine elimination, namely the
6 impact upon long-term graft function.
8 Shown here is the intent-to-treat analysis
9 of serum creatinine and glomerular-filtration rate
10 for patients enrolled in study 310. This
11 conservative analysis includes all enrolled
12 patients including those discontinued from therapy
13 and placed back on calcineurin inhibitors. For
14 both renal-function parameters, there was a
15 statistically significant improvement demonstrated
16 at the twelve-month time point for the Rapamune
19 In addition to the intent-to-treat
20 analysis demonstrating excellent patient and graft
21 survival and statistically significant improvements
22 in renal function, the on-therapy analysis also
23 showed a clear benefit for patients in whom
24 cyclosporine was eliminated and who were maintained
25 on concentration-controlled Rapamune.
1 This group included patients who may have
2 experienced an episode of acute rejection but
3 continued within the study and received study
4 medication. The graph on the left shows serum
5 creatinine. In the Rapamune treatment group, serum
6 creatinine was significantly lower at all time
7 points following randomization. It is also
8 noteworthy that this improvement is sustained
9 through 24 months of follow up.
10 The graph on the right shows calculated
11 glomerular-filtration rates at these same time
12 points. Again, the Rapamune-treated group had
13 significantly higher GFRs at all time points
14 persisting through month 24.
16 The benefits of cyclosporine elimination
17 on renal function were demonstrated by all patients
18 on therapy through twelve months and longer
19 regardless of their baseline renal function.
20 A quartile analysis was performed in which
21 patients were segregated according to baseline
22 renal function at the time of randomization. In
23 all four quartiles, the change from baseline was
24 favorable in comparison to patients maintained on
25 cyclosporine including those with more advanced
1 degrees of renal insufficiency at baseline.
2 Notably, even those patients with normal
3 renal function at baseline benefitted by the
4 removal of cyclosporine nephrotoxicity and its
5 consequent negative impact upon long-term renal
8 In summary, the patients enrolled in study
9 310 were similar to that of the U.S. population
10 with the exception of fewer black patients. At
11 twelve months, following transplantation, there was
12 equivalent patient and graft survival of greater
13 than 97 percent and 95 percent, respectively. In
14 addition, a low incidence of acute rejection at
15 twelve months was similar in the two randomized
16 groups and, perhaps most importantly, there was an
17 immediate improvement in renal function following
18 cyclosporine elimination which has been sustained
19 through 24 months of follow up.
20 Next, we will review the key efficacy data
21 for study 212.
23 Key demographic variables among patients
24 enrolled in study 212 were similar. The total
25 enrolled patient population is similar to that of
1 the two randomized groups. These were well matched
2 for gender, ethnic origin, age, ischemia time and
3 degree of HLA mismatch.
4 The demographics are also similar to that
5 of the UNOS population of renal-transplant
6 recipients in the U.S. except for the study's
7 exclusion of living donor recipients. Therefore,
8 while study 212 is generally representative of the
9 U.S. renal-transplant population, the 212 group was
10 also at a somewhat higher risk given the absence of
11 living-donor recipients.
12 Though not shown on this slide, the
13 patients in both groups had similar donor
14 characteristics including source, ethnic origin and
17 Twelve-month graft survival in study 212
18 was similar in the two treatment groups being in
19 excess of 92 percent in both. There was a slightly
20 higher rate of graft loss due to physical or
21 functional graft loss in the Rapamune plus
22 cyclosporine group compared with the Rapamune
23 group. Again, as with study 212, there was 100
24 percent patient follow up in both randomized
2 The intent-to-treat analysis of patient
3 survival in study 212 was similar. At twelve
4 months, patient survival was excellent and was at
5 least 96 percent on both groups.
7 This Kaplan-Meier plot shows the incidence
8 of first biopsy-confirmed acute-rejection episodes
9 in study 212. Prior to cyclosporine withdrawal,
10 there were similar rates of acute rejection in both
11 groups. Following month 2, there was an
12 incremental increase in the rate of acute rejection
13 in the Rapamune group but the difference between
14 the randomized groups never achieved statistical
16 The intent-to-treat analysis at month 12
17 demonstrated an incidence of acute rejection of
18 18.6 percent for the Rapamune plus cyclosporine
19 group compared with 22 percent for the
20 Rapamune-treated group.
21 As in study 310, it is important to
22 examine the outcome in those patients who
23 experienced acute rejection following the
24 elimination of cyclosporine. Following month 2,
25 there was a modest numerical increase in
1 first-biopsy-confirmed rejections at 14 percent
2 compared with the rejection rate in the control arm
3 of 6.2 percent.
4 Importantly, for patients experiencing
5 rejection in either treatment arm, there was a
6 single death and a single graft loss in the
7 Rapamune group and no deaths or graft losses in the
8 Rapamune plus cyclosporine group.
10 As with study 310, the histologic severity
11 of acute-rejection episodes was similar in the two
12 randomized groups. The majority of these episodes
13 were mild to moderate with only one patient in the
14 Rapamune plus cyclosporine group experiencing an
15 episode of severe acute rejection beyond the two
16 month time point.
18 This analysis compares the calculated GFR
19 in patients who did or did not experience an
20 acute-rejection episode following month 2 and the
21 onset of cyclosporine elimination.
22 On the left, patients without acute
23 rejection had experienced a change in renal
24 function at twelve months consistent with the study
25 as a whole. Specifically, function improved in
1 patients in the Rapamune arm.
2 On the right are depicted patients with
3 acute rejections after month 2. As might be
4 expected, the GFR at twelve months were numerically
5 lower than nonrejectors for both groups. These
6 findings are consistent with study 310 and suggest
7 that renal function outcomes for those patients who
8 had rejection episodes were within clinical
11 Importantly, study 212 was also consistent
12 with study 310 in demonstrating improved renal
13 function in a variety of comparative analyses.
14 Depicted here is the intent-to-treat analysis. The
15 intent-to-treat population includes all enrolled
16 patients including those who experienced an episode
17 of acute rejection or had discontinued study
19 In this group, calculated GFRs were
20 significantly higher at six months and at twelve
21 months in the Rapamune-treated patients.
23 Study 212 demonstrated improved renal
24 function in the primary efficacy population, namely
25 those patients that remained on therapy and
1 rejection-free through month 6. The graph on the
2 left shows serum creatinine compared with the
3 Rapamune plus cyclosporine treated patients,
4 Rapamune treated patients had significantly lower
5 serum creatinines starting at month 6 and
6 persisting through month 12.
7 The graph on the right shows calculated
8 GFRs at these same time points. The Rapamune
9 group, again, had significantly higher GFRs at
10 month 6 compared to the Rapamune plus cyclosporine
11 group and this difference persisted through twelve
14 There was also improvement observed in
15 directly measured GFRs in a subset of the primary
16 analysis population. Patients in the Rapamune
17 group with cyclosporine elimination had higher
18 measured GFRs at both six and twelve months
19 following transplantation.
21 Improved renal function was also
22 demonstrated in the on-therapy population. This
23 group included patients who may have experienced an
24 episode of acute rejection but continued within the
25 study and received study medication. The graph on
1 the left shows serum creatinine. Compared with
2 Rapamune plus cyclosporine treated patients, there
3 was a trend toward lower serum creatinine at all
4 time points in the Rapamune-treated cohort. At
5 twelve months, the improvement in creatinine
6 demonstrated statistical significance.
7 The graph on the right shows calculated
8 GFRs at these same time points. Notably, GFRs were
9 significantly higher at time point 6, nine and
10 twelve months in comparison to the control group.
12 As in study 310, the benefits of
13 cyclosporine elimination on renal function were
14 demonstrated by the majority of patients on therapy
15 through twelve months regardless of their baseline
16 renal function. Again, a quartile analysis was
17 performed in which patients were segregated
18 according to baseline renal function just prior to
19 cyclosporine elimination.
20 The change from baseline was favorable in
21 comparison to patients maintained on cyclosporine.
22 As might be expected, patients with varying degrees
23 of renal dysfunction also showed improvement.
25 In summary, at month 12, studies 310 and
1 212 are consistent in their findings.
2 Specifically, these studies demonstrated that
3 following the elimination of cyclosporine,
4 concentration-controlled Rapamune maintenance
5 therapy results in the following: equivalent graft
6 survival of 95 to 97 percent, equivalent patient
7 survival of 96 to 98 percent, an incremental
8 increase in mild to moderate acute-rejection
9 episodes following cyclosporine elimination with an
10 absolute difference of 6 to 8 percent versus
11 controlled therapy.
12 This compares favorably with previous
13 elimination trials and, perhaps most importantly,
14 both studies demonstrated an immediate and
15 sustained improvement in renal function.
16 This concludes my presentation of the
17 efficacy data for studies 310 and 212.
18 Safety Data
19 DR. NEYLAN: I will now review the safety
20 data for both studies.
22 One-year data will be shown for graft
23 loss, patient death and discontinuation from study
24 medication. The cumulative safety experience for
25 all enrolled patients will be shown for adverse
1 events including infection and malignancy. The
2 cumulative on-therapy data will be presented for
3 all laboratory parameters including blood pressure.
5 The safety assessments will be reviewed in
6 different categories including etiologies of graft
7 loss in patient death, adverse events including
8 those related to immunosuppression such as
9 infection and malignancy and, finally,
10 blood-pressure measurements and laboratory
13 I have already shown you graft survival
14 data for the randomized patients. Graft survival
15 in the randomized groups was in excess of 95
16 percent. An analysis of overall graft survival for
17 all patients enrolled in the study was also high at
18 approximately 89 percent. This group included
19 patients with severe acute or vascular rejection,
20 sustained delayed graft function and other criteria
21 that precluded randomization.
23 The causes of graft loss in study 310 are
24 shown in this slide. An intent-to-treat comparison
25 of the randomized cohorts was conducted censoring
1 graft loss secondary to death. These data revealed
2 similar incidences of graft loss due to infection,
3 renal fibrosis, renal dysfunction, graft vascular
4 thrombosis or recurrent primary disease.
5 The causes of graft loss in these two
6 groups were not statistically different.
8 This slide includes patient survival for
9 all patients enrolled in the study. Patient
10 survival in the overall population which includes
11 the nonrandomized patients was in excess of 94
14 The causes of patient death are shown
15 here. An intent-to-treat analysis at twelve months
16 demonstrated no significant differences in death
17 due to cardiovascular cause or infection.
19 Next we will review the adverse-event data
20 including those events generally associated with
21 immunosuppressive therapy such as infection and
24 The adverse events for this study were
25 similar to the safety profile observed in
1 previously completed pivotal trials that supported
2 the initial approval of Rapamune. What I want to
3 focus on are changes in the profile when increased
4 doses of Rapamune are utilized after cyclosporine
6 As is common in all renal transplant
7 clinical trials, there were a number of reports of
8 adverse events in study 310. These data represent
9 new adverse events occurring following
10 randomization. Shown are the statistically
11 significant differences observed between the two
13 Statistically higher in the Rapamune plus
14 cyclosporine group were cyclosporine toxicity,
15 increased creatinine, edema, hypertension and
16 hyperuricemia. Significantly higher in the
17 Rapamune group were hypokalemia, elevated SGOT and
18 SGPT and thrombocytopenia.
20 All patients in study 310 were followed
21 for the occurrence of serious infections including
22 those requiring hospitalization. In general, the
23 results show no difference in infections in the two
24 randomized groups and are consistent with the known
25 safety profile. The only significant difference is
1 an increased reporting of Herpes zoster infection
2 in the patients in the Rapamune plus cyclosporine
3 group. There was no difference in the incidence of
4 sepsis, CMV infection, pneumonia, Herpes simplex or
5 urinary-tract infection.
7 Similarly, there was no statistical
8 difference in the reported incidence of neoplasia.
9 Specifically, the rates of skin cancer, lymphoma,
10 leukemia and other malignancies were similar and
11 not different between the randomized groups. The
12 overall rates of reporting in this study were also
13 consistent with numerous other studies in which
14 transplant recipients received similar levels of
17 The next safety parameter I would like to
18 discuss is that of blood pressure. Hypertension is
19 common in renal-transplant recipients and an
20 important contributor to cardiovascular risk. In
21 the next two slides, we will review blood-pressure
22 measurements as well as the percentage of patients
23 requiring antihypertensive medications in this
1 The mean systolic and diastolic blood
2 pressures are shown here. On the left, are shown
3 mean systolic blood-pressure measurements.
4 Compared with the Rapamune plus cyclosporine group,
5 Rapamune-treated patients had significantly lower
6 systolic blood pressures at all time points
7 starting at month 6 and persisting through 24
8 months of follow up.
9 On the right are mean diastolic
10 blood-pressure measurements. Similarly,
11 statistically significantly lower diastolic
12 blood-pressure measurements were observed from
13 month 6 through 18 for Rapamune-treated patients.
15 It is important to consider the need for
16 antihypertensive agents in these patients.
17 Although the study was not designed to capture
18 specific dosages of antihypertensive medications,
19 it was possible to analyze the need for combination
20 regimens. The cumulative requirement for multidrug
21 antihypertensive therapy was less in the Rapamune
22 group at month 12. This difference was
23 statistically significant.
24 Thus, the improvement in blood-pressure
25 management demonstrated by the lowering of systolic
1 and diastolic means was also attended by a
2 decreased need for multidrug therapy.
4 We will next review several laboratory
5 parameters. The first analysis will address the
6 issue of lipid elevations, an important risk factor
7 in renal-transplant recipients.
9 In study 310, approximate 19 percent of
10 the patients were receiving lipid-lowering
11 medications prior to transplantation including
12 statins and/or fibrates. Following initiation of
13 study medication, 73 percent of patients in both
14 randomized groups were receiving statins while up
15 to 25 percent of patients in both groups were
16 administered fibrates. The overall use of these
17 agents in both randomized groups was similar.
19 An observation made early in the clinical
20 program was the effect of Rapamune on cholesterol
21 and triglycerides. In study 310, the median
22 fasting cholesterol concentrations in the two
23 randomized groups were similar at month 12.
24 The range of values is depicted in these
25 box-and-whisker plots. 80 percent of the patients
1 in each treatment group are contained within the
2 respective box-and-whisker plots. Thus, the
3 majority of patients were found to have cholesterol
4 values at or below 250 milligrams per deciliter
5 despite the fact that concentration-controlled
6 Rapamune-treated patients had increase sirolimus
7 trough levels as mandated by protocol.
8 The results observed in study 212 were
11 Measurements of fasting HDL and LDL
12 cholesterol levels were also similar. For HDL
13 cholesterol, the two randomized groups were similar
14 except at month 18 when there was a statistically
15 significant increase in the Rapamune group. LDL
16 cholesterol, calculated for those patients who had
17 triglycerides below 400 milligrams per deciliter
18 was similar in the two randomized groups with the
19 exception of month 3 when there was a significant
20 increase in the Rapamune group.
22 As with serum cholesterol, fasting
23 triglycerides were similar in study 310 in the two
24 randomized groups through twelve months of follow
25 up. Again, despite the higher sirolimus
1 concentrations, the Rapamune-treated patients
2 maintained fasting triglycerides in the majority of
3 patients within the 150 to 250 milligram per
4 deciliter range. The results observed in study 212
5 were similar.
7 With regard to liver-function tests, SGPT
8 and SGOT were measured at various time intervals.
9 In the Rapamune-treated patients, SGPT was
10 significantly higher for months 12 through 24.
11 SGOT was significantly higher for months 12 through
12 18. At all other time points, these liver enzymes
13 remained similar in the two randomized groups and
14 below the upper limits of normal.
15 In study 212, the majority of patients
16 also had transaminase levels below the upper limits
17 of normal.
19 Shown on this slide are the causes of
20 elevated liver enzymes in a small number of
21 patients with at least one SGPT value greater than
22 five times the upper limit of normal.
23 Approximately 50 percent of these patients had an
24 infectious etiology as a potential cause for the
25 SGPT elevation.
2 The effects of Rapamune on
3 bone-marrow-derived cells are consistent with its
4 biologic activity in that small decreases in
5 platelets, red cells and leukocytes have been
6 observed. Most important, however, is that there
7 is no evidence of chronic or irreversible
8 bone-marrow dysfunction or depression.
9 In general, white blood-cell counts were
10 similar in study 310 with the exception of
11 statistically significant differences noted at
12 months 3 and 6. However, it is important to note
13 that the mean white-blood-cell counts remained
14 within a clinically normal range for all of the
16 Platelet counts for the two randomized
17 groups were also similar. While statistically
18 significant differences were observed at months 6,
19 15 and 18, mean platelet counts remained above
20 200,000 at all time points. It is also important
21 to note that platelet counts remained stable as
22 patients continued to receive Rapamune through
23 month 24.
24 Similar results were observed in study 212.
1 In summary, in study 310, there was
2 equivalent patient and graft survival. In the
3 Rapamune plus cyclosporine group, there was an
4 increased incidence of cyclosporine toxicity,
5 increased creatinine, edema, hypertension and
7 In the Rapamune group, there was an
8 increased incidence of hypokalemia, increased SGOT,
9 SGPT and thrombocytopenia. There were similar
10 rates of infection and malignancy. Improved blood
11 pressure followed cyclosporine elimination and
12 there were similar effects on lipid profiles and
13 hematologic parameters despite the higher
14 trough-level concentrations in the Rapamune group
15 following cyclosporine elimination.
17 I will now review the safety data for
18 study 212. This slide includes graft survival for
19 all patients enrolled in the study. As previously
20 demonstrated, similar rates were observed in the
21 randomized group. The nonrandomized group
22 demonstrated a lower graft-survival rate not
23 inconsistent with that typically observed in
24 patients with ATN or delayed graft function.
1 Causes of graft loss in this study are
2 shown here. An intent-to-treat comparison of the
3 randomized cohorts was conducted censoring graft
4 loss secondary to patient death. The data revealed
5 a similar incidence of graft loss due to rejection,
6 acute tubular necrosis and hemolytic uremic
9 As previous presented, similar patient
10 survival was observed in the two randomized groups.
11 Patient survival in the nonrandomized group was
12 slightly lower.
14 Causes of patient death in study 212 are
15 shown here. Analysis at twelve months following
16 transplantation demonstrated no significant
17 differences in death due to cardiovascular cause,
18 infection or pulmonary edema.
20 Similar to study 310, there were a number
21 of reports of adverse events in study 212. Again,
22 I will primarily be emphasizing the statistically
23 significant differences. Significantly higher in
24 the Rapamune plus cyclosporine were hypertension,
25 dyspnea, edema, hypervolemia and hypomagnesemia.
1 Significantly higher in the Rapamune group
2 were thrombocytopenia, hypokalemia, diarrhea,
3 abnormal liver-function tests and atrial
4 fibrillation. With the exception of atrial
5 fibrillation, these types of adverse events were
6 previously observed in the pivotal clinical trials.
7 The increased incidence of atrial
8 fibrillation in the Rapamune group is discussed in
9 more detail in the next slide.
11 In study 212, atrial fibrillation occurred
12 in a total of nine patients. This included one
13 patient in the Rapamune plus cyclosporine group and
14 an additional eight patients in the Rapamune group.
15 Six of these eight patients had episodes of atrial
16 fibrillation occurring within the first 40 days
17 following transplantation and thus prior to the
18 elimination of cyclosporine.
19 All cases resolved promptly with therapy
20 and, in the opinion of the investigators, none were
21 considered related to study medication.
22 In the larger study, 310, the incidence of
23 atrial fibrillation was 1.9 percent in the
24 cyclosporine-plus-Rapamune group compared with 3.7
25 percent in the Rapamune group. This difference was
1 not statistically significant. Likewise, in
2 previous registration trials, atrial fibrillation
3 was uncommon and not statistical different from
4 controlled therapies.
6 The intent-to-treat analysis of infections
7 in study 212 is listed here. Infections were
8 typical of the general renal-transplant population
9 and the data showed no statistical difference
10 between the two randomized groups.
12 As with study 310, the overall rates of
13 malignancy observed in 212 were also similar and
14 consistent with previously published studies in
15 transplant recipients. By twelve months, a
16 comparison of the two randomized groups showed no
17 difference in the rates of nonmelanomtous skin
18 cancer and one case of presumed post-transplant
19 lymphoproliferative disease. There was one case of
20 renal-cell carcinoma in a native kidney.
22 In summary, in study 212, there was
23 equivalent patient and graft survival. In the
24 Rapamune plus cyclosporine group, there was an
25 increased incidence of hypertension, dyspnea,
1 edema, hypervolemia and hypomagnesemia. In the
2 Rapamune group, there was an increased incidence of
3 thrombocytopenia, hypokalemia, diarrhea, increased
4 SGOT, SGPT and atrial fibrillation.
5 The infrequent observation of atrial
6 fibrillation was not considered by study
7 investigators to be related to Rapamune. There
8 were similar rates of infection and malignancy and
9 there were similar effects on lipid profiles and
10 hematologic parameters despite the higher
11 trough-level concentrations in the Rapamune group
12 following cyclosporine elimination.
13 To compete the overall safety profile, the
14 next several slides will review patient outcomes in
15 those patients discontinued from treatment as well
16 as the overall success of cyclosporine elimination.
18 The overall disposition of patients in
19 study 310 is shown in this slide. As previously
20 discussed, 525 patients were enrolled at the time
21 of transplantation. 430 patients met the
22 predetermined eligibility criteria at month 3 and
23 were randomly assigned to one of the two treatment
25 215 patients were assigned to each of the
1 groups. the overall rates of discontinuation in
2 study 310 were similar to those observed in recent
3 immunosuppressive registration trials. 18.1
4 percent of patients had discontinued by month 3 and
5 36.4 percent of patients had discontinued by month
8 The reasons for discontinuation in study
9 310 are listed here. A total of 95 patients, or
10 18.1 percent of the total population, were not
11 randomized and were discontinued due to a variety
12 of causes typical for patients in this early period
13 following transplantation.
14 74 percent were discontinued for adverse
15 events including infections, renal dysfunction,
16 surgical complications, laboratory abnormalities
17 and a small number of miscellaneous causes. 13
18 percent of these patients were discontinued because
19 of the acute rejection.
20 Following randomization by month 12, the
21 overall rate of discontinuation was higher in the
22 Rapamune group. Acute rejection was an infrequent
23 cause of discontinuation accounting for only 2
24 percent and 5 percent in the Rapamune plus
25 cyclosporine and the Rapamune groups, respectively.
1 Upon review of the cumulative dataset
2 which includes data for all patients at or beyond
3 15 months, the difference in the rate of
4 discontinuation was no longer statistically
7 While the reasons for patient
8 discontinuations for the study as a whole were
9 similar to other immunosuppressive trials, it is
10 important to look at the special group of patients
11 in whom cyclosporine elimination was not or could
12 not be successfully completed.
13 Given the present availability of other
14 immunosuppressive agents, clinicians were able to
15 choose from a variety of alternative regimens for
16 these patients. Most patients remained on
17 corticosteroids plus a calcineurin inhibitor and,
18 in 26 percent of these cases, patients were
19 converted from cyclosporine to tacrolimus.
20 In many of the cases, an antimetabolite
21 was also added to the regimen. It is notable that
22 in 19 percent of these cases, Rapamune was
23 maintained while the calcineurin inhibitor was
25 Three deaths and two graft losses occurred
1 in the discontinued group. By month 12, there were
2 no acute rejections reported in patients converting
3 to alternative therapies.
5 In the majority of patients randomized to
6 the Rapamune group, cyclosporine elimination was
7 successful. 50 percent of these patients
8 accomplished this within the first 42 days and 90
9 percent were cyclosporine free by day 72 post
10 randomization. In total, 92.6 percent of the
11 patients were successfully withdrawn from
14 The overall disposition of patients in
15 study 212 is shown in this slide. A total of 246
16 patients were enrolled at the time of transplant
17 and randomly assigned to one of the two treatment
18 groups. 97 patients were assigned to receive
19 Rapamune plus cyclosporine and 100 to Rapamune.
20 The overall rate of discontinuation in
21 study 212 was similar to that observed in other
22 recent immunosuppressive registration trials with
23 29.7 percent of patients discontinued by month 12.
24 In the following slides, we will review
25 the outcomes for these discontinued patients.
2 The reasons for discontinuation in study
3 212 are listed here. A total of 49 patients were
4 not randomized. Of these, 28 discontinued due to
5 adverse events, acute rejection or other causes.
6 Post randomization, a total of 45 patients were
7 discontinued from the study by twelve months, 20 of
8 these in the Rapamune plus cyclosporine group and
9 25 in the Rapamune group.
10 These discontinuations were similar in
11 nature to those of study 310. Clinicians
12 participating in study 212 chose to reinitate
13 calcineurin inhibitors for most patients
14 discontinued from the Rapamune group.
16 As in study 310, the majority of patients
17 randomized to the Rapamune group of study 212 had
18 cyclosporine successfully eliminated. On the left
19 is depicted an analysis of all patients randomized
20 to the Rapamune group. 76 percent of patients
21 randomized from the time of transplantation
22 successfully eliminated cyclosporine.
23 On the right is an analysis of these
24 patients who were eligible for cyclosporine
25 elimination at month 2. Note the similar success
1 rate to that of study 310 in that 93 percent of
2 these patients successfully had cyclosporine
3 eliminated from the regimen.
4 Thus, in both studies, patients maintained
5 on Rapamune plus cyclosporine for the first two to
6 three months after transplantation emerged from the
7 high-risk period and went on, in 92 to 93 percent
8 of cases, to successfully eliminate cyclosporine.
10 In conclusion, studies 310 and 212 are
11 consistent in confirming the beneficial safety
12 profile of Rapamune-based therapy following
13 cyclosporine elimination. Both studies
14 demonstrated excellent patient and graft survival,
15 similar rates of infection and malignancy and
16 significantly lower rates of several other
17 cyclosporine-related adverse events.
18 In addition, study 310 demonstrated a
19 significant and sustained improvement in blood
20 pressure. Despite the higher concentration of
21 Rapamune required when cyclosporine is eliminated,
22 the overall Rapamune safety profile is similar to
23 that observed when it is administered as a fixed 2
24 milligram dose in combination with cyclosporine.
1 In addition, rates of discontinuations in
2 these studies were similar to other
3 immunosuppressive registration trials. The reasons
4 for early discontinuation were typical of those
5 observed in renal allograft recipients including
6 surgical complications and delayed graft function.
7 Very few patients were discontinued due to
8 acute rejection. In fact, in study 310, 70 percent
9 of patients experiencing episodes of acute
10 rejection in the first three months went on to
11 randomization. As expected, various alternative
12 therapies were available for patients discontinued
13 from the studies.
14 Importantly, cyclosporine was successfully
15 eliminated in the great majority of patients in the
16 Rapamune group of both studies.
17 This concludes my presentation of the
18 safety data. At this time, I would like to
19 introduce Dr. James Zimmerman, Senior Director of
20 Clinical Pharmacokinetics at Wyeth-Ayerst who will
21 now review the pharmacokinetics of Rapamune
22 concentration-controlled trials and sirolimus
23 therapeutic drug-level monitoring in this patient
25 Dr. Zimmerman?
2 DR. ZIMMERMAN: Thank you, John. Good
5 In our original application, Rapamune was
6 approved for a fixed-dose administration without
7 the need for therapeutic drug monitoring or TDM.
8 TDM was recommended in certain patient populations
9 and to compensate for serious pharmacokinetic drug
10 interactions but it was not required. Today we
11 have proposed a new regimen that will require TDM.
12 This new regimen is proposed based on safety and
13 efficacy data from Rapamune
14 concentration-controlled trials that involve
15 cyclosporine elimination in which drug exposure was
16 guided by TDM.
18 My purpose today is to show you data to
19 support the following four points. First, we have
20 a sufficient understanding of sirolimus PK to apply
21 therapeutic drug monitoring to guide treatment in
22 renal-transplant patients. Secondly, we have a
23 robust and reliable assay for sirolimus. Thirdly,
24 the concentration range for sirolimus TDM has been
25 defined and it is effective. Fourth, we have data
1 to show that transplant physicians can utilize TDM
2 safely and efficaciously in post-transplant
4 Now, before belaboring on these four
5 points, I want to remind you of the conditions
6 under which Rapamune is administered by fixed dose
7 in concentration-controlled regimens.
9 The currently approved Rapamune regimen is
10 a fixed-dose regimen which was based on the
11 administration of Rapamune four hours after a oral
12 formulation of cyclosporine. The fixed-dose
13 regimen is recommended for most patients during
14 coadministration with cyclosporine.
16 Concentration-controlled Rapamune
17 administration is recommended during administration
18 with cyclosporine under certain conditions; in
19 pediatric patients, in hepatic impairment, during
20 administration with strong inducers or inhibitors
21 or the CYP3A P450 subfamily and P-glycoprotein and
22 also after marked changes in cyclosporine doses.
23 Concentration control is required when
24 administered without cyclosporine and it is the
25 method of dose administration for the current
3 Let me start with the assay methodology.
4 Whole-blood sirolimus concentrations were measured
5 during phase II and phase III clinical trials using
6 an immunoassay or a chromatographic assay as we can
7 see by the first two columns.
8 However, as shown in the third column, the
9 immunoassay is not currently available for
10 post-approval use. Instead, HPLC/UV or HPLC/MS/MS
11 are being used at local and commercial
12 laboratories. It is important to realize that the
13 two assays provide different numerical values for
14 sample analysis as shown in the column on the
15 extreme right.
16 For example, chromatographic assay values
17 are 20 percent lower than the immunoassay values.
18 Consequently, the ranges for therapeutic drug
19 monitoring are different for the two assays. In
20 this presentation, sirolimus concentrations are
21 expressed in terms of the immunoassay since the
22 vast majority of the samples for pivotal phase III
23 trials were measured by this method.
24 Turning now to the impact of sirolimus PK
25 on TDM.
2 The fact that sirolimus exhibits dose
3 proportionality over a wide range and also shows
4 linear Cmin versus AUC relationship simplifies
5 concentration-controlled dosing. Dose
6 proportionality has been demonstrated for sirolimus
7 Cmax and AUC first in renal allograft patients
8 after coadministration of Rapamune oral solution
9 and cyclosporine over a dose range of 2 to 22
11 Secondly, in healthy volunteers after
12 administration of Rapamune tablets over a dose
13 range of 5 to 40 milligrams. Therefore, sirolimus
14 trough levels would be expected to increase in
15 simple proportion to the dose over a dose range of
16 2 to 40 milligrams.
17 Moreover, the correlation between
18 sirolimus Cmin and AUC in renal allograft patients
19 is excellent as shown by an r-squared value of
20 0.96. For the regression line over a concentration
21 range of approximately 1 to 30 nanogram per ml.
22 The experimental data is shown on the next slide.
24 This figure is a plot of sirolimus 24-hour
25 troughs on the Y axis and sirolimus 24-hour AUCs on
1 the X axis based on the administration of Rapamune
2 oral solution in combination with cyclosporine
3 during study 301. The individual data points were
4 collected at months 1, 3 and 6 post transplant
5 after doses of 2 and 5 milligrams per day in 42
7 Plotted along with the individual data is
8 the regression line. These data show that troughs
9 can be used for purposes of dose adjustments during
10 sirolimus TDM and the range of concentrations is
11 wide enough to cover the sirolimus target range
12 during TDM as we will see in the final section of
13 this presentation.
14 The important outcome of this relationship
15 is that multiple samples do not have to be drawn
16 during a dose interval at steady state which
17 provides a convenience for the patient and reduces
18 the cost of TDM.
20 Next, there are three PK parameters that
21 affect the implementation of Rapamune
22 concentration-controlled dosing. These are the
23 time to steady state, the loading dose and the
24 maximum dose per day. The mean times to read
25 steady state in renal-allograft patients during
1 coadministration of Rapamune oral solution and
2 cyclosporine was five to seven days. That is
3 without a loading dose although the time to state
4 was as long as thirteen days in individual
6 These results indicate that a blood sample
7 for the determination of a steady-state trough
8 should not be drawn for at least five to seven days
9 after the previous dose adjustment when a loading
10 dose is not administered.
11 A loading dose is necessary to quickly
12 reach steady state and the mean estimated sirolimus
13 loading dose determined in renal-allograft patients
14 during coadministration of Rapamune oral solution
15 and cyclosporine was three times the maintenance
16 dose. When a loading dose is used, it may not be
17 necessary to wait as long as five to seven days to
18 draw a sample for purposes of dose adjustment.
19 The maximum dose on any day that was
20 recommended in study 310 was 40 milligrams. It is
21 also recommended, however, that a loading dose
22 larger than 40 milligrams be administered in
23 divided doses over two days.
24 Now, in the next series of slides, I want
25 to discuss our experience with
1 concentration-controlled trials.
3 Four studies provided data after one year
4 post transplant as shown in this second column.
5 Study 310, the pivotal study for the current
6 submission, study 212, the supportive study for the
7 current submission, and studies 207 and 210, which
8 were early studies directly comparing Rapamune
9 versus cyclosporine using concentration control.
10 Concentration-controlled data were
11 obtained for both the tablet and the oral solution.
12 The remainder of this presentation will focus on
13 the one-year PK data but data beyond one year has
14 also been presented to FDA.
16 The sirolimus target ranges for
17 cyclosporine withdrawal in studies 212 and 310 were
18 set prospectively based on the results from phase
19 II studies 207 and 210. For sample analysis by an
20 immunoassay, these ranges were 10 to 20 nanogram
21 per ml for study 212 and 20 to 30 nanogram per ml
22 for study 310.
23 The adequacies of the prospective target
24 ranges were supported be efficacy results and
25 similarities in the mean sirolimus trough levels
1 for the two studies; that is 18 nanograms per ml
2 for study 212 and 23 nanograms per ml for study
5 We evaluated the implementation of
6 concentration control in four Rapamune studies by
7 estimating the percentages of patients showing
8 concentrations below, with and above the sirolimus
9 target concentration ranges. This slide shows the
10 average percentages of patients among studies and
11 ranges for the sirolimus concentration-controlled
12 treatments or Rapa groups in studies 207, 210, 212
13 and 310. These data are shown by the hatched
14 purple bars.
15 A comparison of the data in the center
16 figure with the data in the left and right figures
17 shows that large majorities of the patients in all
18 four studies fell within the target range. It is
19 important to note that the vast majority of the
20 investigators obtained these results using a
21 central lab and did not have the benefit of an
22 assay at the transplant site.
23 Based on averages among the four studies
24 as shown by the purple bars 12 percent of patients
25 were below the target range. 70 percent were
1 within the range and 18 percent were above the
2 target range. Overall, 88 percent were above the
3 lower limit of the target range.
5 This figure shows the sirolimus and
6 cyclosporine trough levels over time before and
7 after randomization in the sirolimus
8 concentration-controlled treatment or Rapa group of
9 study 310. You are looking at the outcome of the
10 first Rapamune clinical trial in which
11 investigators were required to simultaneously
12 withdraw cyclosporine while increasing the dose of
13 Rapa. The vertical bar represents randomization at
14 90 days.
15 Trough concentration for cyclosporine are
16 plotted on the left Y axis and for sirolimus and
17 the right Y axis. The time is plotted on the X
18 axis. I want to reiterate that the sirolimus
19 concentrations and target range on this slide are
20 for an immunoassay as are the concentrations and
21 target ranges shown on subsequent slides.
22 Before randomization in this region,
23 cyclosporine troughs, shown as triangles, gradually
24 decreased over 90 days as doses were gradually
25 decreased and sirolimus troughs, shown as circles,
1 remained stable at approximately 11 nanogram per ml
2 during the fixed-dose time period.
3 After randomization, in this area,
4 cyclosporine troughs decreased rapidly to near zero
5 concentrations at 150 days as the doses were
6 reduced and sirolimus troughs rapidly increased to
7 reach the target range as doses were increased.
9 Overall, the investigators were quite
10 successful in this first Rapamune trial that
11 required simultaneous adjustment in the dosages of
12 two drugs and cyclosporine was eliminated in 50
13 percent of patients by week 6 after randomization.
14 We can anticipate that the ability to achieve and
15 maintain the sirolimus target range using TDM will
16 improve in the future as more experience is
17 obtained with cyclosporine withdrawal.
19 This figure provides a summary of the
20 sirolimus doses and troughs after reaching the
21 target range in study 310 between 4.5 and twelve
22 months post transplant. In the
23 concentration-controlled treatment, as shown by the
24 purple bars, a mean Rapamune dose of 8.4 milligrams
25 per day produced mean sirolimus troughs of 23.3
1 nanograms per milligram which was within the target
2 range for the study.
3 In the fixed-dose treatment, as shown by
4 the red bars, a mean Rapamune dose of 2.1
5 milligrams per day produced a mean sirolimus trough
6 of 10.8 nanograms per milligram. There appears to
7 be a disparity between doses and concentrations
8 since a fourfold increase in dose produces only a
9 twofold increase in concentration. The apparent
10 discrepancy between doses and troughs is due to the
11 fact that cyclosporine produces about a twofold
12 increase in the extent of absorption of sirolimus.
13 Therefore, without the coadministration of
14 cyclosporine, sirolimus troughs would be decreased
15 by one half compared to those during
16 coadministration with cyclosporine and, therefore,
17 higher doses are required.
19 Let me tell you now what we have learned
20 about implementing sirolimus TDM. There are four
21 parameters that I want to discuss which include the
22 frequency of blood sampling for rapid
23 determinations after randomization, the number of
24 days required to reach the target range after
25 randomization, the number of dose changes required
1 to reach the target range after randomization and
2 the recommended target trough range for sirolimus
4 I will also be commenting on the
5 availability of the sirolimus assay.
7 In pivotal trial 310, blood samples were
8 to be drawn weekly during the first month after the
9 start of cyclosporine withdrawal, every two weeks
10 during months 2 and 3, monthly during months 4 to
11 12 and every three months after month 12.
12 The actual number of samples required for
13 the use of sirolimus TM in new patients will have
14 to be individualized since the number of samples
15 depends on the rate of CSA withdrawal and the time
16 needed for sirolimus to reach the target range in
17 the individual patient.
18 Based on an analysis of the number of days
19 to reach the target range, 50 percent of patients
20 reached the target range by approximately twenty
21 days after randomization and also 90 percent of
22 patients reached the target range by 68 days after
24 Based on an analysis of the number of dose
25 changes to reach the target range, 50 percent of
1 patients reached the target range after two doses
2 and 90 percent reached the target range after five
3 doses--after dose changes.
5 Turning our attention now to the sirolimus
6 TDM range, we conducted a logistic-regression
7 analysis of acute rejection using the
8 post-randomization data but the results did now
9 show significant p-values for either sirolimus or
10 various patient parameters. This result is not too
11 surprising since there were relatively few
12 rejections post randomization and a single limited
13 range of concentrations was investigated.
14 In the absence of the PK/PD model, the
15 sirolimus TDM range was established based on
16 distribution analysis of sirolimus troughs among
17 nonrejectors and rejectors and clinical outcomes
18 for studies 310 and 212.
19 The next slide shows the distribution of
20 average sirolimus trough concentrations among
21 nonrejectors in studies 310 and 212.
23 The figure on the left shows the data for
24 study 310 and the figure on the right is for study
25 212. For study 310, the average sirolimus trough
1 concentrations in individual patients were
2 determined between six weeks post randomization and
3 one year, and for study 212, the averages were
4 determined between three weeks post randomization
5 and one year.
6 The lengths of the blue bars in the
7 figures represent the numbers of nonrejecting
8 patients at a given concentration as determined by
9 the SAS procunivariate statistical procedure. The
10 dashed lines represent the 5th and 95th percentiles
11 for the sirolimus distribution.
12 As you can see, the ranges for the two
13 studies showed considerable overlap although the
14 212 distribution is shifted downward due to the
15 lower protocol target range. We also observed
16 considerable overlap for rejectors in the two
17 studies, as shown in the next slide.
19 In these figures, sirolimus trough
20 concentrations in individual patients are plotted
21 against the rejection times. The concentrations in
22 the figures are those closest to the rejection
23 time. The dashed lines are, again, the 5th and
24 95th percentiles for nonrejectors.
25 As you can see, the ranges for rejectors
1 were very similar for studies 310 and 212 and also
2 a large fraction of the rejectors fell within the
3 5th to 95th percentiles for nonrejectors.
4 Now, one may question whether a fixed-dose
5 regimen could be used in place of TDM. However, as
6 shown in the next slide, sirolimus TDM considerably
7 reduces the intersubject variability compared to a
8 fixed-dose regimen.
10 This figure provides a comparison of the
11 distributions of average sirolimus troughs in
12 nonrejectors beginning a six weeks after
13 randomization in study 310. The box plot on the
14 left is for actual data and the box plot on the
15 right shows the actual concentrations normalized to
16 an 8 milligram daily dose of sirolimus.
17 If patients in 310 had received an
18 8-milligram daily regimen without TDM, the range of
19 sirolimus trough levels would have increased
20 considerably and many patients would have exceeded
21 the 95th percentile observed in study 310 and a
22 number of patients would have fallen between the
23 range of 40 to 70 nanograms per milligram. The
24 data in this slide strongly argued for the need of
25 sirolimus TDM.
1 The next slide provides our
2 recommendations for a TDM range.
4 A sirolimus TDM range of 15 to 25
5 nanograms per milligram, as determined by
6 immunoassay, is recommended based on the
7 distributions of sirolimus troughs among
8 nonrejectors and rejectors in studies 310 and 212
9 and the very similar clinical outcomes in studies
10 310 and 212 with respect to graft survival, patient
11 survival and improved renal function within Rapa
13 These similarities in clinical outcomes
14 were achieved in spite of the different target
15 ranges used in the two studies.
16 As the last topic under the implementation
17 of sirolimus TDM, I want to comment on the
18 availability of the sirolimus assay.
20 Currently, there are 23 bioanalytical
21 lamps that measure sirolimus concentrations by
22 either an HPLC/UV or HPLC/MS/MS assay. Quest
23 Diagnostics in San Juan Capistrano, California, is
24 our central laboratory. Six additional
25 laboratories analyzed samples on a commercial scale
1 and sixteen laboratories are located in transplant
2 centers throughout the United States.
3 The two assay methods include the ranges
4 to the 95th percentiles observed in
5 concentration-controlled studies as shown by the
6 footnotes in the table. The HPLC/UV method has a
7 range of 2.5 to 75 nanograms per milligram and the
8 HPLC/MS/MS method has a range of 1 to 50 nanograms
9 per milligram.
11 Turning to guidance that will be provided
12 to physicians, physicians will be informed with
13 respect to algorithms for estimating both a new
14 maintenance dose and new loading dose. The maximum
15 recommended dose of Rapamune per day, time of blood
16 draws for dose adjustments, action guidelines based
17 on assay results and the limitations of TDM.
18 In conclusion, experience with sirolimus
19 TDM without cyclosporine coadministration has been
20 obtained in four clinical trials during one year
21 post transplant among 347 patients. Efficacy
22 outcomes in the TDM groups were equivalent to the
23 respective fixed-dose groups. Studies 310 and 212
24 provided data to define a range of sirolimus trough
25 concentrations for TDM in the proposed indication.
1 The results show that TDM can guide the
2 safe and effective use of sirolimus.
4 For TDM without cyclosporine
5 coadministration--that is, for the proposed
6 indication--the recommended sirolimus TDM target
7 range is 15 to 25 nanograms per milligram based on
8 the immunoassay or 12 to 20 nanograms per milligram
9 based on a chromatographic assay.
10 This concludes my presentation. Dr.
11 Neylan will now close today's presentation with a
12 few final remarks.
13 Concluding Remarks
14 DR. NEYLAN: Thank you, Jim.
16 I would like to conclude our presentation
17 today by emphasizing that within the past few
18 years, great strides have been made in advancing
19 the clinical science of renal transplantation. In
20 general, these advances have come as a result of
21 our improved understanding of the optimal use of
22 available immunosuppressive agents.
23 While calcineurin inhibitors have played
24 an important role in the past twenty years,
25 long-term patient and graft survival remain
1 suboptimal and the persistent nephrotoxicity
2 associated with maintenance cyclosporine continues
3 to take its toll.
4 The emergence of Rapamune as a new
5 therapeutic option has provided clinicians new
6 opportunities to individualize therapies. Based on
7 the data presented this morning, it is clear that
8 we have made further progress still.
10 The combined safety and efficacy data from
11 studies 310 and 212 are consistent and provide
12 compelling evidence that Rapamune may be utilized
13 to spare the inherent nephrotoxicity long
14 associated with chronic cyclosporine
16 The benefits of concentration-controlled
17 use of Rapamune with cyclosporine elimination
18 include excellent patient and graft survival, a low
19 rate of acute rejection following cyclosporine
20 elimination and an acceptable safety profile.
22 A regimen of maintenance Rapamune is
23 associated with several distinct advantages when
24 compared to long-term use of cyclosporine. These
25 include significantly better renal function that is
1 sustained over time, significantly lower blood
2 pressure that is also sustained and significantly
3 lower incidence of several other
4 cyclosporine-related adverse events.
6 Based upon the population of
7 renal-transplant recipients included in these two
8 trials, it is reasonable to expect that these
9 benefits can be realized by most patients now
10 awaiting transplantation in the United States.
11 Specifically, by initiating Rapamune plus
12 cyclosporine and corticosteroids, clinicians can
13 anticipate that most patients can be successfully
14 withdrawn from cyclosporine.
15 In the current studies, greater than 90
16 percent of patients eligible two to four months
17 after transplantation successfully completed
18 cyclosporine elimination. Therefore, only a small
19 number of patients will not be able to accomplish
20 this goal because of complications in their
21 clinical course or intolerance of the
22 immunosuppressive regimen.
23 For these patients, alternative strategies
24 are at hand and may be utilized according to
25 clinical judgment.
2 We are excited about these data and their
3 implications for the transplant community. We
4 believe that utilization of Rapamune in the
5 proposed indication may significantly improve the
6 practice of clinical transplantation and enhance
7 the lives of transplant recipients.
8 In conclusion, I would like to acknowledge
9 the patients and investigators who participated in
10 these trials. Their diligence and their commitment
11 has made all of this possible.
12 Thank you for your attention. We will now
13 be pleased to address any questions you may have.
14 DR. ENGLUND: At this point, I would like
15 to ask if there are any clarification questions,
16 just clarification only. We will having the
17 discussion questions later.
18 DR. HUNSICKER: I had a couple, just one
19 clarification question.
20 DR. ENGLUND: Go ahead.
21 DR. HUNSICKER: One of the things that you
22 said earlier is that a certain fraction of patients
23 were removed or permitted not to be randomized
24 because of basically physician judgment that their
25 creatinine was too high. Could you tell us how
1 many and what the creatinines were? The issue has
2 to do with what we actually about the group of
3 patients who were randomized and on whom we have
4 effective data.
5 DR. NEYLAN: Yes. Let's see if we can
6 call up a slide looking at the nonrandomized
8 DR. HUNSICKER: That is in study 310,
10 DR. NEYLAN: You want to look at study
12 DR. HUNSICKER: Yes.
13 DR. NEYLAN: Let's show this first.
15 To begin, in study 310, there were 95
16 patients who did not meet the randomization
17 criteria at or before month 3. The reasons for
18 discontinuation in study 310 are listed in the next
21 74 percent of those patients were
22 discontinued because of adverse events prior to the
23 randomization. These adverse events included
24 issues of renal function like ATN, potentially
25 renal-vein or renal-artery thrombosis, cyclosporine
1 toxicity. Another category listed as renal
2 dysfunction, and then a host of the other
3 complications that are not out of the usual sort in
4 the more immediate post-operative period.
6 The next slide shows that, in addition to
7 this 74 percent, there were twelve of the 95 that
8 were discontinued because of rejection. These were
9 early rejections prior to the month-3
10 randomization. Nine of these patients had mild to
11 moderate, one severe and one graft loss. Notably,
12 70 percent of the patients within the enrolled
13 population that experienced rejection within the
14 three-month period actually went on to
17 Then finally, the remaining thirteen
18 patients of this 95 nonrandomized group were
19 discontinued for these listed reasons.
20 DR. HUNSICKER: If I can just clarify my
21 question a bit. I think this is something that is
22 going to have to actually eventually be dealt with
23 by the FDA, the patients in whom we have a
24 comparison are those who were randomized. That is
25 the only group in whom we can make any judgment
1 about the relative efficacy.
2 We have to know very precisely what those
3 randomized patients were so that we will be able to
4 tell the public in the future what group of
5 patients there is now data that you could possibly
6 remove the cyclosporine. I think that I would not
7 want to come across that we could remove
8 cyclosporine in all patients because there are a
9 substantial number of patients who never really had
10 this tested.
11 DR. NEYLAN: We would certainly agree with
12 that. So, in addition to the patients who declared
13 themselves, if you will, in this early time point
14 with either a severe rejection or a prolonged or
15 more severe delayed graft function, we have those
16 patients who emerged from this period at month 3,
17 and it is those patients, indeed, in which the
18 decision should be made.
19 We had a slide previously which I wanted
20 to show.
22 It shows the patients who came to month 3
23 and, at that point, were discontinued. I think
24 this, perhaps, more aptly addresses the question
25 you had asked originally which was what number of
1 the 95 actually, through physician decision at this
2 three-month time point, elected not to, then, be
3 put through the randomization. We see that there
4 were five patients that fit the bill of a
5 creatinine greater than 4.5, five patients that had
6 either severe renal dysfunction or were on
8 The remainder of the patients at this
9 three-month visit mark, which was the time in which
10 physicians decided whether to go on to
11 randomization or discontinue, had these other
12 issues for which the physicians decided not to
13 continue them in the study.
14 DR. ENGLUND: Dr. Auchincloss?
15 DR. AUCHINCLOSS: A couple of reasonably
16 quick questions. The steroid dose you mentioned as
17 being the standard taper. Did that sort of
18 typically end at 15 milligrams a day or were people
19 going even lower?
20 DR. NEYLAN: The tapering went down to
21 lower than 15 milligrams and we have the steroid
22 dosing for the studies. In general, it came down
23 to the range of about 10 milligrams per day.
24 Would you like to see that data?
25 DR. AUCHINCLOSS: No; I don't need to see
1 it. I just need to get a sense of it. Secondly,
2 your S15 slide showing the remarkable similarity of
3 use of lipitore in the two groups despite the fact
4 that one is using a four-times-higher dose of
5 rapamycin in the right-hand panel there. Were they
6 using much more lipitore or dose doesn't matter
7 when you get onto rapamycin?
8 DR. NEYLAN: Unfortunately, these studies
9 were not designed a priori to collect actual
10 dosing, so I am afraid I can't answer that
11 question. The choice of lipid-lowering agents
12 certainly included lipitore but it also include
13 other HMG co-A-reductase inhibitors.
14 As you see, 73 percent of both groups were
15 receiving some form. We are certainly interested
16 in this and we are collecting these data now in
17 other trials and trying to get an assessment of the
18 dose response, if you will, to these agents. But
19 we don't have that information for you, these
20 studies, today.
21 DR. AUCHINCLOSS: Can I do one more?
22 DR. ENGLUND: One more.
23 DR. AUCHINCLOSS: The third one is that
24 212 is the one trial that actually had a number of
25 black patients. I believe it was fifteen. And
1 then we had a slide later that showed rejectors
2 just near the very end, and there were five spots
3 for black rejectors. So five out of the fifteen
4 rejected at some point in the rapamycin group; is
5 that true?
6 DR. NEYLAN: Yes.
7 DR. AUCHINCLOSS: I know the numbers are
8 small, but is there reason to think that blacks
9 would handle this less well?
10 DR. NEYLAN: Well, actually, I think what
11 I would like to do is, if I might, run through a
12 couple of slides on this issue because, to give you
13 the conclusion first, we think that, although the
14 number of black patients was somewhat small within
15 the collected database of these two studies, the
16 results, in general, mirrored the expectations that
17 might be seen in general clinical practice for
18 these patients and, most importantly, the benefits
19 seen with the cyclosporine elimination are also
20 demonstrated in this group.
21 If I could have the first slide.
23 We see that, indeed, in study 310
24 conducted in non-U.S. countries, the number of
25 black patients was very small but was
1 representative of their representation within those
2 general populations. We really won't touch on any
3 of these data since the numbers are, indeed, too
4 small to make much of them.
6 Within study 212, 19 percent of the
7 enrolled population was of black ethnicity. The
8 distribution of their enrollment in the two
9 randomized arms is shown here, 18.6 percent
10 randomized to the control group of 212 and
11 15 percent to the treatment arm. 28.6 percent were
12 not randomized.
14 In the 212 Rapamune group, the
15 cyclosporine elimination arm, as I said, there were
16 fifteen that were enrolled. There were three that
17 were eligible for cyclosporine taper by month 2.
18 Two had experienced acute rejection episodes prior
19 to that.
20 Of those thirteen eligible for
21 cyclosporine taper, all completed the cyclosporine
22 taper. Three had rejection episodes following the
23 cyclosporine withdrawal at days 35, 64 and 122
24 following that elimination.
1 The rates of rejection over time are shown
2 here, are shown for black and non-black patients
3 within 212. You will recall that month 2 was the
4 point in this study at which patients went on the
5 cyclosporine discontinuation or were maintained in
6 the control treatment strategy.
7 Four black patients, at month 2 and,
8 again, prior to cyclosporine elimination, not
9 unexpectedly, we saw higher rates of acute
10 rejection in black patients than nonblack patients
11 in both treatment arms. By month 12, now following
12 these patients on through the period of
13 cyclosporine elimination for the Rapamune treatment
14 arms, you see that black patients in the Rapamune
15 treatment, as contrasted with the control, had
16 similar rates of acute rejection, both 33 percent
17 by month 12, this in contrast to the nonblack
18 patients where we see results essentially mirroring
19 that of the study as a whole with a slightly higher
20 rate of acute rejection for the nonblack patients
21 in the Rapamune treatment arm.
23 Most importantly, though, the effect on
24 blood pressure was also confirmed in black patients
25 in the 212 study. We see that, in black patients,
1 these are now calculated GFRs at months 2 through
2 12, that there was a trend towards improvement in
3 the Rapamune arm for black patients enrolled that,
4 by month 12, was now statistically significantly
6 In fact, this represents a roughly 48
7 percent improvement.
9 There was also a trend in mirroring the
10 results in blood-pressure management as well for
11 black patients although, again, with the small
12 numbers, we don't achieve statistical significance.
13 But, again, we see that four black patients, the
14 systolic and diastolic pressures tended to be lower
15 for black patients in the Rapamune arm than the
16 Rapamune plus cyclosporine arm.
18 Finally, in the last slide, we see that
19 overall patient and graft survival at one year is
20 essentially the same for black and nonblack
21 patients in these two treatment arms, the black
22 patient survival being 100 percent for the Rapamune
23 arm, 94 percent for the Rapamune plus cyclosporine
24 arm, and comparable to that of nonblack patient
1 Graft survival is also comparable, 93
2 percent for the Rapamune arm compared with 94
3 percent for the control arm, again similar to the
4 nonblack groups and none of these showed any
5 statistical difference.
6 So, in sum, although the numbers are
7 small, the outcomes in black patients in study 212
8 do mirror the study as a whole and, importantly,
9 also show the same benefits in terms of renal
11 DR. ENGLUND: Dr. Abernethy?
12 DR. ABERNETHY: I have a couple. Looking
13 at the severity of rejection in both studies across
14 groups, do we have a chi square or some sort of
15 analysis looking at the mild rejectors and the
16 moderate rejectors? Just looking at the numbers,
17 it would appear that the Rapamune-only group had
18 more severe rejection.
19 DR. NEYLAN: If we could show again the
20 310 rejection histology slide.
22 In the presentation I showed you, the
23 rejections that we saw following randomization
24 actually had no episodes of severe rejection in
25 either of the two treatment groups. What we have
1 in the group randomized to the Rapamune was a
2 predominance of mild rejections, 66.7 percent, and
3 moderate rejections, either 2a or 2b, but, again,
4 no severe rejections.
5 These were fairly similar to the severity
6 seen of the rejectors in the control arm of 77.8
7 mild and then there are two types of moderate.
8 DR. ABERNETHY: I suppose one could do a
9 chi-square analysis and see if that is different?
10 DR. NEYLAN: I would have to ask one of my
11 statisticians. Robert, could you speak to that?
12 DR. GOLDBERG-ALBERTS: I am Robert
13 Goldberg-Alberts, Rapamune project statistician.
14 With the sparse numbers there, I wouldn't have done
15 a chi square but I would be happy to get you an
16 exact p-value for the difference in the
17 distribution. I could have that for you after
18 lunch, if you wish.
19 DR. NEYLAN: Thank you, Robert.
20 DR. ENGLUND: One more.
21 DR. ABERNETHY: What was your definition
22 of hypokalemia and thrombocytopenia, just the
24 DR. NEYLAN: Yes. The definitions are
25 slightly different depending on whether we are
1 looking at it from the listing of laboratory values
2 or we are listing it as an investigator-initiated
3 spontaneous adverse-event report.
4 In the case of the laboratory parameters,
5 they simply are those of the laboratory standards.
6 However, in the case of the spontaneous reporting
7 of adverse events, we are simply relying on the
8 investigator's personal view.
9 If I could have the potassium through time
10 for study 310, what I would like to show is that,
11 indeed, we saw in patients in whom cyclosporine was
12 eliminated, that the cyclosporine effect in
13 retarding potassium secretion was demonstrated on
14 those patients and, in addition, the mild kaluretic
15 effect that we have seen with Rapamune was also
18 This summary experience, while it created
19 statistical difference between the treatment arms,
20 did not bring patients down below the lower limits
21 of normal for potassium. So, again, to reiterate,
22 at month 3, as you would expect, these two groups
23 are similar and then, as they proceed through the
24 period in which cyclosporine is eliminated in the
25 Rapamune arm, you begin to see statistical
1 difference which is maintained here at month 12 and
2 here at month 24. Statistical difference, yes; but
3 the Rapamune-treated patients are still maintaining
4 potassiums above the lower limit of normal.
5 MR. LAWRENCE: To be absolutely precise
6 about that, you are showing SEMs there. You are
7 not showing standard deviations. What you really
8 need to show is the fraction of patients that are
9 below the level to say that, John.
10 I am not calling for another slide. I
11 think that it is probably fine. But don't say that
12 the potassiums are all fine because the mean is
14 DR. NEYLAN: We brought 1500 slides, just
15 to warn you.
16 DR. ENGLUND: Let's go on. Dr.
18 DR. SUTHANTHIRAN: John, I wanted to ask
19 you about acute rejection. It is true at the end
20 of the twelve months, both groups seemed to have a
21 nonsignificant difference in the incidence of acute
22 rejection. But if you look at post randomization,
23 excluding the first three months when the patients
24 are on cyclosporine, there is, in fact, an increase
25 in the incidence of acute rejection.
1 I wonder, in your cyclosporine, you
2 actually have three phases, an induction phase, a
3 taper and a discontinuation. Is there a place in
4 the taper time that there is a particular level of
5 cyclosporine at which, when it goes below a certain
6 threshold, you start seeing acute rejection?
7 DR. NEYLAN: First, as we are looking for
8 the slide that I would like to show you showing the
9 changing cyclosporine levels, we can first look at
12 310, as you say, shows that, up to the
13 point of randomization, there were identical and
14 very low rates of acute rejection that were seen
15 for all the patients enrolled in the study.
16 But, subsequent to the point of
17 randomization and, with that, the onset of
18 cyclosporine elimination in the Rapamune-treatment
19 arm, you see an increment difference in the rates
20 of rejection statistically significantly different
21 here comparing new rates but in cumulative
22 accounting, not statistically different there.
23 What I want to find is the histogram that
24 shows the cyclosporine levels as they go through--I
25 believe it is in your slide packet, Jim. What we
1 saw was that, not unexpectedly, with the attendant
2 decrease in cyclosporine exposure, there was an--at
3 the beginnings of the increase in these incremental
4 rejection episodes following the randomization.
5 There was a window of time, in showing
6 this histogram, between the elimination of
7 cyclosporine completely.
8 Yes; this is the slide. Thank you.
10 What we see here in study 310 are, in the
11 red bars, the mean cyclosporine trough levels.
12 Here is day 90, the point of randomization, the
13 point at which cyclosporine is beginning to be
14 tapered by the investigators for patients in the
15 Rapamune arm.
16 In these line drawings, you see the rates
17 of acute rejection for the patients randomized to
18 the Rapamune arm and the patients randomized to the
19 control arm. So, following the cyclosporine
20 troughs, you can see that, at this point, things
21 are fairly similar and there begins an incremental
22 increase at or about the time that cyclosporine is
23 being completely eliminated.
24 This incremental increase appears to
25 continue a bit longer beyond the point at which, at
1 least for the mean, the cyclosporine has been
2 completely eliminated. This may relate to, also,
3 the rapidity at which the investigators were
4 achieving the target ranges for Rapamune.
5 So, again, we have two moving targets
6 here. We have cyclosporine coming down and
7 Rapamune, of course, being adjusted upward to
8 achieve the new target ranges.
9 DR. ENGLUND: Dr. DeGruttola had a
11 DR. DeGRUTTOLA: I just had a question on
12 a similar point. You made a statement in the
13 summary that there are similar incidents, similar
14 rates of acute rejection, between the two groups,
15 the 13.4 and the 20 percent with a p-value of 0.08.
16 I am just wondering what the definition of similar
17 rates is there.
18 Usually, statistically, when you describe
19 something as similar, we are saying we can reject a
20 difference of a certain amount or define a window
21 of equivalence. I was wondering if that is how
22 similar is defined or is it just reflecting the
23 fact that the p-value doesn't happen to be below
25 DR. NEYLAN: I see Jim Burke shaking his
1 head. I think I will ask him to address this
2 question. Jim, if you could first identify
3 yourself at the microphone.
4 DR. BURKE: Jim Burke, Wyeth-Ayerst
5 Research. It is the latter that is true, that we
6 call them similar because the p was not less than
8 DR. DeGRUTTOLA: Another question that I
9 had was regarding the analyses of cholesterol
10 values and triglycerides and so on. Are those done
11 on an intent-to-treat or on an on-therapy
13 DR. BURKE: These are on-therapy.
14 DR. ENGLUND: Dr. Shapiro?
15 DR. SHAPIRO: John, that was a really nice
16 presentation. I have a couple of questions. As
17 you know, most patients entered into trials tend to
18 be somewhat selected. And then you selected again,
19 throwing out 18 percent of the patients in the 310
20 trial and 20 percent of the patients in the 212
21 trial. These were the nonrandomized patients.
22 Then you end up with patients who have
23 extremely good outcomes. What were the patient and
24 graft survival rates, rejection rates and resistant
25 rates in the nonrandomized patients in both 310 and
2 DR. NEYLAN: Let's show this slide while
3 we are getting that data for you.
5 This is first to look at the study 310 and
6 compare the demographic features of the patients
7 who were not randomized against those patients who
8 went on to randomization. They are actually the
9 same, or at least similar, with two exceptions.
10 As you might expect, the nonrandomized
11 patients had a higher percentage of delayed graft
12 function and a higher percentage of acute rejection
13 than the patients who went on to randomization.
14 And that addresses your point that, from a
15 clinical-utility standpoint, these are both studies
16 in which patients are enrolled but then followed
17 through a critical window of time, a high-risk
18 window of time.
19 Those patients who get to that subsequent
20 time point are the ones that are logically
21 candidates for this kind of strategy.
23 This next slide shows the breakdown of the
24 histologic grade of rejections by twelve months
25 comparing the two randomized groups to that of the
1 nonrandomized group. To walk you through it is to
2 say we have this period of time prior to the point
3 of actual randomization. These patients went on
4 to, of course, be randomized but their rejection
5 episodes occurred in that early period of time.
6 As I say, 70 percent of patients that had
7 acute rejections within the first three months
8 actually went on to randomization. So that is the
9 first point. We have mandated by protocol that
10 only the severe rejection episodes would be
11 disallowed from being considered for randomization
12 subsequently at three months.
13 In contrast, we have, during this same
14 window of time, this early three-month, the types
15 of rejection, the histologic grades of rejections
16 seen for the nonrandomized group. Being
17 nonrandomized, then, we have only follow up for
18 those. You see a small number of patients that, in
19 the follow-up period, had rejection episode within
20 that time frame.
21 Does this address your question?
22 DR. SHAPIRO: It doesn't discuss the
23 patient and graft survival.
24 DR. NEYLAN: All right. Show this slide,
2 What we saw for the treatment arms in
3 study 310 was the overall one-year graft survival
4 that was comparable, actually numerically superior,
5 for the Rapamune treatment arm. These are the
6 causes of graft loss within these groups. In
7 comparison, we see the 95 patients who, again, were
8 not randomized at the three-month mark and the
9 causes of graft loss in this group.
10 DR. ENGLUND: Dr. Mannon?
11 DR. MANNON: My question relates more to
12 the TDM aspect. I guess these results are based on
13 the immunoassay and, in your conclusion, you
14 related both either targets towards the immunoassay
15 or the HPLC. Is the expectation that the
16 immunoassay may be eventually available and, if
17 not, do you think we could obtain comparable
18 results if we stuck with HPLC?
19 DR. NEYLAN: I think I can just tackle
20 this, Jim, if you don't mind. I think what we have
21 seen is that there is a clear correlation between
22 the immunoassay and the HPLC methodology so we can
23 readily adapt values and put them in the context of
24 what we have seen with these studies and the
1 Those centers are available now and they
2 include both the central laboratories as well as,
3 in some cases, on site within the transplant
4 centers. As to the future, yes; an immunoassay is,
5 indeed, in our future. At long last, I am happy to
6 report that we are now working hand-in-hand with a
7 company who will in, I hope, the very near future
8 have a immunoassay out and available in a manner
9 similar to the assays available for other
11 DR. MANNON: My last question again
12 relates to levels. Were patients in either of
13 these studies required or encouraged to be on a
14 particular diet for the morning meal or was there
15 any follow up or guidance regarding their diet?
16 DR. NEYLAN: No; there was no specific
17 dietary restriction.
18 DR. ENGLUND: Dr. Ebert?
19 DR. EBERT: A couple of questions related
20 also to TDM. First of all, it appears from your
21 serum-concentration ranges that you have
22 established, certainly there appears to be some
23 evidence for the lower level, not going below a
24 certain level, based on the fact that you had a
25 higher number of rejectors.
1 But I am curious if you have any evidence
2 in your upper level that you are looking for from a
3 target range. Were there any adverse events that
4 were correlated with exceeding that value.
5 DR. NEYLAN: Jim, do you want to say just
6 very briefly? We did, indeed, look at that.
7 DR. ZIMMERMAN: We did look at several lab
8 parameters. We looked at potassium. We looked at
9 liver-function tests and I believe triglycerides
10 and cholesterol and we did not find any trends for
11 patients above 25 nanograms per milligram that
12 would lead us to believe that there is a
13 relationship there.
14 DR. EBERT: The second question is I
15 realize you had to do a number of serum
16 concentrations to titrate your regimens. Were
17 there any population parameters, age, preexisting
18 liver disease, et cetera, that might have helped
19 you to more closely predict the ultimate
20 maintenance dose?
21 DR. NEYLAN: We don't think so because we
22 conducted the logistic regression analysis for the
23 time period after randomization up to one year. We
24 looked at factors such as HLA mismatch,
25 donor-related--can we bring up that slide? I don't
1 have all the parameters. We looked at about five
2 or six different parameters in that regression,
3 also sirolimus concentrations But we could not
4 find the relationship.
6 This is for 310. As you can see, we have
7 both drug concentrations there, gender, increasing
8 recipient age, cadaveric HLA mismatch, increased
9 ischemia time, increased donor age and number of
10 rejections. Except for increasing donor age, there
11 were no significant p-values.
12 DR. EBERT: These are things that predict
13 rejection; is that correct?
14 DR. NEYLAN: That's correct.
15 DR. EBERT: I am looking at were there
16 patient-related variables that predicted the drug
17 clearance, the final dose that was required to be
18 achieved in those patients.
19 DR. NEYLAN: We didn't do it in this
20 population but, from all of our previous data with
21 the tablet submission and the oral-solution
22 submission, we did not find any patient-related
23 factors that would help.
24 DR. ENGLUND: I think with that, we are
25 going to actually take a break now. There is going
1 to be time for questions after lunch, after the FDA
2 proposal. So let's take a break now. We are going
3 to start at ten minutes after 11:00, fifteen
6 DR. ENGLUND: We will now hear from the
7 FDA Presentation.
8 FDA Presentation
9 DR. TIERNAN: Good morning.
11 My name is Rosemary Tiernan and I work in
12 the Division of Special Pathogens and Immunologic
13 Drug Products. I would now like to begin the FDA
14 presentation of our review of Rapamune for the
15 indication of cyclosporine withdrawal in renal
18 Before I begin, I would just like to
19 acknowledge the efforts of the members of the
20 Rapamune review team who are listed on this slide.
21 I would especially like to thank our statisticians
22 Dr. Cheryl Dixon and Dr. Karen Higgins.
24 The presentation will cover the following
25 areas; background information regarding the initial
1 approval of Rapamune in 1999 and the phase IV
2 commitments that were negotiated. They will be
3 briefly reviewed. I will highlight certain issues
4 regarding the design of the clinical studies
5 submitted in the current NDA to support a labeling
7 Efficacy and safety considerations will be
8 discussed. Finally, our Division Director, Dr.
9 Renata Albrecht, will present the questions to the
10 advisory committee
12 The basis of the initial approval for the
13 prevention of acute rejection in renal
14 transplantation included two randomized,
15 double-blind, phase III studies, study 301 and 302,
16 comparing Rapamune, 2 milligrams and 5 milligrams
17 to azathioprine or placebo. Both studies
18 demonstrated noninferiority with respect to
19 12-month patient and graft survival and a
20 significant reduction in the incidence of rejection
21 at six months.
22 Despite a lower rate of acute rejection at
23 six months post transplant, renal function, as
24 measured by serum creatinine, and calculated GFR
25 was decreased at twelve months in the
1 Rapamune-treatment groups compared to controls.
3 As a phase IV commitment, the applicant
4 agreed to report long-term follow-up safety and
5 efficacy data from studies 301 and 302. It was
6 requested the data pertaining to GFR and serum
7 creatinine be included as follow-up information and
8 be collected throughout the entire duration of the
9 study whether or not patients remained on study
11 Based on 24-month data of only those
12 patients who remained on assigned therapy, renal
13 function continued to be decreased in the Rapamune
14 treatment groups compared to controls.
16 It had been noted in the double-blind
17 studies 301 and 302 that mean and median
18 whole-blood cyclosporine concentrations had
19 remained at or above the upper limit of the
20 specified target concentration ranges. An
21 additional commitment was to evaluate the optimum
22 therapeutic range for sirolimus and the value of
23 reduced cyclosporine concentrations in combination
24 with sirolimus.
25 Proposed sirolimus concentration ranges
1 were based on preliminary PK/PD analyses on a
2 subset of patients in the phase III studies. The
3 concentration ranges were evaluated prospectively
4 in subsequent controlled trials including those
5 that we will be discussing today.
7 The applicant is proposing to amend the
8 label to include a consideration of cyclosporine
9 withdrawal at two to four months after
10 transplantation and the use of
11 concentration-controlled sirolimus adjusted to 15
12 to 25 nanograms per milligram when used without
15 The application for the labeling change is
16 supported by two studies that utilize cyclosporine
17 withdrawal with Rapamune in
18 concentration-controlled regimen. Study 310 was an
19 open-label non-IND study conducted in Europe,
20 Canada and Australia with randomization at month 3
21 post transplant. Study 212 was an open-label study
22 conducted in the U.S. and Europe with randomization
23 at days 2 to 7 post transplant and we are in
24 general agreement with the applicant's description
25 of these studies and the reported results.
2 In the cyclosporine-withdrawal arm, the
3 dosage of sirolimus was increased after withdrawal
4 and was adjusted to maintain whole-blood
5 concentrations by immunoassay. Study 310 targeted
6 trough levels of 20 to 30 nanograms per milligram
7 while study 212 targeted trough levels of 10 to
8 20 nanograms per milligram.
10 The strengths of these studies include the
11 randomized controlled design, the quality of the
12 concentration control of cyclosporine and sirolimus
13 and the quality of follow up for patient and graft
14 survival. Weaknesses of the study include the
15 open-label study design which creates a potential
16 for bias in the assessment of acute rejection
17 episodes were comparative safety, the lack of
18 adequate representation of subpopulations of
19 interest such as African-Americans and Hispanics
20 and the early randomized in study 212 allowed for
21 dropout before reaching the time of cyclosporine
24 We would now like to briefly cover the
25 following efficacy considerations; the patient
1 population, discontinuations during treatment,
2 patient and graft survival at twelve months, acute
3 rejection after cyclosporine withdrawal and renal
4 function at twelve months.
6 Study 310 excluded high-risk transplant
7 recipients from randomization to cyclosporine
8 maintenance or withdrawal at two to four months
9 after transplantation. Based on protocol-specified
10 criteria which included Banff grade III
11 acute-rejection episodes or vascular rejections
12 occurring four weeks before random assignment,
13 dialysis dependency, serum creatinine greater than
14 400 micromoles per liter or inadequate renal
15 function in the opinion of the investigator to
16 support cyclosporine elimination.
18 In study 212, patients were randomized at
19 an earlier time than in study 310. Patients with
20 adequate renal function, as determined by the
21 investigator, were randomly assigned within 48
22 hours after transplantation to cyclosporine
23 maintenance or withdrawal. The remaining patients
24 were eligible for randomization if their acute
25 tubular necrosis or delayed graft function had
1 resolved sufficiently by the seventh day to allow
2 them to receive cyclosporine A. Patients whose
3 acute tubular necrosis or delayed graft function
4 had not resolved by day 7 after transplantation
5 were not randomized.
7 Discontinuation after randomized
8 assignment to treatment is problematic in
9 open-label studies and it is difficult to determine
10 if the actual regimen led to the discontinuation or
11 if it was due to patient or physician concern over
12 randomized treatment. More patients discontinued
13 during assigned treatment in the Rapamune arm
14 compared to the Rapamune plus cyclosporine arm.
15 This difference is statistically significant in
16 study 310.
17 However, all patients were followed
18 through twelve months for rejection, graft loss
19 and death whether they continued assigned treatment
20 or not and the majority also had retrievable
21 renal-function information.
23 This table depicts the reasons for
24 discontinuation in study 310. Although the overall
25 rate of discontinuation in study 310 is
1 significantly higher for the Rapa treatment arm,
2 comparison of the individual reasons for
3 discontinuation fail to show any noteworthy
6 We are in general agreement with the
7 applicant's description and report of patient and
8 graft survival at twelve months after
9 transplantation. As the applicant discussed
10 earlier, patients and graft-survival rates were
11 high, well over 90 percent, despite the difference
12 in discontinuation from study drug between
13 treatment groups in study 310, patient and graft
14 survival among those in the Rapa arm was not
15 inferior to those in the Rapamune plus cyclosporine
18 This slide presents the rates of acute
19 rejection following cyclosporine withdrawal for the
20 two studies. There was an excess of
21 acute-rejection episodes observed in the Rapa arm
22 compared to the Rapamune plus cyclosporine arm.
23 This was consistent across both studies.
24 The excess in acute rejection, however,
25 was not associated with a detectable decrease in
1 patient or graft survival at twelve months after
2 transplantation as show in the previous slide by
3 the high patient and graft survival rates.
5 Renal function at twelve months post
6 transplantation was measured by serum creatinine
7 and GFR as calculated by the Nankivell method.
8 Rather than performing an on-therapy analysis, the
9 analysis of renal function that we will present
10 attempted to include all patients with a
11 functioning graft at twelve months including those
12 who discontinued study drug.
13 There was a small amount of missing data
14 reflected by the numbers of subjects included in
15 the following tables. Overall renal function is
16 better for patients in the Rapa arm. However,
17 patients who experienced an episode of rejection
18 had worse renal function regardless of which
19 treatment group they were assigned.
21 This slide presents the mean GFR at twelve
22 months post renal transplant. In both studies,
23 significant increases in GFR are noted for the Rapa
24 treatment arms when compared to the Rapamune plus
25 cyclosporine arm.
2 This slide presents similar results for
3 serum creatinine and creatinine results are
4 significantly better in the Rapa arm.
6 The next two slides present that and serum
7 creatinine results by post-transplantation
8 rejection status. In patients who have not had a
9 rejection within the first twelve months post
10 transplant, the improvement in GFR in the Rapa arm
11 compared to Rapa plus cyclosporine remains.
12 However, patients who experience a rejection have
13 decreased GFR regardless of treatment.
15 This slide presents similar results for
16 serum creatinine. In patients who have not had a
17 rejection within the first twelve months post
18 transplant, the improvement in serum creatinine in
19 the Rapa arm compared to Rapamune plus cyclosporine
20 remains and, once again, patients who experience
21 rejection have decreased renal function regardless
22 of treatment.
24 Safety considerations that we will present
25 will include defining the exposure to sirolimus, a
1 review of the original Rapamune NDA adverse-event
2 profile for the 5 milligram dose compared to the 2
3 milligram dose and then we will highlight specific
4 adverse events that occurred in the current two
5 pivotal trials.
7 The mean trough concentration for
8 sirolimus following 2-milligram and 5-milligram
9 doses in the original NDA, study 310, are depicted
10 on this slide. Note that the observed sirolimus
11 trough concentrations in the current study 310, in
12 the sirolimus concentration arm, are comparable to
13 those observed in the 5-milligram arm of study 310.
15 Trough concentrations were determined
16 using an immunoassay method in the clinical trials
17 and the applicant is proposing a validated HPLC
18 methodology for therapeutic dose monitoring. This
19 involves sending samples to analytical centers,
20 laboratories, for determining the trough
23 The original Rapamune NDA was approved in
24 September of 1999 and, at that time, when
25 considering treatment-emergent adverse events that
1 occurred at a frequency of greater than 20 percent,
2 a significantly higher incidence of fever,
3 diarrhea, anemia, leukopenia, thrombocytopenia and
4 hyperlipidemia occurred with the use of the higher
5 5-milligram dose of Rapamune when compared to the
6 2-milligram dose.
7 Consequently, our safety review focused on
8 ascertaining whether these side effects would be
9 more problematic in the current studies which
10 utilize concentration-controlled Rapamune with
11 higher drug exposure and, indeed, diarrhea in study
12 212 and thrombocytopenia in both studies 212 and
13 310 occurred at a significantly higher incidence in
14 the Rapa treatment arm.
15 The incidence of hypercholesterolemia and
16 hypertriglyceridemia and the use of lipid-lowering
17 agents was not significantly different across the
18 two treatment arms in study 212 and 310.
20 Now, considering treatment-emergent
21 adverse events that occurred in the original NDA at
22 a frequency of greater than 5 percent and less than
23 20 percent, one notes a significantly higher
24 incidence of chills, face edema, hypotension,
25 hypokalemia, increased LDH, skin ulcer,
1 lymphocoele, tachycardia, insomnia and epistaxis
2 with the use of the higher 5-milligram dose of
3 Rapamune when compared to the 2-milligram dose.
4 In the present studies, 310 and 212,
5 hypokalemia occurred in a significantly greater
6 frequency in the Rapa arm.
8 There were discontinuations for elevated
9 liver-function test in the Rapa arm in study 310.
10 Hepatitis B virus and hepatitis C virus data was
11 not available on all patients. There was an
12 increased incidence of elevated LFTs again in the
13 Rapa arm versus the Rapamune plus cyclosporine
14 treatment arms of both studies. There were no
15 deaths in study 212 or 310 which were due to
16 hepatic failure or attributable to study drug.
18 The majority of the patients in the two
19 studies were at lower risk to develop CMV
20 infection. Approximately 12 percent of patients in
21 study 310 were high risk with CMV-donor positivity,
22 recipient-negative for CMV. There were no
23 significant differences in the incidence of
24 infection across treatment arms except for the
25 higher incidence of Herpes zoster in the Rapamune
1 plus cyclosporine arm in study 310 and a higher
2 incidence of fungal dermatitis in the Rapa arm in
3 study 212 which Wyeth has already discussed.
4 There were no detectable differences in
5 the treatment arms related to malignancy or
6 post-transplant liver proliferative disease.
8 To summarize, finally, please consider the
9 risks and benefits of utilizing
10 concentration-controlled Rapamune in a cyclosporine
11 withdrawal regimen for renal-transplant patients.
12 The risk of cyclosporine withdrawal include the
13 surge of early mild rejection seen in these studies
14 coupled with higher exposure to sirolimus and the
15 associated adverse events such as thrombocytopenia,
16 hypokalemia and elevated liver-function tests.
17 The benefit of cyclosporine withdrawal
18 include the less cyclosporine-associated toxicities
19 and mean renal function was improved in those
20 patients who did not experience rejection.
21 That's the conclusion for the FDA review.
22 Fairly brief.
23 DR. ENGLUND: Questions?
24 DR. ABERNETHY: With your review of the
25 data, what do you believe the definition of
1 hypokalemia and thrombocytopenia was? I am just
2 trying to understand. Is it less than the other
4 DR. TIERNAN: It is less than the other
5 treatment arm; right.
6 DR. ABERNETHY: But we are really not
7 talking about below 3.5 or below 50,000?
8 DR. TIERNAN: No. It is more of a
10 DR. HUNSICKER: One thing I didn't get
11 from the rapid thing. I, of course, have the
12 advantage of the briefing document from
13 Wyeth-Ayerst and only a brief thing from you. When
14 you did the analysis for creatinine on an
15 intent-to-treat basis rather than on a, whatever
16 they called it, the basis that excluded patients
17 who were not still on drugs. If you include all
18 the patients, including the patients who rejected
19 and whatever, what was the difference at the last
20 analysis at one year? What was the difference in
21 creatinine between those that were on the Rapamune
22 and those that were on the Rapamune plus
24 DR. TIERNAN: Dr. Cavaille-Coll, do you
25 want to--
1 DR. CAVAILLE-COLL: I think we want to
2 look again at slide 20, please.
4 I have to first apologize that these
5 analyses are not in the briefing package we gave
6 you. We had to have our briefing package prepared
7 a month ago and we only received the data that
8 allows us to do these within the last few days.
9 The numbers, the n's, we see here show the
10 numbers of patients for whom we were able to
11 retrieve data. We believe that we have data on
12 practically all the patients that still had a
13 functioning graft. This represents, basically, the
14 serum creatinine in micromoles per milliliter at
15 twelve months for the different groups. This did
16 not separate them out for whether they rejected or
17 did not reject.
18 DR. HUNSICKER: This includes rejectors
19 and nonrejectors.
20 DR. CAVAILLE-COLL: Yes.
21 DR. HUNSICKER: So long as they still have
22 a functioning graft.
23 DR. CAVAILLE-COLL: Yes.
24 DR. HUNSICKER: And we have the problem of
25 the loss because of a nonfunctioning graft and we
1 would have to deal with that if they were uneven.
2 But they are relatively even so we are going to be
3 able to ignore that.
4 DR. CAVAILLE-COLL: Actually, since these
5 were very low-risk patients already, there were
6 very few graft losses and deaths.
7 DR. HUNSICKER: I want to say this now as
8 sort of a preparation to what I would like to say
9 later on about the relationship between rejection
10 and creatinine that, at the end of the day, taking
11 all the patients, the patients assigned to Rapamune
12 on an intent-to-treat basis wound up with about a
13 13, which is about--what does that translate, about
14 1 milligram per deciliter difference?
15 DR. ENGLUND: Who could translate the
16 micromoles into milligrams per deciliter?
17 DR. HUNSICKER: It is about 0.1. It is
18 about a 0.1 milligram per deciliter difference.
19 DR. CAVAILLE-COLL: Yes.
20 DR. HUNSICKER: In the favor of Rapamune
21 even taking into account the increased numbers of
23 DR. CAVAILLE-COLL: Do you want to also
24 see the next slide, 22, which will show you how it
25 breaks down by rejector and nonrejector?
1 DR. HUNSICKER: Yes.
3 I actually did see that one and what I
4 noticed was that amongst the rejectors, there is no
5 difference meaning that--well, I will just simply
6 say there is no difference whereas there is a
7 substantial difference in the nonrejectors. But at
8 least it is not worse in the rejectors.
9 DR. CAVAILLE-COLL: I think that is what
10 the slide says; yes.
11 DR. ENGLUND: Other questions? Dr.
13 DR. SUTHANTHIRAN: In both these studies,
14 this is a concentration-controlled trial keeping
15 sirolimus levels at 15 to 25. Do we have any data
16 in terms of whether these levels are actually
17 therapeutic? Is there any relationship between
18 these levels and the absence or presence of acute
19 rejection because when I looked at earlier data
20 when it was presented, it appeared that the
21 majority of patients, rejectors or nonrejectors,
22 fell within this 15 to 25 nanograms per milligram,
23 because we are going to place a lot of emphasis on
24 keeping patients at these levels.
25 I wonder whether keeping them at this
1 level really has a clinical benefit in terms of
2 either absence or presence of rejection or in terms
3 of creatinine levels or in terms of clearance. I
4 don't know whether the FDA looked at it.
5 DR. ENGLUND: Could the FDA respond to
7 DR. CAVAILLE-COLL: We didn't look at that
8 specifically. Again, I must say that the
9 information that we had on the retrievable
10 information on twelve-month data for creatinine
11 clearance, for creatinine and GFR really we have
12 only had for less than two weeks. The company made
13 a very good effort to try to retrieve that since
14 that was not something that they had planned to
15 collect originally under their protocols.
16 DR. ENGLUND: So we don't have, really,
17 that much intent-to-treat pharmacokinetics at
18 twelve months?
19 DR. ABERNETHY: I think that the issue at
20 least some of us are feeling is that there has been
21 no rationale presented yet for therapeutic drug
22 monitoring with this drug. I think we are seeking
23 that rationale.
24 DR. ENGLUND: We certainly want to discuss
25 that after the FDA presentation. So, be
2 Do we have any other questions concerning
3 the FDA presentation specifically that was given to
4 us here?
5 DR. HUNSICKER: I guess I would like to
6 ask the FDA, as they discussed with the sponsor the
7 planning of this trial, there are two things that I
8 find surprising. The first is that a lot of the
9 analyses, the toxicity analyses, which are really
10 the basis on which a superiority is being proposed,
11 were not done on an intent-to-treat basis making it
12 very difficult to understand.
13 Was this an understanding that you all had
15 DR. CAVAILLE-COLL: The FDA had very
16 little input in the planning of these studies.
17 Study 310 was conducted outside the U.S. and not
18 under the U.S. IND. Most of the planning of study
19 212, FDA had very little input on that
20 DR. HUNSICKER: Okay.
21 DR. CAVAILLE-COLL: As far as analysis for
22 safety, it is customary to do an analysis in the
23 population of all patients who received at least
24 one dose of study drug. Another variation, though,
25 is to do an analysis only based on patients who are
1 still on the study drug up to a certain number of
2 days after discontinuation of study drug.
3 DR. HUNSICKER: Yes. I guess the reason I
4 am coming down on this though is that the role of,
5 in quotations now, toxicity here is very different
6 in this application from the typical one in which
7 you have a major comparison in which you are
8 showing superiority and you just want to make sure
9 you are not killing people or doing something nasty
10 on the side.
11 There the toxicity is really supportive of
12 the major conclusion. In this particular
13 situation, the whole world has been turned upside
14 down. You are showing equivalence for what we
15 consider to be--or looking at the question of
16 equivalence--for what are the major outcomes and
17 you are justifying this new agent on the basis of
18 less toxicity.
19 Under those circumstances, it seems to me
20 that there is a real requirement that the toxicity
21 analysis be done the same way that we would have
22 done any other analysis for a major outcome; that
23 is to say, on an intent-to-treat basis. We have to
24 see all of the data.
25 DR. ENGLUND: Are there any more
2 DR. DeGRUTTOLA: A brief follow up on that
3 question. I thought that was an excellent point
4 and I think one of the issues here is whether
5 toxicities are likely to persist after therapy has
6 been discontinued.
7 On the one hand, there is the issue of
8 whether comparisons are interpretable because they
9 are based on the randomized populations which I
10 think the previous speaker mentioned and the other
11 issue I think pertains to the persistence of
12 toxicity. So I think reconsidering this issue in
13 the discussion about how to interpret the toxicity
14 results with those issues in mind--
15 DR. HUNSICKER: I do have another question
16 for the FDA when it is my turn again.
17 DR. ENGLUND: What I would like to propose
18 is to finish up FDA questions and then, since we
19 have a little bit of time, to go back to our
20 pharmacokinetics questions yet before lunch. So,
21 if we have any other questions, if this is an FDA
22 question having to do with this presentation.
23 DR. HUNSICKER: This is a--I am almost
24 embarrassed to say it is probably a legal question
25 but there is an issue here about the requirement
1 for a sponsor to show sufficient numbers of major
2 subpopulations of the United States for us to be
3 able to say anything.
4 My question is--here, I will tell you in
5 advance my opinion that we don't have enough
6 information about blacks or hispanics to be able to
7 say anything very substantial about them. We just
8 simply don't have the data. I don't think that the
9 small numbers of patients that were randomized to
10 the 212, I guess it was, trial are sufficient
11 really to give us any confidence about where things
12 are going to be, particularly if you take it from
13 the point of view that this is a group in which we
14 know the risks, both acutely and longer term, are
15 much higher.
16 The question is what do we have to say at
17 the end of the day about the entire application
18 when it does not have enough information about
19 subpopulations? Can we say that this is a
20 reasonable proposal for people who are in the
21 population, that they were studied but that we
22 don't have information, or do we have to say, "You
23 really have to show information about your
24 subpopulations before you come to us." I don't
25 know the answer to that.
1 DR. ALBRECHT: I would like to say that
2 what we are looking for you to say to us, from a
3 patient-management scientific approach, is is the
4 absence of that data so critical that, in fact, it
5 is not possible to recommend whether there is a set
6 of patients that can responsibly be managed with
7 this regimen or whether the absence of that
8 information is such that, in fact, it precludes
9 putting the drug on the market because of possible
10 risks for patients by not having that information.
11 In the end, when we approve a regimen,
12 what we need to do is be able to provide labeling
13 that can be followed by clinicians and others to
14 manage patients. If, after deliberation, you
15 believe that labeling cannot be written which can
16 overcome some of these limitations that you are
17 identifying, then it would be good if you were to
18 let us know that so that we can then proceed
20 DR. HUNSICKER: My shy partner over here
21 who is the representative of the public interest
22 has shoved over to me just the single datum that
23 currently on the UNOS renal waiting list,
24 African-Americans constitute 35 percent of the
1 DR. ENGLUND: Dr. Shapiro?
2 DR. SHAPIRO: Can I ask a corollary
3 question. The pivotal trial here is entirely
4 non-USA patients, the 310. What are the
5 implications of that in terms of approving a change
6 in the labeling for USA patients?
7 DR. ALBRECHT: The regulations do allow
8 the FDA to take into consideration data from
9 foreign trials when making a decision about
10 marketing and approving a drug product. However,
11 the caveats to that are that the foreign data are
12 of the quality and caliber that would be requested
13 to be provided from US patients in addition to
14 which the results of such studies must be
15 applicable to populations within the United States.
16 If those parameters are met, then we are
17 to consider foreign data in making a decision.
18 DR. ENGLUND: Dr. Johnson.
19 DR. JOHNSON: I have another question
20 about the labeling. What are the federal
21 limitations on what the label can say in respect to
22 ethnic populations? Is there such a thing?
23 DR. ALBRECHT: Are you asking whether, if
24 there is an absence of data, we can put such
25 information into the package insert?
1 DR. JOHNSON: I guess that is my question.
2 DR. ALBRECHT: Just wanted to make sure.
3 Again, we can put into the labeling information
4 that factually reflects studies that were conducted
5 and the results from such studies with the caveat
6 that such labeling should then be able to direct
7 physicians to properly use the drug in managing the
8 patients that they would encounter in their
10 Again, to follow up Dr. Hunsicker's
11 question, we will look to you to give us guidance
12 on whether the absence of certain subsets of the
13 population are such that they would actually
14 preclude clinicians being able to effectively use a
15 particular drug regimen.
16 DR. JOHNSON: I guess my question is a
17 little bit more to the point and that is I am not
18 really asking whether or not somewhere within the
19 insert that we can place that, "This drug was not
20 studied in the subpopulation." I guess what I am
21 asking specifically in the labeling statement, can
22 we have limitations upon which groups this drug
23 should be approved for for the current labeling
25 DR. ALBRECHT: I think the short answer is
2 DR. ENGLUND: With that, we have a little
3 bit of time. I really think now would be a good
4 time to go back. We have such good pharmacologic
5 expertise on the panel and with Wyeth-Ayerst.
6 Perhaps, if you would like to, Dr. Abernethy, just
7 rephrase briefly your one sentence and we could
8 have a response from the company.
9 DR. ABERNETHY: I think the issue is that,
10 with the data from these two studies presented, we
11 really didn't see good data suggesting that a
12 better outcome could be obtained by bracketing
13 concentration ranges. If that data is absent, then
14 the clinician part of my says it is easy. If there
15 is a question, you just give a higher dose because
16 there is no toxicity to pay for that.
17 In the FDA presentation, there was some
18 data from historical studies that did suggest some
19 dose relationship to some of the side effects. I
20 am just trying to get a feel because the data we
21 are seeing here is at a higher concentration range
22 than any of the stuff that that came from.
23 DR. BURKE: I am Jim Burke with
24 Wyeth-Ayerst Research. I have a slide coming up.
1 This is a slide of the PK/PD analysis
2 during the first 75 days following transplantation.
3 It is up to 75 days. We looked at all the
4 different possible explanatory factors that could
5 lead to rejection.
6 Here is a simplified diagram showing only
7 the effect of cyclosporine and sirolimus. So one
8 can see that, indeed, there is a concentration
9 effect between the concentrations of cyclosporine
10 and the concentrations of sirolimus in outcome.
11 This was done in all patients during the
12 first 75 days. So we have 525 patients in a fairly
13 large range of concentrations. If one looks at the
14 data after randomization and one wants to look at
15 those that went on to Rapamune therapy, the number
16 of acute rejections have gone down considerably and
17 also the sample size has gone down to 215 patients.
18 So the power of doing an analysis of the
19 relationship between effect and concentration after
20 randomization is limited by those factors. Indeed,
21 one should remember that we only studied a single
22 concentration range after randomization. Although
23 you have a few outliers, you should consider all of
24 the outcome as part of the population.
25 So we defined the concentration as the
1 distribution of the concentrations in that
2 population that was studied. Could we have used
3 higher concentrations? Should you worry about
4 higher concentrations? For that, I think you
5 should go back to two earlier studies that were
6 done, studies 207 and 210.
7 We started off on concentrations targeted
8 at a mean of 30 milligrams per milliliter in the
9 first two months. In those studies, although the
10 overall safety and efficacy was acceptable, if one
11 looks at toxicities at those higher concentrations,
12 cholesterol, triglycerides, hypokalemia, they were
13 considered unacceptable for chronic maintenance.
14 So when we designed study 310, we had
15 those data available so we chose a lower range of
16 concentration rather than retesting a higher
17 concentration where we had observed toxicities.
18 DR. HUNSICKER: My recollection is that
19 there was a slide shown, I think at the end of the
20 pharmacokinetic section, which dealt with the
21 values of sirolimus levels that were observed and
22 what would have been observed if there had not been
23 dose correction. That showed predominantly that
24 there was an excess--the imputed, the presumed,
25 levels would have been higher. There were very few
1 lower levels.
2 That is my recollection of that study;
3 that is to say, using the non-dose-adjusted thing,
4 you had very few people who were below the lower
6 DR. BURKE: What we have heard now is that
7 there is a weak relationship between the sirolimus
8 levels above that and toxicities. There is
9 probably some but we haven't seen strong
10 relationships. So the argument from your data that
11 you present, as I see it, is that the advantage of
12 the dose monitoring is primarily to avoid
13 excessively high doses for which we don't have very
14 much toxicity demonstrated to us as opposed
15 to--this is the slide over here--the possibility of
16 having excessive low levels which would be
17 associated with rejection.
18 I am aware of some things that I can't
19 cite to you because they are in the literature.
20 One was a regression in the earlier pivotal trials
21 of the actual achieved levels with rejection that
22 showed that people who were higher than, I guess it
23 was 8 or something like that, very rarely had
24 rejection episodes.
25 I believe that there are other data in the
1 literature that show, with low-dose cyclosporine,
2 that also there is a critical relationship between
3 the lower end, that you need to get above a certain
4 level to avoid rejection.
5 But the question, I think, that is being
6 implicitly put is whether we really are achieving
7 anything on the low end here with the TDM as
8 opposed to just simply avoiding the high end for
9 which we have not yet defined toxicities.
10 DR. BURKE: Certainly, this slide does
11 demonstrate the preference of doing therapeutic
12 drug monitoring over giving a fixed dose. If one
13 goes back to the toxicity and the data from the
14 previous studies, actually the concentration-effect
15 relationships on study 310 that I just showed you
16 were very similar to the pooled data analysis of
17 301 and 302.
18 So we have reproduced that. What is the
19 cutoff on the lower end? Well, in this early
20 period where we do have sufficient rejections and a
21 sufficient distribution of data, we were able to do
22 an analysis where we dichotomized the data based on
23 cutoffs of the lower end of recommended levels.
24 That was at 5 for sirolimus and 150 for
25 cyclosporine. Indeed, we do find that, if they are
1 below those levels, they have a significant
2 increase of the incidence of acute rejection. We
3 can do that during that early period. I will admit
4 that, in the later period, in the maintenance
5 period, we don't have sufficient evidence to do
7 But I think the ranges that we are
8 recommending will avoid clinicians treating
9 patients with too low levels. We have seen that
10 there are a few additional rejections and we
11 certainly don't want to increase that number.
12 DR. HUNSICKER: Getting back to what is up
13 there, and I am going to throw in a little
14 bit--believe it or not, I take care of patients and
15 I also have noticed that sometimes the levels are
16 much lower than you expect. I have used sirolimus
17 levels to adjust that.
18 But what you have here is a predicted--the
19 range that you would get if you did TDM as opposed
20 to what you would have had had you used an
21 8-milligram fixed-dose regimen and you would make
22 the adjustments based on the proportionality of
23 dosing levels.
24 What you see is that, at the bottom level,
25 which is the risk for rejection where I think that
1 the data are fairly solid, there isn't a hell of a
2 lot of difference. What you are really seeing is
3 that you are avoiding higher levels with your drug
4 monitoring. That is where--at least, I have taken
5 the argument from that side of the table. There
6 isn't a hell of a lot of evidence that there is
7 much toxicity there.
8 It does bring in complexity. So the
9 question is does the avoidance of those higher
10 levels really justify the complexity of the issue.
11 DR. BURKE: I will go back and did see a
12 slide showing the relationship between
13 concentration and lipids and I think there is
14 another parameter during those earlier phase II
15 studies. You can put that up.
17 To repeat the design of this study, we
18 compared cyclosporine direction to sirolimus from
19 the time of transplantation. There were about 40
20 patients in each group. As I say, the sirolimus
21 concentrations were targeted at 30 during the first
22 two months. After two months, the concentrations
23 were to be reduced to a target concentration of
24 about 15. You can see they are slightly higher
25 than that.
1 Let's take a look at this early period
2 when the concentrations are high, the average got
3 as high as 35. You can see, in the yellow, the
4 triglycerides that got up to over 4 millimole. I
5 think that is over 400 milligrams per deciliter.
6 Cholesterol; the average was up to 8, which is--I
7 am trying to convert that. That is about 300
8 milligrams per deciliter. So it would not be
9 reasonable to treat a population at those high
10 concentrations for a maintenance therapy.
11 When you see that the sirolimus
12 concentrations have been increased to levels very
13 similar to those they were recommending, a mean
14 slightly less than 20, you can see that there was
15 an improvement in these laboratory parameters.
16 Here I have shown two parameters. I could also
17 show others that are affected by sirolimus. This
18 is platelets.
19 So I think there was reasonably
20 justification in the study design not to study much
21 higher levels of concentration. Indeed, there is
22 reasonable evidence that we should put that in our
23 labeling today to avoid toxicities.
24 I have one more I will show you here, the
25 SGPT values.
2 You can see, once again, higher levels in
3 the beginning and lower levels later when the
4 concentrations are decreased. It is not quite as
5 evident. I know they were very nice on these
6 platelets. So there is evidence for us to instruct
7 clinicians not to target very high levels.
8 On the lower end, to go back to the one
9 slide we showed, you saw, whether you had given it
10 on dose or whether you had given it on therapeutic
11 drug concentration, there are a number of values
12 that are low.
13 You have to realize that that presentation
14 is an intent-to-treat presentation, that it
15 includes data on patients, even those that
16 discontinued a few days after randomization and did
17 not have time to have their target concentrations
19 So it is an extremely vast population. If
20 one went out further, one would find very few
21 patients that are below what we are recommending.
22 So you shouldn't confuse that intent-to-treat
23 population with what patients are actually
24 receiving beyond six months, twelve months, and so
1 DR. HUNSICKER: Let me just do one last
2 stab as sort of a provocateur here, the issue
3 having been raised. Then I am going to cede to the
4 pharmacologists who raised this question in the
5 first place.
6 I can imagine three policies. One is you
7 just give a fixed dose and you ignore what is
8 happening. The second is you give what you have
9 got, you would get therapeutic dose monitoring.
10 The third is that you give a fixed dose and, as
11 long as you stay out of trouble, you do what you
12 are doing and, if you find that you have got some
13 more toxicities, you go back and check your dose.
14 Or, if you find that you are having a rejection,
15 you recheck that dose.
16 What I am trying to get across is that I
17 am not sure that we need to absolutely, in the
18 indication, nail people to the requirement for this
19 kind of therapeutic monitoring. I think that it
20 might be sufficient to advise them that you can
21 have levels that are lower than you expect and
22 there is a lower level that you should be achieving
23 and that you can find out about this. Of you can
24 have toxicity and you can find out about the level
25 with a TDX or with whatever measurement you are
1 using, rather than require that it be done in every
3 I think that--I am imputing to you what
4 your question was, but I think that is really the
5 issue that we are raising. We have to tie this to
6 therapeutic dose monitoring.
7 DR. SUTHANTHIRAN: May I make a point. My
8 question has been rephrased and I have been called
9 a pharmacologist. I don't find anything bad about
10 it, but the issue I was trying to make, I think
11 your first slide made the point that, when you use
12 different levels of sirolimus and different
13 concentrations of cyclosporine, if the sirolimus
14 concentration is high, you can reduce the incidence
15 of rejection even with the lower levels of
16 cyclosporine. There is a synergy between the lower
17 levels of cyclosporine and high trough levels of
19 That point is very clear and you had
20 enough cases in the first three months. My concern
21 was, after the patient is randomized, when we
22 suggest certain levels, 15 to 25, there is really
23 not much data to support that 50 to 25 levels, in
24 fact, prevents acute rejection because the number
25 of patients who had acute rejection were in the 15
1 to 25 nanogram level. In fact, 16 out of 23
2 patients who had acute rejection were within this
3 suggested target.
4 It appears to me a higher target level may
5 be problematical from the toxicity perspective and
6 the current data doesn't tell us what is the actual
7 level we need to keep the patient at in order to
8 prevent an acute rejection episode.
9 I wonder whether we could, in fact, go a
10 little bit under the level. Maybe we will avoid
11 some of the toxicity and have the same therapeutic
12 benefit. This was the point I was trying to make,
13 whether there is any data you analyzed or the FDA
14 analyzed that tells us that a particular level of
15 sirolimus is therapeutic in terms of preventing an
16 episode of acute rejection.
17 DR. BURKE: The data that we do have is
18 simply the quartiles that we presented. We know
19 that, beyond a certain point, those 207 and 210
20 patients are now out to five or six years, about a
21 quarter of those patients. They haven't lost their
22 grafts. They haven't had an increase in their
23 creatinine. They haven't had a rejection.
24 That doesn't mean that additional work
25 does not need to be done, and this is always very
1 difficult when you are talking about long-term
2 outcome, how do you target levels. Indeed,
3 additional work probably needs to be done in that
4 early post randomization period, or after three
5 months, to learn how to better adjust those
7 So additional work does need to be done
8 but the evidence we have today does support the
9 concentrations that we are recommending.
10 DR. NEYLAN: I don't know if this would
11 help so I need to ask permission first. But we
12 have additional data for 310. As you know, this is
13 a five-year study. Most of these patients are now
14 approaching the three-year mark. So, on this issue
15 of the relationship between the suggested target
16 range and the incidence of acute rejection, we do
17 have data that is subsequent to the twelve-month
18 mark on rejection frequency in these randomized
20 I will again remind you that the
21 randomized arm in 310 to the Rapamune maintenance
22 therapy was downregulated in the Rapamune exposure
23 to approximately the range that we are suggesting
25 So the question is, first, would that data
1 be of any use in addressing your question and, if
2 so, would we be allowed to show it.
3 DR. SUTHANTHIRAN: I think so. If you can
4 show that patients who are kept at the levels you
5 suggest had a lesser incidence of acute rejection
6 subsequently compared to patients who had lower
7 than that level, I think it will support the idea
8 that keeping the sirolimus at a particular level
9 would be of benefit.
10 DR. ENGLUND: Yes; if you are going to be
11 showing levels and rejection after the twelve-month
13 DR. NEYLAN: Let me show you, then, the
14 trough levels first.
15 DR. ENGLUND: Wait. I think we need to
16 hear from the division.
17 DR. NEYLAN: Oh; I'm sorry.
18 DR. ALBRECHT: I just wanted to comment.
19 I don't believe that information has been submitted
20 to the FDA for our review.
21 DR. NEYLAN: No; it hasn't.
22 DR. ALBRECHT: So we would be hearing your
23 viewpoint, but we could not comment on it from the
25 DR. ENGLUND: Are we allowed to see it?
1 DR. ALBRECHT: Yes.
2 DR. HUNSICKER: Can they show it is the
4 DR. ALBRECHT: Having said what we said,
5 certainly you can show it.
6 DR. NEYLAN: Do I have permission to show
7 it? First, let's see the rejection slide. Then we
8 will go back to that slide.
10 This is the follow up then beyond the
11 twelve-month mark onto 24 months for study 310.
12 What we have seen in that, after the twelve-month
13 mark, there have been no rejections in the Rapamune
14 maintenance group and only two rejections in the
15 Rapamune plus cyclosporine group.
16 The Rapamune maintenance group, again, is
17 a group of patients that are receiving Rapamune
18 doses at the suggested target range. I should also
19 comment here that there were a handful of
20 rejections seen in both of these groups at the
21 twelve-month mark because of protocol biopsies.
22 If we could go to the next slide.
23 DR. HUNSICKER: Were those protocol biopsy
24 rejections clinically manifest?
25 DR. NEYLAN: No; they were not.
1 DR. HUNSICKER: So we don't even know they
2 are rejections other than by histological criteria.
3 DR. NEYLAN: Right. Exactly so.
4 DR. HUNSICKER: Just so that some of the
5 nonnephrology and nontransplant people are aware of
6 that, there has been a lot of debate about what
7 "rejection" on histology means. There has been a
8 lot of debate about the meaning of rejection found
9 on histology without clinical correlates.
10 I don't take a side on that but I think
11 that does put a very different picture on that
12 little cluster of rejections that happens, if they
13 are not clinically manifest but simply the
14 consequence of protocol biopsies. It is not ever
15 clear that they are rejection.
16 DR. NEYLAN: Right. But, again, let me
17 emphasize the point that, at the twelve- to
18 24-month mark, there were no subsequent rejections
19 in the Rapamune maintenance group. This group was
20 receiving, now, on average, 6 milligrams of
21 Rapamune today and maintaining mean sirolimus
22 trough concentrations as measured either by the MS
23 or by the immunoassay within this suggested target
24 range today.
25 So, again, I just wanted to add that in
1 case it sheds any additional light on the
3 DR. CAVAILLE-COLL: May I ask a question,
4 since we have not seen this data. The previous
5 slide, please, that graph.
7 Does this represent all patients
8 randomized or does this just represent those
9 patients who are still on study therapy at up to
10 month 24 and, if so, what proportion are still on
11 study therapy at month 24?
12 DR. NEYLAN: Jim, since you have access to
13 the 310.
14 DR. BURKE: This is all randomized
15 patients so that we are counting 215 patients in
16 both groups. The number of patients on therapy is
17 nearly identical, 145 and 146.
18 DR. CAVAILLE-COLL: Thank you.
19 DR. ENGLUND: Dr. Ebert?
20 DR. EBERT: Another question that relates
21 to these two graphs that I have, the second graph
22 that you showed I believe showed the mean
23 concentrations over time. But I am assuming there
24 was probably a pretty wide variation in the
25 concentrations over a given period of time.
1 I think this really relates to my
2 questions about what was your strategy for dosing
3 and adjusting doses after randomization and did
4 you, in fact, perhaps, have--and I don't know if
5 you did or not, but did you have a group where
6 maybe the adjustment took longer, you had a longer
7 period of time where concentrations were low and
8 whether that early adjustment period might have
9 contributed to the fact that you saw rejections
10 early on in the trial.
11 If you went back to that three-line graph
12 with the cyclosporine and the sirolimus
13 concentrations, as you start to drop off on your
14 cyclosporine concentrations, you do somewhat
15 compensate by increasing the sirolimus
16 concentrations, but I am not sure if you do that
18 So, the bottom line is I am wondering if
19 maybe just not being aggressive enough early on may
20 have contributed to some of the rejections that you
22 DR. NEYLAN: If we could show the core
23 slide from the pharmacokinetics showing the
24 divergence of cyclosporine taper and sirolimus
25 concentration ranges. Yes; this slide.
2 This is the slide I believe you were
3 referring to that shows the overlap period in which
4 the cyclosporine is coming down. These are the
5 mean trough levels of cyclosporine for the group
6 and the sirolimus concentrations are coming up and
7 are, at this point, just entering into the target
9 Yes; there is a window of time here in
10 which that overlap is occurring and it is at least
11 possible, from a clinician's standpoint, that some
12 of these patients may have been experiencing
13 rejection because there was, at the time, a
14 relative decrease in net immunosuppression.
15 We have those two studies which both
16 sought, at a time point post-transplant, to have
17 clinicians change these two important variables in
18 the immunosuppressive regimen. Both of these
19 studies were somewhat groundbreaking. So I think
20 it is not surprising that clinicians were
21 exhibiting some degree of caution in making these
23 I believe that, as this is better
24 understood, that the rapidity of this change can be
25 improved upon.
1 DR. ENGLUND: One more question?
2 DR. AUCHINCLOSS: It is actually a subject
3 that I want to come back to this afternoon at some
4 length, but if you could just put up D10. There is
5 all this talk about how we are changing multiple
6 drugs at the same time, but that wasn't true in
7 study 212, was it? They were already, from day 10,
8 on high-dose sirolimus.
9 When they withdraw their cyclosporine in
10 the withdrawal group, that is a month or two later;
12 DR. NEYLAN: That's correct. The only
13 difference is the target range of the sirolimus.
14 DR. AUCHINCLOSS: Oh; I understand. It is
15 a slightly lower target range.
16 DR. NEYLAN: Which was slightly lower.
17 When you adjust that for HPLC--
18 DR. AUCHINCLOSS: But there is only one
19 adjustment at the time of cyclosporine withdrawal
20 in this group of patients.
21 DR. NEYLAN: That's correct.
22 DR. AUCHINCLOSS: The other thing that I
23 didn't understand, and this is what I want to talk
24 about this afternoon, is that these two groups are
25 completely different from early on. The top group,
1 that never had cyclosporine withdrawn, was the
2 low-dose sirolimus and moderately high-dose
3 cyclosporine whereas the group that eventually gets
4 withdrawn is the low-dose cyclosporine from the
5 beginning with high-dose sirolimus from the
6 beginning; right?
7 So there is no comparison that you can
8 make between these two groups when it comes time
9 for the cyclosporine withdrawal in group No. 2.
10 Events have already happened in the group above,
11 and we will look at that this afternoon, that are
12 completely separate from what--that don't have
13 anything to do with cyclosporine withdrawal.
14 So I am interesting in looking at what
15 happens in the second group, the
16 cyclosporine-withdrawal group. I can only compare
17 what has happened up until that time in that group
18 with what happens to it afterwards. It is a very
19 strange trial design.
20 DR. NEYLAN: You are right in pointing out
21 that the phase II trial, 212, was asking a slightly
22 different question than the pivotal trial upon
23 which, obviously, the bulk of this indication is
25 This question specifically about whether,
1 right from the beginning, lower exposures to
2 cyclosporine coupled with the combination of a
3 concentration-controlled use of Rapamune might be
4 beneficial was one of the questions that was being
5 asked by this study.
6 DR. AUCHINCLOSS: If you put up the E21
7 results, it looked to me like you got a great
8 protocol there.
9 DR. NEYLAN: If you are about to show the
10 rejection rates--is that what this is? Yes.
11 DR. AUCHINCLOSS: At the time that you
12 came to cyclosporine withdrawal, you have got a 6
13 percent rate of accumulated rejections.
15 What you did, when you showed these
16 results, is you compared the cyclosporine arm to
17 the red arm and you said, "Gee; you know it all
18 comes out the same." The red arm was bad to begin
19 with, or certainly less good. What I see when I
20 look at that slide, is you have a 6 percent rate of
21 rejection up until the moment of cyclosporine
22 withdrawal and now, suddenly, you are 20 percent
23 within six months afterwards.
24 I think you get 10 to 15 percent
25 acute-rejection rates when you withdraw
1 cyclosporine. Don't look at the red bar. Just
2 look at blue bar. That is what happens when you
3 withdraw cyclosporine.
4 What I find most amazing is that the
5 levels of cyclosporine at the time of withdrawal
6 were only 100 to 150.
7 DR. NEYLAN: Right.
8 DR. AUCHINCLOSS: You have got a fantastic
9 synergy. Why do you want to tell people to
10 withdraw cyclosporine? Tell them to go to low-dose
12 DR. NEYLAN: What we are trying to do with
13 these two studies is basically define the margins,
14 if you will, of how to use cyclosporine and
15 sirolimus. On the one hand, we have the pivotal
17 DR. AUCHINCLOSS: And you have defined it.
18 DR. NEYLAN: On the one hand we have the
19 pivotal trials that were approved in '99.
20 DR. AUCHINCLOSS: Well, I think the
21 pivotal trial shows pretty clearly that you get a
22 10 to 15 percent acute-rejection hit if you
23 withdraw cyclosporine.
24 DR. HUNSICKER: I actually calculated the
25 difference and it is--well, we will do it later
1 this afternoon.
2 DR. AUCHINCLOSS: This one goes from 5 to
3 20. That one went from 10 to 20, something like
5 DR. NEYLAN: What we have with these two
6 sets of trials is, on the one hand, with the
7 original trials, rejection rates that were in the
8 range of 15 to 20 percent and the potential
9 detrimental impact upon renal function when the
10 combination was used in relatively full dosage for
11 both in the long term.
12 On the other hand, we have now these sets
13 of studies which define, if you will, a different
14 limit where we can see similar rates of rejection,
15 in this case in the range of about 20 percent, and,
16 with that, the elimination of cyclosporine, a
17 vastly different outcome in terms of renal
19 I think what you are suggesting is that
20 there may also be opportunities to explore
21 variations in between these two margins; that is,
22 the combination in some lower dose or
23 concentration-controlled mediated fashion, of both
24 of these drugs in a maintenance regimen. I
25 certainly would not discount that.
1 The goal, though, today is to convince you
2 that these two studies also represent a safe and
3 effective way to use Rapamune and that safe and
4 effective way is that, in fact, in many patients,
5 we can eliminate the calcineurin inhibitors.
6 DR. AUCHINCLOSS: There is no doubt about
7 that. Probably about 80 percent of them, maybe
8 even 90 percent, of them. But you have portrayed
9 to us, and you intend to portray in the intended
10 labeling, the notion that there is not going to be
11 any increase in acute rejection. To me, your data
12 strongly indicate otherwise, that you will, in
13 10 percent of your patients, pay a price with an
14 acute-rejection episode that wouldn't have occurred
16 DR. NEYLAN: I would not want to argue
17 with you that there is not an incremental increase
18 in rejection.
19 DR. AUCHINCLOSS: Shouldn't that go into a
20 labeling change, that when you consider
21 cyclosporine withdrawal, it is quite likely that
22 there is a 10 percent or some finite risk, some
23 measurable risk, to your patient population?
24 DR. NEYLAN: I am reasonably confident
25 that, when all of this gets to the stage of
1 labeling discussion, that the data will be a part
2 of that label. The data clearly demonstrates that,
3 in fact, that incremental increase is there, yes.
4 One other--
5 DR. ENGLUND: Final sentence, or
7 DR. NEYLAN: I was just going to--very
8 quickly, then, if we could show this next slide.
10 I was just going to raise the point that,
11 even with lower doses of cyclosporine, in
12 combination, there is potentially a penalty to pay
13 in terms of renal function. This is a study that
14 was done in psoriatic patients, so non-transplant
15 patients. It looks at mean creatinine over a
16 period of treatment in which these patients either
17 received cyclosporine at relatively conventional
18 doses for transplantation or received sirolimus as
20 The middle group is a group receiving
21 low-dose cyclosporine and this same dose of
22 sirolimus. You can see the spectrum of renal
24 DR. AUCHINCLOSS: I agree with you. I
25 know you want to go to lunch, so save E29 for me.
1 We will come back to that this afternoon.
2 DR. ENGLUND: Good. We are going to break
3 now for lunch.
4 [Whereupon, at 12:15 p.m., the proceedings
5 were recessed to be resumed at 1:10 p.m.]
1 A F T E R N O O N P R O C E E D I N G S
2 [1:15 p.m.]
3 DR. ENGLUND: We are now back from lunch.
4 I would now like to open the meeting for the open
5 public hearing. We have one registered speaker who
6 is going be talking to us, Dr. Alan Wilkinson. He
7 has some slides, too.
8 Open Public Hearing
9 DR. WILKINSON: I didn't realize I was, in
10 fact, the entire joint public but I am pleased to
11 be there and I would like to commend the
12 presentations teams on the thoroughness of the
14 I am here really to provide both, I
15 suppose, an experienced and a naive viewpoint on
16 the studies. I am a nephrologist, transplant
17 nephrologist, at UCLA. I am here in part as a
18 consultant to Novartis and they have paid for my
19 trip here.
20 I have also done studies for all of the
21 companies that make immunosuppressant drugs and
22 have, in fact, lectured and received honoraria for
23 speaking for both Novartis, Wyeth-Ayerst, Fugisawa,
24 Abbott. I don't think I am too selective in my--
1 What I wanted to talk about was my
2 perception of where study 301 stands in terms of
3 what we do, and also where we stand as transplant
4 physicians with regard to cyclosporine and
5 withdrawing cyclosporine. I know that when John
6 presented the data, he used still the half-life of
7 transplants for about ten years.
8 I think it is true, but I think we just
9 need to remind ourselves of this paper from Harry
10 Hiriharan that appeared in the New England Journal
11 of Medicine where, if you took out people who had
12 died--and, of course, we include death as an
13 endpoint in many of these things and that is not
14 necessarily fair to the transplanted organ.
15 If you took out people who died and looked
16 at living donors, the recipients of living donors,
17 then the half-life is approaching forty years.
18 This is in a calcineurin-inhibitor-rich
19 environment. For cadaveric transplants, where the
20 donor characteristics, of course, are less certain
21 and there is pre-death injury presumably that we
22 think affects the kidney, even in kidneys that are
23 set up to be very subject to the effects of
24 calcineurin inhibitors, even there, the half-life
25 is approaching twenty years.
1 This is the UNOS data that was used. The
2 USRDS data is, perhaps, a little less optimistic
3 than that. But I think we have to accept that,
4 during the calcineurin-inhibitor period, we have
5 improved transplant survival dramatically. That
6 isn't to say that the TOR inhibitors, Rapamune and
7 potentially Certicam are not advances in what we
8 do, but I think we have to place them in context of
9 where we are coming from.
10 I wanted just to start off with saying, in
11 addition, that I am not somebody who is particular
12 in favor of using calcineurin inhibitors in high
13 dose. I have written quite extensively on the
14 effects of calcineurin inhibitors, or rather, on
15 renal dysfunction in recipients of heart and liver
16 transplants and, in fact, have just done a big
17 review on liver-transplant recipients and renal
18 function and dysfunction in those patients, large
19 parts of which are, of course, due to calcineurin
20 inhibitors. Some of it is due to injuries to the
21 kidneys separate from that in liver recipients.
22 But, certainly, I am not in favor of
23 keeping calcineurin inhibitors there if we can
24 avoid having them. I also wanted to talk a little
25 bit before I went further on sort of the power and
1 authority of this committee before us here today.
2 I think it is true that the committee here has
3 enormous power in terms of deciding what drugs are
4 approved and how they are used to some extent.
5 But I think the labeling confers authority
6 on the usage of drugs which goes beyond, in a
7 sense, the power of committee. So, if you, as a
8 committee, say that a drug should be used in a
9 different way, that confers authority on that usage
10 and, to some extent, we have to look at your
11 fairness to the producer of the drug, in this case,
12 Wyeth. Is it fair? Is the data they are bringing
13 to you such that it is fair to them to change the
15 But, at the same time, I think you have to
16 be fair to both physicians and patients in this and
17 make sure that labeling doesn't put physicians,
18 particularly, in a difficult circumstance when they
19 choose to use different protocols in patients
20 because, if we have labeling that says that, for
21 example, the use of cyclosporine with Rapamune
22 beyond three months in low-risk patients is
23 something that is not recommend, if we continue to
24 do that, that, to some extent, I think, puts us at
25 some risk.
1 So I think we have to be very careful as
2 you make determinations about labeling what impact
3 that has on clinical practice or what impact that
4 has on standard of care and what impact that has on
5 the legal liability of physicians who are
6 prescribing these drugs.
7 Remember that you have approved sirolimus
8 for use with cyclosporine and prednisone.
9 Sirolimus is used in large numbers of patients with
10 tacrolimus. Although you are debating today
11 whether, in fact, it is feasible to withdraw
12 cyclosporine from patients on sirolimus, there are
13 many patients out there on whom that has already
14 been done in circumstances where physicians thought
15 that was a sensible thing to do.
16 So, really, what you are looking at here
17 is a trial which has addressed that. But we have
18 to remember what clinical practice is achieving in
19 the community and remember that the labeling of
20 drugs and their usage are, in a sense, two separate
21 things, whether the FDA likes that or not. But I
22 would like to believe that the labeling of drugs
23 should make it as simple as possible for the
24 prescribers within the safety of those agents.
25 I also think the question before you here
1 today is different from the question before the
2 European committee that addressed this issue
3 because, in that case, they had actually refused,
4 and I thought it was the wrong decision--they
5 refused to approve sirolimus when it was first
6 presented to them and then only approved it when it
7 was presented to them with the improvement in renal
9 I think that the analysis actually
10 misconstrued what was shown by the study, by the
11 withdrawal study, because one comment they made in
12 their scientific analysis of that data was that
13 they recommended that sirolimus not be used with
14 cyclosporine because there was evidence of additive
15 nephrotoxicity when the two were used together.
16 As it happens in that study, there is no
17 arm which shows whether there is additive toxicity
18 when you have cyclosporine and sirolimus used
19 together. If you had had an arm in that study
20 where you had actually withdrawn sirolimus, you
21 might have shown that. But you don't actually have
22 that to show in that study.
23 If we go back to the 301 and 302 studies
24 and look at the comparator arms in both of those
25 studies, the GFRs in the comparator arms--in the
1 American study, azathioprine was used. In the
2 European study a placebo was used.
3 But if you look at the GFRs at twelve
4 months in the control arms of both those studies,
5 they are as robust as the GFRs in the
6 Rapamune-withdrawal study before you today. So, I
7 think when we look at GFR and look at outcome, we
8 have to be very careful not to jump from GFR to a
9 recommendation about the usage of drugs.
10 I don't think any of us would go back to
11 say that the correct protocol to use today is
12 cyclosporine, prednisone and azathioprine. I think
13 there would be few people who would argue for that
14 although many centers may still be doing that. So
15 I think that is an important thing to recognize.
16 I also think if you look at the change in
17 GFR--let me get to that in a moment. Can you move
18 on one?
20 The other thing which I think is important
21 in all the data, and Dr. Hunsicker, I am sure, will
22 talk to this at length later this afternoon, is
23 that rejection is one of the best predictors of a
24 less-good long-term outcome. If you look at the
25 patients in whom the half-life has improved, it is
1 those patients who have not had a rejection. So
2 rejection is a very profound effector of long-term
3 graft function.
4 We shouldn't trivialize that, I think. I
5 know, in this study, it didn't reach statistical
6 significance. But we should not trivialize the
7 effect of rejection on long-term graft outcome.
8 Remember, for each patient, their graft is the only
9 one. In these venues, we discuss large trials and
10 lots of numbers but, for each patient, their graft
11 is the only one.
12 The other thing which may be addressed
13 later is the predictability using the serum
14 creatinine at one year or at some time period in
15 terms of long-term graft function. I would like to
16 remind you that that data holds best for patients
17 that were on calcineurin inhibitors because that is
18 the population in which that study was done.
20 We have no really good data long-term in
21 these studies. So I think my concerns are that we
22 don't really know the effects of late acute
23 rejection in this group yet. The data is still
24 very early. Even the two-year data is still early
25 compared to the long-term data.
1 The improved renal function certainly is
2 there but, in any study in which you withdraw
3 cyclosporine, you are going to get improved renal
4 function. In fact, the delta GFR in this study is,
5 perhaps, surprisingly small. If you look back at
6 some of the old studies done by Curtis and Luke and
7 some other studies, they had bigger improvements in
8 renal function when they switched from
9 cyclosporine-prednisone to prednisone-azathioprine
10 which suggests that the effect of cyclosporine at
11 this point is less than it maybe was in those
13 The other thing which I think we should
14 realize is that the patients who had rejection, if
15 we look at their renal function subsequent to
16 rejection, it was brought down to a greater extent
17 than the patients who were on the
18 cyclosporine-sirolimus arm, that the end result for
19 the two groups was equivalent but the starting
20 point was actually better for the Rapamune group.
21 So the effect of rejection in patients--I
22 know it is small numbers but we are, in fact,
23 arguing from small numbers, the effect of rejection
24 was greater in those patients on sirolimus and
25 prednisone only.
1 The other thing which I think is important
2 in that data is that the GFR in the
3 cyclosporine-prednisone-treated patients was, in
4 fact, stable, that there was no decline. So when
5 we talk about additive toxicity and progressive
6 toxicity in those patients who were kept on
7 cyclosporine, there was no proof of that in that
9 The GFRs were certainly lower. We would
10 expect that in patients treated with cyclosporine.
11 We don't know if those patients were taken off
12 cyclosporine now at two years whether, in fact,
13 their GFRs would improve to the same extent and
14 that they would have GFRs equivalent to those
15 patients maintained on cyclosporine because the
16 effect on GFR of cyclosporine is, of course,
18 There is the hemodynamic effect of
19 cyclosporine which affects the flow of blood into
20 the glomerulus, the afferent arteriolic
21 constriction, so the pressure in the glomerulus is
22 reduced. I am going to show a slide at end of a
23 blood-pressure study which is interesting at this
25 So cyclosporine has an effect on the
1 glomerulus by affecting flow in, and cyclosporine
2 also has an effect because of its tissue toxicities
3 which the experts on this committee are on as well.
4 So what we don't know in the study is whether the
5 continued reduction in GFR compared to the
6 sirolimus group is, in fact, occasioned by injury
7 to the kidney or whether it is occasioned just by
8 perpetuation of the hemodynamic effect of
10 You might even argue, and I have actually
11 wondered about this for the TOR inhibitors,
12 whether, because they affect intimal hyperplasia,
13 perhaps reduce that, and whether they, in fact,
14 might be protective against some of the fibrosis we
15 see so that a combination of a TOR inhibitor and a
16 calcineurin inhibitor might actually mitigate some
17 of the long-term toxicities even though, when you
18 just look at the GFR and the creatinines, that may
19 not, at first blush, be apparent.
20 So I think we just don't know that data
21 and, for that reason, I am anxious about us moving
22 along too fast. So I think the relationship you
23 have between renal function at a given time and
24 long-term outcomes, we don't know. I have covered
25 my concern that labeling shouldn't be too directly
1 prescriptive, that it should allow us a great deal
2 of freedom in using these drugs.
4 The other issue I think before us is that,
5 because of the way studies are done, the comparator
6 drug here is cyclosporine. That is not the only
7 calcineurin inhibitor. The FDA would rule here on
8 one agent within a class of drugs. I think that,
9 to me, again, is not something I would like to see
10 done because we don't have comparable data using
11 tacrolimus. There are many people, I think, right
12 across this room who, I think, have favored
13 tacrolimus over cyclosporine and who believe that
14 you can, very effectively, use low-dose
15 cyclosporine and TOR inhibitor regimens to achieve
16 excellent outcomes.
17 Of course, these studies, too, don't
18 always include an anti-R2 inhibitor and the
19 rejection rates on those studies are very low and
20 the increase in rejection in this study may be
21 unacceptable in that context.
22 A lot of the discussion here I think is
23 reverberating now about where you can or couldn't
24 discontinue cyclosporine. I would be concerned if
25 every transplant nephrologist and surgeon in this
1 country did not know the data that we have
2 presented here today. I would be dismayed if
3 people were making adjustments to immunosuppression
4 and yet didn't know this data.
5 It has been published. It ought to be
6 known. So I don't think there is any question that
7 this ought to be known by people changing the doses
8 and the way in which we use drugs.
9 But I, for example, am an African. I
10 don't look like an African at first sight but, in
11 one definition, I am an African. I was born in
12 South Africa. When I get my citizenship, I will be
13 an African-American. To some extent, the decision
14 as to whether or not you are African-American or
15 not is your own decision.
16 There is also, in a sense, the prejudicial
17 decision in this country of who is and who isn't an
18 African-American. I am a South African and so I am
19 very sensitive to these issues. At the height of
20 apartheid in South Africa, if you did HLA typing
21 and looked at genetic mix within the white
22 Africaner race, about 40 percent of them showed
23 evidence of African parentage.
24 So when we talk about subgroups and
25 cleanly dividing subgroups of patients up so it is
1 safe in this group, it is not safe in that group, I
2 think we have to be very careful in what we are
4 I wanted, also, just to remind you of the
5 steroid-withdrawal studies where we have had
6 studies that have looked quite good in the short
7 term where the five-year data, perhaps, doesn't
8 look quite as good. So, again, I think we have to
9 be careful.
10 I would also like to just mention again
11 the potential cost. You have to use considerably
12 more Rapamune to get an adequate level when you
13 take cyclosporine away. Of course, you don't have
14 to pay for the cyclosporine anymore.
16 Then, finally, if I could just show you
17 one last slide, just to go back to the GFR, I
18 wanted to show you this slide because I like to
19 think of kidney transplants as, in every patient
20 with a kidney transplant, to some extent, there is
21 some renal, chronic kidney, disease. I think we
22 can presume that most kidney transplants have had
23 some injury.
24 If you look at how we treat patients these
25 days with chronic kidney disease, particularly
1 patients with proteinuria, the recommendation is
2 that we use ACE inhibitors aggressively. We use
3 ACE inhibitors aggressively even though we know
4 that the GFR falls. The GFR falls, not because you
5 are doing anything to the afferent arteriole
6 leading into the glomerulus, but because you are
7 opening up the efferent arteriole.
8 But the net effect is a reduction in
9 glomerular pressure. Now, the other effects of ACE
10 inhibitors, I am not going to get into that in too
11 great detail here, but in all the metaanalyses of
12 the protection of kidneys in patients with chronic
13 kidney disease, the dihydropyridine, the nifedipine
14 family, has been shown to be less good in
15 protecting kidneys than ACE inhibitors. The
16 reduction in proteinuria and the maintenance of GFR
17 has been less good.
18 The title of this paper was Sustained
19 Increase in Glomerular Filtration Rate in Kidney
20 Transplant Patients with Hypertension Treated with
21 Nifedipine. You can see here--unfortunately, the
22 baseline was post treatment so they don't actually
23 have a baseline before they were put on nifedipine.
24 But nifedipine is a calcium channel
25 blocker and the argument for why this was good was
1 that it counteracted some of the afferent
2 construction of cyclosporine. These patients were
3 treated with cyclosporine and azathioprine and
5 When placed on nifedipine, the GFR rose
6 over twelve months to 56 compared to 46 where as
7 those on lisinopril, an ACE inhibitor, remained the
8 same. The take-home message that the authors put
9 into this paper that, therefore, we should be
10 treating patients with hypertension who have renal
11 transplants with nifedipine and not with ACE
12 inhibitors because the GFR is better.
13 In fact, in this presentation today, there
14 has been discussion about the lower blood pressures
15 in patients on sirolimus. But patients on
16 sirolimus don't have the afferent construction that
17 cyclosporine confers on the patients we give it to.
18 When you treat somebody with the
19 dihydropyridine for blood pressure, you lower the
20 blood pressure, but you also open up the afferent
21 arteriole. So, if you don't drop the mean arterial
22 pressures sufficiently, the actual pressure
23 reflected on the glomerulus may actually be higher
24 than it was when the afferent arteriole was
25 constructed and the mean arterial pressure was
2 So we don't know if you have got a
3 slightly lower blood pressure, not at the target
4 level we would recommend now for patients with
5 kidney disease, a slightly lower systemic blood
6 pressure, mean arterial blood pressure, but a
7 wide-open afferent arteriole, whether, long-term,
8 that will be good or bad for the kidneys.
9 That is true for this study, to some
10 extent, and it is true for the sirolimus studies as
11 well. Over the short term, it certainly looks
12 good. The GFRs are higher.
13 There is also a paper recently published
14 in the Journal of Urology I wanted to bring to
15 committee's attention, and that was a paper that
16 looked at the long-term GFRs in transplant donors.
17 It was a patient that had actually twenty years,
18 so, of course, much longer than this. But the GFRs
19 in those patients were actually, for the men, I
20 think roughly 73. Corrected for age, they ran at
21 about 68 to 67.
22 So the GFRs we are achieving with
23 sirolimus and with azathioprine and with placebo
24 were actually almost as good as you can get with a
25 single kidney. You have a mild reduction in the
1 GFR with cyclosporine, that's true. But, provided
2 the calcineurin inhibitors are not actually
3 injuring the kidney over long-term, and we don't
4 know that yet. I am not pretending we know that.
5 But, with low doses, it may be that we could
6 successfully use both combination of calcineurin
7 inhibitors and the TOR inhibitors and actually
8 achieve long-term GFRs which are very good,
9 long-term creatinines that are very good.
10 So, if you could go back one.
12 I just wanted to say we have, in fact,
13 many studies now that are being published and are
14 underway looking at combinations of either
15 sirolimus or certicam with low-dose cyclosporine or
16 tacrolimus in which the outcomes, in terms of
17 rejection, are very good and which the outcomes in
18 renal function appear to be better than when the
19 higher doses of calcineurin inhibitor were used.
20 The doses of calcineurin inhibitor in
21 these studies, which are called low-dose, are
22 actually still quite high-dose in the context of
23 those studies. I think there was a question
24 earlier about that in terms of what we do.
25 I think I would be hesitant at this point
1 with what we know from what is front of us today
2 to, in a sense, change the prescription boundaries
3 of this drug to an extent beyond which I think the
4 current evidence actually allows us to do.
5 Thank you very much.
6 DR. ENGLUND: Thank you.
7 For the committee, are there any questions
8 regarding this presentation?
9 For the sponsor, any comments or
11 DR. NEYLAN: No.
12 DR. ENGLUND: Are there any other speakers
13 that wanted to say anything at this point in
14 time--not from the table. At this point in time,
15 then, I would like to close the Open Public Hearing
16 and I would like to ask Dr. Albrecht to give us the
18 Charge to the Committee
19 DR. ALBRECHT: We would like to ask you to
20 discuss three questions, and specifically to vote
21 on the first one. So, while we are waiting for the
22 slide to go up, let me go ahead and start the first
25 Do the data presented support the
1 effectiveness or efficacy and safety of
2 cyclosporine withdrawal and
3 concentration-controlled sirolimus two to four
4 months after kidney transplantation in patients
5 treated initially with a regimen of sirolimus,
6 cyclosporine and corticosteroids?
7 If I could elaborate a little bit on that
8 question. We heard from Dr. Neylan the results
9 from these studies where the patient survival
10 graft-loss rates were reported as comparable. Then
11 we did see presentations of slides, for example
12 slide E8 in which acute rejection was reported to
13 be statistically significantly different in favor
14 of the Rapamune and cyclosporine, for example slide
15 E13 where treatment failure showed a difference of
16 25.6 versus 37 percent.
17 So we would appreciate it if you could
18 discuss the significance of those kinds of results
19 within these studies. In addition, for example, if
20 we think about slides E15 and E27, as was noted
21 before, some of these analyses represent
22 on-treatment patient subsets, not the
23 intent-to-treat population, so, therefore, do not
24 take into consideration all the patients that were
25 randomized. We would appreciate you addressing
1 that as well.
2 Briefly, as far as during your
3 deliberation of safety, again, which sets are
4 presented and, for example, for slide S33 where we
5 learned that discontinuation was 18 percent versus
6 27 percent and, again, the lower number in favor of
7 the Rapamune plus cyclosporine arm.
8 If we can go to the next slide.
10 If, after you consider these factors, the
11 answer to the first question you believe is yes,
12 should this consideration for this regimen be
13 restricted to a particular subpopulation or,
14 conversely, is there a particular subpopulation for
15 which cyclosporine withdrawal should not be
17 I think this has already been touched on
18 during the earlier discussions so, specifically,
19 the factor that between 18 to 20 percent of the
20 patients in these studies, in fact, did not go on
21 to randomization and how they reflect the patients
22 that could not participate.
23 We have already heard that 94 percent of
24 the patients, for example, in study 310 were white
25 and a relative underrepresentation of other
2 Then, to continue, if the answer is no,
3 what additional studies would be needed to support
4 approval of such a maintenance regimen.
6 On the question that I just finished
7 speaking about, we would actually like a formal
8 vote. On the following two, we are looking
9 basically for your suggestions, namely, what
10 additional phase IV studies would you recommend. I
11 say phase IV because the drug Rapamune, of course,
12 is already approved and, therefore, we have asked
13 for some phase IV studies but others may be
14 appropriate based on today's meeting.
16 Finally, the last slide, and this is an
17 area that is of great interest to us and we would
18 like to ask if you have any comments or
19 recommendations regarding study design and/or
20 endpoints for controlled clinical trials that are
21 intended to support the safety and efficacy of
22 maintenance immunosuppressive regimes in renal
24 DR. ENGLUND: Thank you.
25 Subcommittee Discussion and Vote
1 DR. ENGLUND: This is the discussion
2 phase. I would like to give everyone around the
3 table a chance to--why don't we go around the
4 table. It will be easier. Dr. Mannon?
5 DR. MANNON: Do you want me to address
6 each of these questions in turn?
7 DR. ENGLUND: No, no. I think we should
8 just address question 1. I think we should address
9 question 1, just the first part here because then
10 we are going to have to go further on.
12 DR. JOHNSON: May I ask a question. I
13 thought, after lunch, we were going to have an
14 opportunity to ask the sponsor some additional
15 questions before discussion. Is that not true?
16 DR. ENGLUND: There is, but my intention,
17 although we can talk about that, was as it relates
18 to each of these three questions. The sponsor is
19 here and they are available to answer our
20 questions. So this is not voting. This is
22 DR. MANNON: Let me pass to Dr. Hunsicker
23 first and then come back to me.
24 DR. ENGLUND: We don't have to do it
25 around the table. If we have people that want to
1 respond to somebody else on the committee, then we
2 can do that, too.
3 DR. HUNSICKER: It will surprise nobody
4 that I have some thoughts on these issues and I
5 have something that I have sort of organized to
7 You would like us to address these
8 questions one at a time, but they are interleaved
9 and if you don't mind, madame chairman, I would
10 like to have permission to interleave them to some
12 DR. ENGLUND: To some extent is fine.
13 DR. HUNSICKER: Okay. I want to start out
14 with that we are in a new category here. I have
15 already said this. The usual thing that we have
16 looked at is to show that an agent, a drug, is more
17 effective than either a placebo or a comparator and
18 that it is relatively safe. The emphasis has been
19 on the type I kind of analysis, can we be sure that
20 this is better than what the alternative is. And
21 the safety stuff has, to some extent, been
23 What we have today is the first of what I
24 suspect is going to be a series of studies that
25 really turn this paradigm upside-down entirely.
1 The efficacy issue is one of equivalence. The
2 sponsor is not trying to convince us that the new
3 regimen is superior to the old regimen in terms of
4 the traditional hard outcomes but, rather, they are
5 arguing that it is as good as that and that the
6 side effects which will come down under the area of
7 toxicities, if you will, are better.
8 I think it is important for to move down
9 this line, but I think we have to do some things
10 that are different from what was done today in
11 order to go down this line.
12 Let me turn first to the issue of
13 equivalence. The nature of an equivalence trial is
14 basically that it is looking for type II error
15 rather than type I error. You are trying to show
16 that there is no real likelihood that there is a
17 difference greater than a certain amount that would
18 have happened with your new drug compared to the
19 others or, perhaps, that it is superior.
20 To do that, what you really need to look
21 at is confidence intervals. P-values are utterly
22 meaningless in dealing with a type I error. No
23 significant difference doesn't mean that there
24 isn't a difference. It just means that you can't
25 determine that there is a difference. You all know
2 So what I would like to urge the sponsor
3 today, if he does more along this line, or other
4 sponsors in the future, is to phrase their analysis
5 of equivalence in terms of confidence intervals and
6 we ought to have, in advance, a statement of how
7 much of a difference makes a difference.
8 So, for instance, if we say that
9 equivalence is that the treatment is no more than
10 10 percent worse than whatever, we can come to
11 agreement that if, in fact, the confidence interval
12 doesn't include 10 percent that they have shown
13 equivalence. But we need to have agreement before
14 we start that that 10 percent is an appropriate
16 My own personal opinion is that 10 percent
17 would be a reasonable number for acute rejection
18 but it would not be a reasonable number any longer
19 for graft survival. A 10 percent difference in
20 graft survival between two regimens is clearly
21 clinically meaningful.
22 So I found myself--what I, in fact, had to
23 do, I went back when I got the briefing document
24 and went through and calculated confidence
25 intervals for all of these things. In fact, the
1 sponsor does relatively well for some of them but
2 clearly not well for others.
3 The fact of the matter is that numerically
4 the new regimen did better than the comparator
5 regimen, the Rapamune plus cyclosporine regimen,
6 with respect to graft survival and, because of
7 that, the confidence intervals, in fact, are
8 reasonable and don't suggest that there is a high
9 likelihood that the new regimen is going to be
10 worse within the period of time that we are looking
11 at with respect to graft survival.
12 But it would have been a whole lot easier
13 had these things been all explained in advance and
14 clearly so we knew what we were accepting as
15 equivalence. Now, with respect to rejection, it is
16 clear that the new regimen is not as good as the
17 old regimen. I have to say here that rejection, in
18 my community--I don't know what FDA thinks about
19 it--rejection has had sort of a dual life because
20 it is a clinically meaningful outcome on its own.
21 And I don't want ever to forget that.
22 So the fact that the new regimen is
23 clearly less good than the old regimen with respect
24 to rejection episodes can't be washed away, but it
25 also has been used in our community as a predictor
1 of what is coming downstream and I have to talk
2 about that separately.
3 When I say that the rejection episode was
4 clearly higher, if you look at pivotal study 310, I
5 think is the number--if you look at the number of
6 rejection episodes following randomization, it is
7 clearly higher in the patients that were assigned
8 to the withdrawal of cyclosporine.
9 Is that disastrous? No; I don't know that
10 that is disastrous, but it can't be ignored and we
11 have to have that clearly stated up front.
12 Then, when we turn to the issue of the
13 toxicity things, traditionally, it has been done
14 that toxicity is based on treated patients or
15 something like that. But today, now, we are really
16 basing our long-term judgment on the acceptability
17 of this regimen, on what it promises to us in terms
18 of toxicity. For that, it seems to me, we have to
19 insist on intent-to-treat analyses, across the
21 We have to understand what is--if we are
22 going to say that this is a better way to go
23 because of less toxicity, we have to understand
24 that that is true for the entire randomized
1 I also think we have to distinguish
2 between what I would call clinically apparent and
3 numerically apparent toxicities. What I mean by
4 clinically apparent toxicity is that an infectious
5 episode, a pneumonia, or whatever, is clinically
6 apparent but changes in blood pressures and changes
7 in creatinines are not important today. They are
8 important for what they may mean for the future and
9 there is a smaller degree of certainty as to what
10 their significance is for the future and we have to
11 look at these in terms of what they mean for the
13 So I would like to see all of these
14 analyses within intent-to-treat analyses and I
15 would like to see a distinction between the
16 clinically evident things today and the long-term
17 outcome. This is because what I see as the issue
18 before us today, the tradeoff of an increased
19 frequency of rejection when you withdraw
20 cyclosporine, which is as clinically meaningful
21 outcome, increased today, for which you receive as
22 compensation better serum creatinine and the hope
23 of long-term better outcome with respect to graft
25 Turning to that, I have already spoken
1 informally to the sponsor and said that I think
2 that there is a more appropriate analysis than the
3 analysis that we have of the renal function and
4 progression over time.
5 First of all, to look at the patients at
6 risk at each time point and take the average over
7 time is statistically not an appropriate way to
8 look at what is happening over time. There is a
9 different group of patients at risk in each pool
10 and you really can't compare the values from time
11 to time.
12 The issue here is critical. Is there, in
13 fact, a difference of creatinine over time, an
14 analysis which I would like to suggest is a
15 reasonable one. There may be other ways of doing
16 this, to do a GEE analysis on the delta from
17 baseline, the baseline being the time just
18 immediate before randomization.
19 So what you are looking for is whether
20 there is a stepped decrease in the first period of
21 time and what is the trend of the creatinine after
22 that time, or clearance or whatever other measure
23 that you are having.
24 Most of my colleagues here, both in the
25 audience and around this table, know that I have
1 done an analysis of what I call intercepts and
2 slopes on creatinine clearance following renal
3 transplantation. The results of this analysis
4 which involved some 48,000 patients from the UNOS
5 database are, in essence, that you can, on average,
6 treat the progression of renal disease over time as
7 linear loss of renal function, of GFR or creatinine
8 clearance over time, just as you can with native
10 If this is the case, if my analysis is
11 correct, which I believe it is and it represents
12 the reality--and I would like to just call Alan
13 Wilkinson's caveat into consideration here; this
14 analysis was done virtually entirely on patients
15 who were receiving calcineurin inhibitors. So
16 there is some question of whether it would be
17 extrapolatable across.
18 If there is a difference in serum
19 creatinine today and if there is no difference in
20 slope--that is to say, if there is a step
21 decrease--that step decrease will translate into
22 longer graft life. The term that I have there is
23 that about 2.5 milliliters of GFR is equivalent, on
24 average, all other things being equal, to one year
25 of graft life.
1 So if you have an improvement, a step
2 improvement, of somewhere between 5 and 10
3 millimeters per minute better GFR estimate at one
4 year or six months or whatever the time is, the
5 anticipation is that that would lead to a two to
6 four year improvement in graft life for the
7 patients that were on the Rapamune-only regimen.
8 But this is conditional that the trends of
9 serum creatinine or creatinine clearance following
10 that time don't converge. That we don't really
11 know. We have no idea what is happening to the
12 difference over time. So we have a promissory note
13 in exchange for a payment of an increased rejection
14 rate which is a clinically important event and we
15 need to know how solid that promissory note is
16 before we can know whether this is a reasonable
17 bargain or not.
18 I am going to go off that to the second
19 series of questions that I have about this
20 application. Section 2 in my little list of notes
21 here has to do with approval and indication. I
22 constantly annoy my friends at the FDA by pointing
23 out that most of the transplant community pays no
24 attention to what goes into an indication anyway.
25 We never read the damned things and we do whatever
1 we please.
2 So the question comes up, then, what is
3 the impact of approval and what is the impact of
4 the indication. I, for one, believe that it is
5 essential that our community continue to explore
6 the issue of calcineurin-free regimens. I think
7 that there is, from these data and other data that
8 I am aware of with respect to sirolimus, the
9 suggestion that, in fact, there may be major
10 long-term improvements--may be. But it is a long
11 way from saying that we have to continue these
12 things, to say that we should say that they have
13 now met the standard of use everywhere.
14 So the question comes up how right are we
15 for calcineurin withdrawal and who should be doing
16 it. I am lucky because I don't get to vote today,
17 you know. I just get to express my opinion and
18 raise the questions and let the rest of the
19 committee decide to vote.
20 I think we have to explore this but I am
21 not sure that I want this explored primarily in the
22 least-expert groups of patients. If I ask myself
23 where the approval of the FDA and where the
24 indication would have the greatest effect, it is
25 likely to have the greatest effect amongst the
1 people who are not as thoroughly involved in all of
2 these issues themselves; i.e., in the less expert
4 That troubles me because I would like to
5 see these issues addressed first in the most expert
6 group of people. I have a feeling that what I am
7 telling you I think it is still investigational. I
8 am not sure we know the long-term impact.
9 This is complicated by the fact that we
10 have a major limitation in the population about
11 which we could say anything. We have already
12 discussed the fact that there are no
13 African-Americans. There are no Hispanics. Some
14 of the groups in whom our problems are greatest are
15 not represented with sufficient numbers, in my
16 opinion, for us to be able to say anything.
17 I want to make sure that that does not say
18 that there is not a benefit. I just don't think
19 that it is at all established that there is a
20 benefit or a harm. I think we do not know what
21 would happen in African-Americans. I don't think
22 we would know what would happen in Hispanics.
23 I also don't think we really know what
24 would happen in people with initial ATN because,
25 largely, those people are delayed graft function.
1 Those people were not randomized and so we have
2 really no idea what would happen in this group.
3 In fact, the group that wound up getting
4 randomized is still very fuzzy in my mind. One of
5 the charges I would put to the FDA is it has got to
6 be very clear what were the patients in whom this
7 experiment was really done because, clearly, we
8 don't know anything beyond the patients in whom the
9 experiment was done.
10 Now, if an indication can be drafted that
11 says that this should be done only in patients who
12 don't have initial graft dysfunction, have not had
13 a type III rejection within the first six months,
14 whose creatinine is less than thus and such, and so
15 forth, and who, by the way, are neither
16 African-American nor Hispanic because we can't say
17 anything about that.
18 If you can come up with an indication,
19 that would be fine but I think it is going to be so
20 complicated that I am not quite sure where you are
21 going to wind up.
22 So my issues here are first methodologic.
23 I want to have the way we present these kinds of
24 studies changed so that we know exactly what at
25 cost is, the potential cost, when we are talking
1 about equivalence and then exactly what the benefit
2 is that we would see on the other end from the
3 reduction in toxicity.
4 In this case, this means, what can we
5 extrapolate to in terms of long-term graft
6 survival. I have problems with whether this has
7 reached a state of ripeness that I really want to
8 have the least expert people in our community begin
9 doing it which is what I think is implied by
10 approval and by the indication and I really have
11 some reservations about what the population is in
12 whom we could say that this has now been
13 established as safe and effective.
14 DR. ENGLUND: Did you have any specific
15 questions for the sponsor?
16 DR. HUNSICKER: No. I was giving a
17 philosophic tirade and I am sorry for that, but I
18 am asked what my opinions are about these things
19 and you now know my opinions. I feel good about
20 this because I have to leave at 3:30 because I have
21 got to make a plane to get home.
22 I know that the sponsor--I have spoken
23 with them about some of these things in
24 between--has some slides that they would like
25 eventually to show that relates to the question of
1 whether there is a trend in creatinine or clearance
2 or something over time that can be established. If
3 you want them to show that, that would be fine with
5 I am happy to tell my folks at the FDA
6 that they have got to establish that there is as
7 reasonable likelihood that a short-term delta
8 creatinine is going to translate into a long-term
9 graft survival before I am going to feel that that
10 is a benefit that will balance the increased rate
11 of rejection early.
12 DR. ENGLUND: Let's go on and see. I
13 heard you say you didn't have any questions, so
14 let's go on. If someone has a question, or I might
15 have a question--
16 MR. LAWRENCE: First I would like to thank
17 the FDA for inviting me to participate in this. It
18 is always reassuring to the patient community to
19 know that at least somebody was there with their
20 best interests up front. Even though the
21 physicians and the pharmaceuticals are laboring on
22 our behalf all the time, we still like to be there,
23 so thank you for that.
24 I agree with everybody here. Everyone has
25 said things that are intelligent and compelling
1 but, coming at this from a lawyer's viewpoint, the
2 question that hasn't been precisely answered for me
3 is what, exactly, are we supposed to be doing here.
4 What words are we supposed to be changing?
5 In the stuff that you sent out several
6 weeks ago that we all go to review before this, it
7 says that the application is proposing to modify
8 the indication that says that Rapamune shall be
9 used in concert with cyclosporine. This says that
10 the applicant is proposing to modify that to allow
11 consideration of cyclosporine withdrawal.
12 Then I see the slides that were presented
13 by Wyeth and it says cyclosporine withdrawal should
14 be considered. This is much more directive. I
15 think that there are probably a large number of
16 patients who would benefit by having cyclosporine
17 withdrawn. I take cyclosporine, myself. I am not
18 unaware of the renal implications of taking this
20 I also gather from comments that have been
21 made by all of the knowledgeable people here that
22 there are probably some patients in whom it should
23 not be withdrawn or the jury is certainly still
24 out. I am not here representing UNOS, who is my
25 employer, but on the UNOS website, anybody can pick
1 up these data that I am about to give you.
2 The current waiting list which is
3 tragically approaching 90,000 or something--it is a
4 lot of people waiting for organs in this country.
5 Caucasians represent 42.3 percent of the current
6 renal waiting list. This is renal waiting list.
7 Hispanics, 14.5, Asians, 5.6 and blacks, 35.1 So
8 the data that we have seen today actually applies
9 most directly to 42.3 percent of the waiting list.
10 That is simply an insufficient
11 representation to support language which is direct,
12 saying that cyclosporine withdrawal should be
13 considered. I think that the use of the word
14 "should" would be of much more interest to my
15 fellow lawyers than it would be to physicians, most
16 of whom--I spoke to a number of them before coming
17 here and they said, "We don't care what they say
18 because we are going to do what we feel is right
19 for our patient anyway."
20 That may be, in reality, how medicine is
21 practiced, but I don't think that a case has been
22 made to be as directive as it should be. I would
23 like to see something along the lines of
24 cyclosporine withdrawal "may" be considered
25 because, obviously, it would be in the interest of
1 many patients that cyclosporine, in fact, be
2 withdrawn. I think that is conclusively true for
3 many patients, but it is also conclusively true to
4 me that that does not apply to all patients.
5 Therefore, saying that cyclosporine
6 withdrawal should be considered is too strong a
7 statement. I would just suggest that I would agree
8 with Wyeth that withdrawing cyclosporine, where
9 that can be done without any deleterious effect,
10 should be done, in fact, and probably that is a
11 majority of patients although what that means, I
12 don't know.
13 So I would suggest simply reconsidering
14 the terminology we are using here. Thank you.
15 DR. ENGLUND: Thank you.
16 DR. MANNON: I let Dr. Hunsicker go first
17 because I knew he would--not that I knew that he
18 had his plane but because I knew that he would have
19 a lot of things to say.
20 Just a couple of things that may be in
21 agreement with him and may not be totally in
22 agreement with him, and the comments that I heard
23 earlier today is that the question always comes as
24 to who is doing this. Yes; I think that transplant
25 nephrologists and surgeons do have ways of using
1 drugs in different fashions that may not be on the
2 label, necessarily.
3 How it is being done is also important.
4 The issue is that, if the label goes in a certain
5 way, it means that anybody who has that kind of
6 certification can and it may not be in a large
7 academic center. It may be in a smaller transplant
8 center. I think that is one of the concerns is
9 that if this labeling goes as black and white, will
10 everybody be doing it that way or is that on the
11 entree for people to go ahead and do.
12 Clearly, there are caveats to doing that
13 therapy. I do have questions about the
14 applicability. Again, I think the race issue is
15 one that was again reiterated by a number of people
16 around this table. The issues of children are
17 obviously not addressed in this and that is a small
18 population. But, again, that should be addressed.
19 I also wanted to point out that in these
20 studies, this was a very large population of
21 cadaverics. In fact, living transplants were a
22 minority of about 60 patients that were in the 212
23 study. Again, should the indications--I know in my
24 practice, when we see living transplants, we tend
25 to ease off on immunosuppression based on their
1 long-term outcomes.
2 I think the issues, again, that were
3 brought up regarding delayed graft function and
4 ATN, we don't know enough, I guess, based on the
5 randomization about how to manage them. Along
6 those lines is should there be indications
7 regarding ischemic time. Can we tease apart the
8 patients that had those rejection episodes based on
9 maybe they had more prolonged hold time.
10 PRA or highly sensitized patients, how are
11 they in this population and how are they thrown in
12 and is there a way of going back and looking at the
13 data collected by the sponsor to say that maybe
14 that would be an indicator of someone that you
15 would not really choose.
16 I think if I went around this room and
17 said, "You have a PRA of 90 percent," the majority
18 of us would probably not choose to put that person
19 as a withdrawal patient, per se, but maybe there is
20 data available.
21 My last, I guess, sort of point is about
22 the monitoring. I have a lot of practical clinical
23 experience about monitoring in this drug. Although
24 there are eighteen centers available, I want to
25 point out that, for most of us, we Fed-Ex our
1 samples or UPS our samples, so there is a 24-hour
2 delay to get the sample to be monitored and another
3 24 hours, about a one-day turnaround time. So you
4 are talking about a total of 48 hours which,
5 although the drug has a fairly long half-life, it
6 is sometimes difficult to monitor.
7 I think the availability of the more
8 rapid, less labor-intensive, test would be--there
9 are two issues. One is should we be monitoring
10 these patients. I know that was brought up. The
11 other issue is if we are going to monitor them,
12 what is the best way to do that.
13 I think if you are going to have a mass, a
14 large number of centers doing numbers of these
15 tests, it will become a very important issue as far
16 as the turnaround time and documenting--I think it
17 would be helpful--I know that they talked about
18 doing an algorithm on the labeling. It would be
19 important for us to look at that algorithm,
20 perhaps, and sort of decide if that would be of any
21 help in the long-term monitoring of the patients.
22 DR. ENGLUND: We are going to go around
23 the room, but I think in terms of the monitoring
24 issue, perhaps could we spend a minute or two? Are
25 there any other comments about the monitoring as we
1 go around? It really is implied in the part of the
2 question that it would be part of the approval to
3 do it, as has been done in the study.
4 Dr. Shapiro?
5 DR. SHAPIRO: I would just have a comment
6 about monitoring. I guess two-and-a-half years
7 ago, the position was that this drug did not
8 require monitoring. We learned, at least in my
9 case, the hard way that that was not correct. Even
10 now in the context of this particular protocol, we
11 found that we have not been able to use sirolimus
12 safely without close monitoring.
13 I think that is probably a consensus among
14 most people who are involved in transplantation.
15 DR. AUCHINCLOSS: I was going to say the
16 same thing. I can't imagine trying to use this
17 drug in any protocol at this point without
19 DR. MANNON: It is difficult. We can't
20 even agree about what the--I know one question was
21 can you predict the level based on the patient or
22 the race or the age or the weight. I can tell you,
23 in my limited experience, it has been difficult to
24 tell when you use a loading dose of 15 and then go
25 on 5. We have been trying to look at peak--post
1 load doses to see if we can predict.
2 So I agree. I think you need--monitoring,
3 for me, has been essential.
4 DR. HUNSICKER: Very briefly, a comment
5 about monitoring. I agree with the people who have
6 spoken who say that, in fact, we do monitor the use
7 of this drug. The question I would have is whether
8 the specific recommendations as to monitoring are
9 based on anything other than grabbing some numbers
10 out of the air.
11 I would not, at all, mind if this is an
12 indicated drug, having an indication saying that
13 there is a high variability of bioavailabilty and
14 that it might be wise to check the levels. But to
15 tie yourself to a specific monitoring program, as
16 was described to us, on the amount of information
17 we have to say that that makes sense would be
18 difficult for me.
19 DR. ENGLUND: Dr. Abernethy?
20 DR. ABERNETHY: I would support that
21 assertion, to simply say that, in my clinical
22 experience, monitoring is essential. One can say
23 that about many drugs. However, then, at a later
24 point in time, one looks at the data, it sometimes
25 turns out that the data support that that was a
1 correct statement and other times it turns out that
2 that just was a clinical impression that doesn't
3 stand up to scrutiny.
4 I think, at this point, I don't know. I
5 haven't seen data either in the material we were
6 provided or this morning that told me that we know
7 that there is a therapeutic index such that,
8 particularly at the high end of the concentration
9 range, that we know where we should put a cutoff on
11 If that is correct, clinically as well as
12 with the data, then the correct response, I
13 believe, is that one simply increases the dose when
14 there is a question about whether things are
15 happening the way they should. If that is
16 incorrect, then I think we need more data in order
17 to assert that it is incorrect.
18 DR. SHAPIRO: There was the figure that
19 the sponsor had shown showing that there were lower
20 rejection rates with higher sirolimus levels and
21 this interacted with the amount of cyclosporine
22 patients were receiving also. So it is not
23 completely pulled out of the air.
24 DR. ABERNETHY: That is very complicated
25 because when you have those two drugs together,
1 they are interacting both pharmacokinetically with
2 each other as well as pharmacodynamically. So that
3 was an interesting chart without confidence
4 intervals and without data points. I will have to
5 say, I would have to really look at that data a
6 long time before I could come to any conclusion
7 about what it was trying to tell me.
8 I am not saying it is incorrect. I am
9 just saying I can't look at a slide like that and
10 say, "Oh; right."
11 DR. ENGLUND: Dr. Ebert?
12 DR. EBERT: Just maybe a short addendum to
13 that. Again, most of the association that we are
14 seeing here is largely, at least in my opinion,
15 kind of a post-hoc analysis where patients were at
16 least initially dosed on the drug, subsequently or
17 retrospectively, were found to have certain
18 outcomes associated with certain serum
20 I think that differs from what might be
21 considered to be a concentration-controlled
22 prospective study where patients are randomized or
23 targeted different target concentrations and then
24 looking at outcomes. I am not sure that the two
25 are equivalent as far as the conclusions that we
1 can draw.
2 DR. ENGLUND: Back to general comments
3 about question No. 1?
4 DR. AUCHINCLOSS: The question is do the
5 data support the safety and efficacy of
6 cyclosporine withdrawal. I think, in a general
7 sense, the answer to that question is yes. But the
8 problem is, well, yes, it is apparent that that
9 would be true for some patients, that there would
10 be some associated risk and that there would be
11 some associated benefit.
12 The problem is that both from limitations
13 of numbers and from study design, it is very hard
14 for us to answer precisely any of those aspects of
15 where this efficacy applies. I think it is clear
16 that we are talking about a group of patients that,
17 in general, are doing well and I would second the
18 comments of others that there are distinct
19 populations including African-Americans about whom
20 I would have tremendous concern.
21 What is the risk? I have no doubt that
22 there is, indeed, a risk of acute-rejection
23 episodes precipitated by cyclosporine withdrawal.
24 It looks to me like it is about 10 percent. I am
25 sure there are other side effects of high-dose
1 sirolimus. We saw dose-response curves for
2 cholesterol, et cetera. So there is some
3 additional risk by going to this protocol.
4 What are the benefits? Clearly, you are
5 going to get rid of some side effects of
6 cyclosporine. I have no doubt that there will be
7 an improvement in renal function and I believe
8 those data. What I don't know is what the
9 long-term consequences of that are.
10 So what does all that mean to me as a
11 clinician? From the data that I have seen today, I
12 think I would consider cyclosporine withdrawal in a
13 group of patients who are on sirolimus who are
14 generally doing well but who are tolerating
15 cyclosporine in some fashion very poorly and who
16 demonstrated the capacity to tolerate Rapamune
17 without side effects, or without major side
19 I am not sure exactly how you turn that
20 into a label. I am sure that the labeling words
21 "should--" the word "should" should not be the one
22 that is used. Frankly, I really think overall, at
23 this point, that the data that we have are
24 insufficient and premature to define the answers to
25 these kinds of questions that make a labeling
1 change appropriate at this point.
2 DR. ABERNETHY: I really don't have much
3 to add. I think that we, saying it slightly
4 differently, are handicapped by trial design and
5 that we are looking at a very selected group. I am
6 struggling with how to generalize that effectively
7 or if it, perhaps, should be generalized.
8 DR. ENGLUND: Dr. DeGruttola?
9 DR. DeGRUTTOLA: I have a number of
10 comments. I think what Dr. Hunsicker and Dr.
11 Auchincloss were referring to is what statisticians
12 refer to as a surrogate-endpoint problem. We have
13 evidence that there is adverse effect on acute
14 rejection which is not, apparently, a clinical
15 event but indicative of potentially future higher
16 risk of clinical event. And we have apparent
17 benefit on some measures of kidney function
18 although it is not clear whether those would
19 translate into longer-term benefits.
20 In addition, there is a concern about
21 whether creatinine levels measured at a particular
22 time have the same meaning regardless of the
23 treatment that a patient is on. In other words,
24 does a benefit in creatinine levels that results
25 from a treatment have the same impact as naturally
1 having better creatinine level.
2 I think, to answer those questions
3 generally requires longer-term follow up to
4 understand the relationship between treatment, the
5 surrogates of creatinine or measures of acute
6 rejection and the longer-term clinical benefit in
7 the absence of compelling evidence that we can
8 infer longer-term benefit from the shorter-term
9 outcome. That is difficult.
10 I think that the problem of interpretation
11 of results would exist anyway, but it is compounded
12 by the fact that we have been presented with a lot
13 of as-treated analysis and, as Dr. Albrecht
14 pointed out, the analyses that we saw of creatinine
15 and GFR looked at the as-treated population or
16 on-therapy population and such results are harder
17 to interpret.
18 The FDA analysis provided us with
19 intent-to-treat comparisons showing a benefit of
20 the Rapamune alone which was useful. But the FDA
21 analysis just gives us the two-by-two tables. The
22 sponsor's analysis gives us the time trends which
23 are really valuable to know for the reasons that
24 Drs. Hunsicker and Auchincloss pointed out. We
25 would really like to have some sense of whether
1 these are persisting or increasing.
2 It is precisely when you are trying to
3 evaluate time trends in these effects that the
4 difference between an intent-to-treat and an
5 as-treated population would be so important to know
6 because, in an as-treated or on-therapy population,
7 where the populations are changing, it is hard to
8 interpret the time trends.
9 So I think that it would certainly be
10 useful to able to see the intent-to-treat analysis
11 at least to give us a sense of whether the effects
12 are increasing as they appear to be from the
13 on-therapy analysis, the effects of benefit of the
14 Rapamune alone on creatinine.
15 I believe that there may be additional
16 evidence in support of a relationship between
17 markers like creatinine and longer-term outcomes.
18 I would be very interested in seeing such results
19 from the sponsor if we can request that.
20 DR. ENGLUND: Would you like to show them
22 DR. NEYLAN: Yes; I would. Thank you.
23 What I wanted to do was to show you some of the
24 longer-term data and also look at some of the
25 different analyses that address some of the
3 First, just a reminder, this first slide,
4 we have the intent-to-treat analysis of renal
5 function which concurs with the FDA analysis that
6 the patients in 310 had enjoyed an improvement in
7 both the mean serum creatinine and the calculated
8 GFRs which was statistically significant.
9 What I would like to do is call up the
10 slides that look at the slope intercept analyses.
11 This is, I think, an analysis that is probably
12 somewhat near and dear to Dr. Hunsicker.
14 Calling up this first slide, looking at
15 UNOS data, this recent publication from Johnson and
16 colleagues looked at over 100,000 renal-transplant
17 patients within the UNOS database between 1988 and
18 1998. As Dr. Hunsicker has pointed out to us both
19 today and in his prior publications, it is
20 important to consider not only where you are
21 starting from but how quickly you are getting to
22 the next place.
23 So the baseline creatinine as well as the
24 rate of change in that creatinine are important
25 measures when determining the likely success or
1 lack thereof of a kidney transplant. Indeed, in
2 the best-case scenario, looking at this large
3 database, when you start off with a great
4 creatinine and you have a very small change in that
5 creatinine from the six-month to the twelve-month
6 mark, you can expect a half-life of 11.6 years.
7 If, on the other hand, you see a more
8 rapid change, and, by change, I mean increase in
9 serum creatinine, over this time point from six to
10 twelve months, then that half-life is decreased and
11 so on down the way. If you start off at baseline
12 with a poorer functioning graft, you will have a
13 reduced half-life even if your rate of change is
14 relatively minor.
15 The worst-case scenario, of course, is
16 when you start off with a poorly functioning graft
17 and see a rate of change that is greater. There,
18 the half-lifes are, of course, the worst. Taking
19 this kind of approach, we looked at our own data
20 and if we can show the next slide.
22 What we looked at was a kind of similar
23 slope-intercept analysis and looked at, in the case
24 of the 310 patients, the patients who had the serum
25 creatinines that were either excellent or greater
1 than 1.5. We looked at the rate of change between
2 six and twelve months.
3 Is this correctly labeled, this
4 creatinine? Is that at twelve months?
5 DR. BURKE: That is creatinine at twelve
7 DR. NEYLAN: Looking, then, at this
8 baseline and the rate of change of getting there,
9 you can see the following. You see in the Rapamune
10 group that there is a preponderance of the patients
11 who fit this bill--namely, excellent creatinines
12 and a small rate of change. Again, the
13 six-to-twelve-month mark is relevant because, as
14 was alluded to, with the relief of cyclosporine and
15 the relief of that vasoconstriction, one would
16 expect that the short-term change up to six months
17 might one thing but, subsequent to that, rate of
18 change may well be related to other factors.
19 So we see this rate of change being the
20 least in the Rapamune group compared to roughly
21 half as many patients in the control group and so
22 on down the way. Conversely, at the bottom, we see
23 more patients, or twice as many, in the control
24 group that start off with a worse baseline and have
25 a more rapid rate of change.
2 We also did another analysis that is a
3 slope analysis of patients in the next slide
4 who--this is 24 months. Is this data part of the
5 package? Could you turn that slide off for a
7 DR. BURKE: That includes data that is not
8 part of the package. It is creatinines after
9 twelve months.
10 DR. CAVAILLE-COLL: May I ask you a
11 question about the previous slide where you were
12 showing--you were applying Johnson's analysis to
13 your data. Was that submitted to the application
14 and does that analysis include all patients treated
15 or just the information on patients on therapy?
16 DR. NEYLAN: That is an on-therapy
17 analysis, I believe.
18 DR. CAVAILLE-COLL: An on-therapy
19 analysis? Was that analysis submitted to the
21 DR. NEYLAN: No; excuse me. Was that--
22 DR. BURKE: The analysis was not
23 submitted. The data that was used for that
24 analysis is in the application.
25 DR. CAVAILLE-COLL: So it is the
1 on-therapy analysis. It is the on-therapy data
2 that you submitted to the application. It is not
3 an intent-to-treat analysis.
4 DR. BURKE: No.
5 DR. CAVAILLE-COLL: And it is not an
6 analysis that you have submitted to the FDA for
8 DR. BURKE: That's correct.
9 DR. CAVAILLE-COLL: Okay. Thank you.
10 DR. NEYLAN: So, rather than show you the
11 other slope intercept which includes 24 months,
12 what I would like to show it completor's analysis.
13 One of the problems that we have in fulfilling the
14 more rigorous statistical requirements of
15 intent-to-treat is, in this case, the problematic
16 return to calcineurin inhibitors which can occur in
17 patients discontinued from the treatment group
18 which then creates a kind of convergence. That
19 makes it sometimes challenging to discern important
20 clinical differences.
22 One way to get around that is to do a
23 completor's analysis. Here we have, again, an
24 analysis that is taken from the dataset that FDA
25 has received, although this particular analysis
1 that was--rather the dataset is within your hands.
2 The analysis that we did was separate.
3 DR. CAVAILLE-COLL: Do we have the dataset
4 up to 24 months?
5 DR. NEYLAN: Yes; you do.
6 DR. CAVAILLE-COLL: That does not include
7 all the subjects on the study, then?
8 DR. NEYLAN: What this shows, working
9 backward, is a completors' analysis so it includes
10 only those patients who, from the starting point on
11 through, are successfully treated in either group.
12 So it takes away that bias of patients who are
13 dropping out along the way in an on-therapy
15 What we see here with the mean creatinines
16 is, again, data which is representative of the
17 other datasets that we have shown you, namely that
18 serum creatinines in the control group stabilize or
19 slightly increase over this time period whereas the
20 slope of the treatment arm is stable or, in fact,
21 slightly downward.
22 I would certainly be open to any inquiries
23 about that.
24 DR. ENGLUND: Dr. DeGruttola?
25 DR. DeGRUTTOLA: I just wanted to comment
1 on a couple of points. I think that the
2 intent-to-treat analysis is valuable even if
3 patients do end up crossing over to another
4 treatment because that is the information that you
5 really want, what is the outcome when you intend to
6 treat a patient in a particular way but the reality
7 is you may not necessarily be able to treat them in
8 the way that you want to, and finding out whether
9 there is, in fact, a benefit, in terms of
10 creatinine, over time for patients who are intended
11 to be treated with Rapa is exactly what you want to
13 If you do something like a completors'
14 analysis, you are getting sort of a filtration
15 effect in the populations. You are taking out the
16 people that are having difficulty, so you may see
17 an effect that is increasing but that may be purely
18 artifact of who is left in that population.
19 While I think that there are questions of
20 interpretation when you do the intent-to-treat
21 because patients are switching therapy, you can do
22 analyses that will tend to indicate whether the
23 fact that the curves are coming together results
24 from the changes in therapy for the population who
25 must change therapy or loss of an effect in the
1 patients who remain on therapy.
2 You can do additional analyses to help
3 with the interpretation, but the most directly
4 interpretable analysis will be the intent-to-treat.
5 The fact that patients have to change therapy is a
6 result. It is an important outcome of the study
7 and I don't think that you can solve the problem by
8 doing the completors' analysis.
9 DR. NEYLAN: I apologize if I meant to
10 suggest that we were solving the problem. But, in
11 addition to the intent-to-treat analysis which
12 shows the benefit, I was just hoping to provide
13 some additional analyses which, while not perfect,
14 can help to address some of the issues of patient
15 dropout and, again, the challenges of comparing
16 these groups of patients when the alternative to
17 not staying within the study is most typically a
18 return to the calcineurin inhibitor.
19 DR. DeGRUTTOLA: I think the problem is
20 that we have the intent-to-treat analysis for the
21 two-by-two table but we don't have the
22 intent-to-treat analysis over time, which means
23 that we can't get a valid estimate of the time
24 trend. I think that is concern.
25 If you want to do completor analysis as an
1 additional analysis in order to help with the
2 interpretation, that is okay. But I think that it
3 would be valuable to be able to see the time trend
4 for the intent-to-treat analysis to see what is
5 going on.
6 DR. NEYLAN: I will ask the group. Do we
7 have any time-trend analysis?
8 DR. BURKE: We are unable to provide an
9 intention-to-treat time analysis at this time. We
10 recently gathered the intent-to-treat at twelve
11 months. We will be gathering additional time
12 points but, at this present time, we cannot provide
13 time analysis on intent-to-treat.
14 DR. NEYLAN: We may be able to very
16 DR. ENGLUND: I am going to interrupt as a
17 prerogative here. In the specific slides that I
18 would be interested in as intent-to-treat are E15
19 and E28.
20 DR. NEYLAN: Could we call those up.
21 DR. ENGLUND: You are showing me here
22 improved renal function and these are really nice
23 slides, but it is not intent-to-treat.
24 DR. HUNSICKER: There are two things.
25 First of all, it is not intent-to-treat and the
1 second thing is that the people at risk are
2 different at different times. They have got to do
3 a proper analysis. I think that it would not serve
4 Wyeth-Ayerst. It would not serve the FDA and it
5 wouldn't serve reality for us to try to squeeze out
6 an analysis between now and two hours from now.
7 I thoroughly second your comment about
8 intention to treat and I am not going to say
9 anything further. I think that this is a given.
10 We have solved these problems long since. We don't
11 have to resolve them. This is the standard.
12 I do want, for the purposes of the record,
13 to put in a comment about the timing from which you
14 are measuring slope and why I am so insistent upon
15 that. There is, as has already been said by I
16 guess it was Alan, a strong understanding that the
17 acute effect of administering a calcineurin
18 inhibitor is that you get a vasospasm in the kidney
19 and that results in an acute decrease in renal
21 When you take off the calcineurin
22 inhibitor, if you do it within a short period of
23 time, that returns. So you have an acute effect
24 that is vasomotor. You then have, we think, as a
25 result of calcineurin inhibitors, progressive
1 fibrosis and other long-term changes of the kidneys
2 that are not likely to be reversed when you reverse
3 the cyclosporine.
4 The reason I make this comment is that if
5 you are going to do a slope analysis, you have to
6 make sure that your slope finishes after you have
7 had the completion of your acute effect or the
8 acute effect will be bundled in with your chronic
10 That you showed, for instance, in the
11 two-by-two analysis that the creatinines were still
12 superior at 23 months or whatever the last time
13 period was, doesn't really answer the slope
14 question because that buries into that delta the
15 effect of taking off the cyclosporine acutely. So,
16 what we need to do is to get an estimate of what
17 has happened acutely with the removal of the
18 cyclosporine and then what the trends are
19 long-term, independent of changes in cyclosporine
21 DR. NEYLAN: We have an analysis that is,
22 again, based on the dataset that has been submitted
23 to FDA but the analysis, itself, was not part of
24 the packet and that is a slope analysis at a later
25 time point.
1 Would it be all right to show that? I
2 think it helps to address some of the questions you
3 are relaying about the acute versus chronic
5 DR. CAVAILLE-COLL: Is this the on-therapy
6 analysis or intent-to-treat analysis?
7 DR. NEYLAN: This is an on-therapy, is it
9 DR. CAVAILLE-COLL: Because you submitted
10 two datasets to us. You submitted to us very
11 recently which I think is a closer intent-to-treat.
12 Then there is the original data set with the
13 application which was just on-therapy.
14 DR. NEYLAN: So this is on-therapy. Jim,
15 I might ask you, again, since this is your data, to
16 speak to it.
17 DR. BURKE: I will be showing two slides.
19 They are slopes of creatinine over time.
20 This shows data between six and 24 months, but,
21 indeed, any patient for which we could determine a
22 slope after six months was included in this
23 analysis. So, even if they didn't complete twelve
24 months, if they had a slope between six and twelve
25 months, they are included. So this is sort of
1 between an on-therapy and a total intent-to-treat.
2 Let's look at two things, first of all,
3 the slopes. If one looks at the slopes, one can
4 see that, in both cases, they are significantly
5 different from zero. We see that here. One takes
6 a look at the slopes. One is negative for the
7 group. That still includes cyclosporine which
8 means their renal function is decreasing. In the
9 patients for which had they had cyclosporine
10 limited, the slope is positive showing that their
11 renal function is improving.
12 If one takes at a look at the difference
13 between those two, it is significant. So the two
14 slopes are not converging. The time at which this
15 was done; at six months, the initial effect of
16 eliminating cyclosporine is no longer there, so we
17 are looking at a true evolution after that. But if
18 one wants to be even more conservative, I would to
19 show the next slide.
20 DR. ABERNETHY: If I could interrupt and
21 show my statistical ignorance here, but, doesn't
22 this get us back to this issue of looking at
23 equivalence of these slopes versus looking at
24 differences between these slopes and are these
25 5 percent confidence intervals--I mean, am I headed
1 in the right direction with that thought?
2 DR. DeGRUTTOLA: Is the question the fact
3 that the confidence intervals don't overlap imply a
4 difference in the slopes?
5 DR. ABERNETHY: Apply nonequivalence,
6 which is what is being suggested, I think.
7 DR. DeGRUTTOLA: I think that, on the face
8 of it, it does appear that those slopes are
9 different and the fact that you are rejecting zero
10 implies that there are differences between those
12 DR. HUNSICKER: Not only are the
13 individual slopes different from zero but the
14 difference in the slopes, the slopes, themselves,
15 differ by class.
16 DR. BURKE: That's right. Once again, in
17 one group, those that are on cyclosporine, their
18 renal function is decreasing. Those that
19 cyclosporine has been removed, their renal function
20 is improving.
21 So, one more slide.
23 This is more conservative. We are looking
24 at a slope after twelve months. One can see that
25 the slope analysis for those who remain on
1 cyclosporine is still negative and significantly
2 different from zero. On the other hand, the slope
3 for Rapamune is, one would say, not significantly
4 different from zero. So it is neither--it is flat.
5 Once again, the difference between the two
6 treatments is significant.
7 DR. CAVAILLE-COLL: On those slides, do
8 you have the actual n's of the numbers that are
9 included in each one of those analyses? Which
10 subset of the study is being looked at here?
11 DR. BURKE: I don't have them on the
12 slide. Obviously, in the first set, to be
13 included, they would have to be on-therapy at six
14 months and have at least two points to be able to
15 determine the slope. So, in the first analysis, if
16 one looks at the rate of discontinuation before six
17 months, let's say there were about 190 or 200
18 patients, approximately, in each group. So it is
19 not an intent-to-treat analysis. We do exclude
20 those that discontinued before we could establish
21 the slope. But they didn't have to complete twelve
22 months to be included.
23 DR. NEYLAN: Thank you for the opportunity
24 to present that data.
25 DR. ENGLUND: Are there specifically more
1 questions relating to what has just been discussed
3 DR. HUNSICKER: Could I just say, from my
4 point of view as an amateur statistician, that
5 these are very encouraging data but this is still
6 not the definitive analysis. It needs to be done
7 right and we shouldn't try to rush this.
8 I am willing to trust that, between the
9 company and FDA, that they can look at this and
10 make sure that they have got the best possible
11 analysis. But this is not a trivial issue. This
12 really is at the nub of where I said--we are asking
13 whether we are paying for the increased number of
14 rejection episodes with something substantial. It
15 has got to be convincing.
16 DR. ENGLUND: Dr. Ebert, would you like
18 DR. EBERT: I don't really have a lot to
19 add to what has been discussed. I think, maybe to
20 summarize my own thoughts, it appears that the
21 efficacy really depends on the definition that one
22 uses. If you are talking about acute rejection,
23 obviously, there is a difference. If you are
24 talking about renal function at a later time, at
25 least from the twelve-month data, it appears that
1 there may not be a difference.
2 One is kind of, I think, challenged to
3 decide whether the early rejections are more of a
4 bump in the road or are they considered to be
5 failures. I agree that the analysis needs some
6 improvement. I would like to see the
7 intent-to-treat analysis of renal function over
8 time to be able to try to get an overall
9 determination of the efficacy with this particular
11 With regards to the monitoring, again, I
12 think there is some evidence for concentration
13 versus effect. I don't know that it is strong
14 enough that, as noted earlier, if we should get
15 into the "should" say side of "should" monitor
16 versus perhaps making a statement and saying that
17 the majority of patients who experienced rejection
18 had a concentration below X and that elevated lipid
19 concentrations were associated with a concentration
20 above X and then maybe leave it at that and to try
21 to enable the clinician to use those serum
22 creatinines in patients where it is indicated.
23 DR. ENGLUND: Thank you.
24 DR. SUTHANTHIRAN: I think, over the last
25 decade, we have been basically adding on
1 immunosuppressive drugs. We went from one to two
2 to three to four drugs. So I think
3 philosophically to try to keep transplant patients
4 on a lesser number of immunosuppressives is a very
5 attractive option.
6 I actually had a lot of difficulty with
7 this question about what should be the answer, like
8 many other members here. I think the data clearly
9 shows that the patient survival and the graft
10 survival are very similar. You don't pay a price
11 by holding back cyclosporine. The creatinine and
12 creatinine clearances are better. We don't know
13 what the significance is.
14 Clearly, some of the complications suggest
15 the number of hypertensive drugs you may need.
16 Blood pressure seems to be better with cyclosporine
17 withdrawal. These all I would put on the paucity
18 side of supporting cyclosporine reduction and
20 On the other hand, I do think that the
21 incidence of acute rejection is increased. If you
22 see the data from the point of randomization, then
23 the increase is real, both in the 310 study as well
24 as the 212 study. Almost all of the drugs we have
25 approved in the last four to five years,
1 mycophenolate, Rapamycin, IL2-receptor antibodies,
2 were all approved on the basis of the ability to
3 reduce acute rejection in the six months.
4 In fact, that was the endpoint we all
5 used. Now, we are coming up with a strategy that
6 actually increases the acute rejection. On the
7 other hand, this acute rejection doesn't seem to
8 extol a very heavy price in terms of a one-year
9 graft-survival rate. So I am very concerned about
10 this acute-rejection increase.
11 The other issue is that, in both the
12 studies, about 20 percent of the patients were
13 nonrandomized. In other words, this kind of an
14 approach is probably not applicable to broad-based
15 patients but, perhaps, to more of a lower-risk
16 patient population that are much more a selected
17 patient population.
18 So this is all the data we have. I think
19 it is very difficult for us to make a very strong
20 case, either to vote no or to vote yes. But, as an
21 advisory committee, we have to come up with some
22 calculation and we can't take the Larry Hunsicker
23 route saying, "I have got a flight at 3:30." So we
24 need to make some recommendation.
25 I kind of lean towards a qualified yes. I
1 am not at all comfortable with the way the
2 sponsor's proposed indication of how this should be
3 changed. I share the view that the word "should"
4 be done. I think it is a very important point.
5 The proposed indication, I probably would
6 be more comfortable about would be to remove the
7 word "initially." Here it says, "It is recommended
8 Rapamune be used initially." I don't think we need
9 that word and just leave it as it was originally.
10 Then, the second part of the statement
11 where it says, "Cyclosporine withdrawal should be
12 considered two to four months after
13 transplantation," maybe--I don't know whether this
14 is feasible. One way of defining it may be
15 cyclosporine reduction or withdrawal may be
16 considered in a selected patient population.
17 I think, of all the protocols that were
18 used today and the data we saw, the best protocol
19 was the patients in 212 in group B who were on
20 low-dose cyclosporine and a good dose of rapamycin.
21 They had a very nice, about an 8 to 10 percent,
22 acute-rejection rate before they were randomized
23 and then they went into what was intended in the
25 Mechanistically, there is some good data
1 to support synergy between cyclosporine and
2 rapamycin. I am not sure we need to have an
3 abstinence protocol, complete elimination. We may
4 get the best bang for the buck by having a smaller
5 dose of cyclosporine and have the option rather
6 than have the recommendation that it should be
8 So my suggestion would be to consider this
9 indication statement that would say something like
10 not just withdrawal but, "Cyclosporine reduction or
11 withdrawal may be considered." I think it is very
12 important to point out that this is in a subset of
13 patients, that we simply don't have the data to
14 recommend it universally, given the patient
15 population we have studied.
16 Also, it is very clear in the 18 percent
17 discontinuation in 310 and the 20 percent
18 nonrandomized in 212 that we need to focus it on a
19 very select population of patients. That would be
20 my thoughts at this time.
21 DR. ENGLUND: Dr. Shapiro?
22 DR. SHAPIRO: I don't have a lot to add to
23 what Dr. Suthanthiran said. I guess if I had to
24 answer the question it would be, "Yes, but." I am
25 not convinced that having, as the pivotal trial of
1 a large non-U.S. population makes it remotely
2 applicable to U.S. populations which I think are
3 more heterogeneous.
4 The analysis has done a lot of selecting
5 out, 18 percent in 310, 20 percent in 212, and the
6 selected-out patients did very poorly, as I guess
7 one would have expected. And then we had 37
8 percent failure in the 310, in the group randomized
9 to Rapa. So you are dealing with sufficient
10 winnowing that you get close to a cherry-picking
11 situation with relatively small numbers of patients
12 who, in fact, did quite well.
13 I share all the concerns about
14 intent-to-treat but the reality is that there are
15 some very convincing data about how well the
16 patients who made it through the gauntlet of
17 getting randomized and not having an efficacy
18 failure, they did quite well but they certainly do
19 not represent the mainstream of the patients that I
20 transplant and I don't think they represent a great
21 deal of the mainstream of the patients waiting for
22 kidneys right now.
23 If you are going to say that this is okay
24 to do, you are going to have to word it in a very
25 careful way because, otherwise, you will open the
1 door to having a lot of kidneys ruined by people
2 that are doing this in the wrong way and applying
3 this to the wrong patients.
4 I think there are some very narrow
5 indications for patients who have sailed through
6 their transplant and are doing quite well who may
7 be able to tolerate the increased risk of rejection
8 who will do well without a calcineurin inhibitor.
9 What is less well defined is who those
10 patients are. I am not sure we have enough data to
11 say with confidence who those patients are and who
12 those patients are not.
13 DR. ENGLUND: Dr. Johnson?
14 DR. JOHNSON: I would like to make a
15 comment and, perhaps, Dr. Neylan can respond if he
16 it appropriate, but I am somewhat troubled by the
17 data with respect to the charge that the committee
18 has given us. My difficulty is that, as a
19 practitioner, I would utilize the drug very much
20 similar as the sponsor has suggested in many
22 But, as a committee member, in respect to
23 evaluating the data, particularly in regards to
24 safety, I am having some difficulty. The
25 difficulty, really, revolves around the question of
1 consistency with respect to the fact that the data
2 that is presented is not consistent with the target
4 I don't want to beat the dead horse but
5 the main emphasis of the data is the preservation
6 of renal function with the removal of the
7 calcineurin inhibitor. However, in previous
8 studies that were shown here a few years ago when
9 the drug was first approved, the sponsor showed
10 that the African-American population was not
11 comparative to the Caucasian population with
12 respect to rejection, particularly at the lower
14 We are now presented with data that really
15 shows, or a study that really shows, no data with
16 respect to this subgroup. It is pretty easy to
17 say, "Okay; well, let's just exclude that subgroup
18 in the labeling," but I don't think it is that
19 easy. As was mentioned, demographic data that was
20 given in the presentation stated that 23 percent of
21 kidney recipients in the United States are black.
22 But, in reality, as was noted, 35 percent
23 of the waiting list is black and UNOS is dealing
24 with that disparity by lessening, and maybe even
25 eliminating, HLA matching with regards to kidneys
1 in the future and, therefore, that population will
2 likely expand and, in some areas, may represent 50
3 percent or half of the patients who are going to be
5 We also showed that the benefit in
6 eliminating the calcineurin inhibitor, to some
7 degree, is eliminated in those patients who have a
8 rejection episode. Therefore, if you have half of
9 the group, just hypothesizing, that may be eligible
10 for a protocol such as this, who you know are a
11 higher responder group, who may have a higher
12 incidence of rejection, those folks may, indeed,
13 have very little benefit from this regimen and, in
14 reality, may be harmed by this because we don't
16 Maybe the rejection rates in this group
17 are going to be zero. Maybe 10. Maybe a third.
18 Maybe a half. We just don't know and so it is very
19 troubling for me to sit back and think about how
20 you would label this given the data that we have to
21 evaluate and given the demographics of the United
22 States renal-transplant population and what that
23 population is likely to look like a few years from
25 DR. NEYLAN: I would be happy to respond
1 if you like.
2 DR. ENGLUND: Actually, I doubt that you
4 DR. NEYLAN: I would like to. Thank you.
5 First, we certainly don't want to give the
6 impression that the data from 310 and 212 should be
7 universally applied or rather one-size-fits-all
8 kinds of thinking. In fact, in the proposed
9 labeling document that we have sent to FDA, we have
10 said that the data in black patients in
11 insufficient to make a specific recommendation.
12 The current labeling for Rapamune has
13 looked, as you mention, quite thoroughly at the
14 potential difference that black patients might well
15 require a different dosing strategy and, indeed,
16 the 301 study is supportive of that idea in that,
17 from the efficacy standpoint, the acute rejections
18 were statistical lower for black patients in the
19 5-milligram dosing arm as opposed to the
21 However, we realize that that, in itself,
22 is not enough and we have continued additional
23 studies and we have postmarketing agreements with
24 FDA to continue in these efforts to expand our
25 understanding of how Rapamune is best utilized in
1 black patients.
2 I think one of the overriding concerns for
3 us in presenting this data on top of the previous
4 data is that we want to afford clinicians the
5 opportunity to optimize and individualize treatment
6 strategies. I think Dr. Hunsicker has intimated
7 earlier that we are long past the early days of
8 transplantation where we can look at a kind of
9 one-size-fits-all approach. I dare say, also as
10 Dr. Hunsicker mentioned earlier, that in
11 near-future applications to this committee, many
12 other groups may be proposing strategies which look
13 at the long-term maintenance to start from a sort
14 of nonequivalence standpoint and say, "Okay; that
15 is the bench where we have to stay level but, from
16 there, what can we do to reduce long-term
18 So what we have shown you today is a
19 balance of some tradeoff. We will agree with
20 everything you have said that this isn't meant to
21 fit all patients. But we want to get this out
22 there because we think it represents a potential
23 viable option for some patients.
24 We studied the patients we did because
25 that is who we had at hand. But we know our job
1 isn't finished. We have additional studies to do
2 and we want to take those on.
3 DR. ENGLUND: While I have you up there,
4 my question is what is being planned or actually
5 done in terms of pediatric studies?
6 DR. NEYLAN: I'm glad you asked. We have
7 three pediatric studies ongoing now. Two of them
8 are being done in concert with Napratix and NIH.
9 The first is a large-scale study of some 400
10 patients looking at the use of Rapamune in
11 combination with cyclosporine to determine whether
12 steroid withdrawal is feasible in this group of
13 patients in which corticosteroid complications are
14 especially problematic.
15 We have a second large-scale study also
16 being done in concert with napratix looking at the
17 potential efficacy of Rapamune in combination with
18 either of the calcineurin inhibitors for high-risk
19 pediatric recipients, those being defined as
20 patients who have had at least one prior episode of
21 acute rejection.
22 There, we are looking at not only
23 longer-term graft survival but also examining
24 histology at later dates. Finally, we have a study
25 being done through an NIH grant looking at
1 calcineurin-inhibitor-free regimens in the
2 pediatric population. So we fully recognize our
3 responsibilities in that area as well and we are
4 moving forward.
5 DR. ENGLUND: Do you have any studies
6 ongoing that haven't been mentioned here in terms
7 of African-American and Hispanic populations?
8 DR. NEYLAN: Yes; we do, and we have
9 ongoing discussions with FDA about future trials as
10 well. One of those is, indeed, a postmarketing
11 commitment that stems from the original submission
12 of the 301 and 302 data.
13 DR. ENGLUND: Dr. Hunsicker?
14 DR. HUNSICKER: On a slightly different
15 tack, I noticed, of course, that you had a lot of
16 biopsies at twelve months. Do you have anything to
17 say about what you found in the biopsies in terms
18 of fibrosis?
19 DR. NEYLAN: We, unfortunately, have run
20 into much the same problem that other protocols
21 have in their attempt to incorporation protocol
22 biopsies into the regimens. If we could show this
23 next slide.
25 What we found, in asking all principal
1 investigators to obtain protocol biopsies in all
2 patients enrolled in 310 was that many of them were
3 fairly good at getting the baseline biopsies, those
4 biopsies at the time of transplantation. But,
5 unfortunately, we had a much lesser number, roughly
6 a third of the study population obtaining
7 twelve-month biopsies as dictated by the protocol.
8 So our ability to analyze the paired
9 biopsies in these two treatment groups is severely
10 limited by the small numbers. What we found with
11 those small numbers is that the composite score,
12 the chronic allograft damage index, which is a
13 summation of individual elements 0 through 3 for
14 the six categories and can be ranked, therefore,
15 from a summation score of 0 to 18, was, for both
16 groups, on the order of about 3.5 and not
17 statistically different.
18 We found that there was probably a little
19 bit of sampling bias as well in obtaining these
20 biopsies in the net slide.
22 In that, again, of these very small
23 numbers of patients, the renal function at the time
24 in which these biopsies were obtained was somewhat
25 different for the yes/no of obtaining biopsies
1 between these two treatment arms so that, for the
2 Rapamune group, the biopsies were more likely to be
3 obtained. These are numeric trends, not
4 statistically significant. But the GFRs tended to
5 be slightly lower for those that got biopsies as
6 opposed to those that did not whereas, for the
7 control group, the GFRs were just the opposite.
8 They tended to be slightly more than those that did
10 Given that this is an open-label study and
11 clinicians knowing full well that patients are
12 going to have an important element of the regimen
13 removed, it is not surprising that there was as
14 sort of differential predisposition to this kind of
16 I should add that, as I said, this study
17 is five years. We held an investigator's meeting
18 in the fall just at the time now where the patients
19 are starting to enter the three-year mark. We have
20 exhorted, extolled and badgered in any way we can
21 the investigators to obtain three-year biopsies on
22 as many patients as possible because we, again, do
23 have a number of baseline biopsies.
24 So, even if these investigators haven't
25 gotten the one-year biopsies, we are hoping they
1 will get the three. It may be that the difference
2 in function that we are seeing may be more easily
3 expressed in the histology with a longer period of
4 time on these two separate regimens.
5 So we are certainly anxious to see those
6 three-year biopsies and certainly, as the data
7 becomes available, they will be brought before the
9 DR. HUNSICKER: I guess I find myself with
10 another question for my FDA hosts over here, and
11 specifically Dr. Cavaille-Coll, I have spoken with
12 you about this before. Let us assume that they
13 submit, and you agree to, an analysis of the
14 creatinines over time that is very rigorous and
15 that shows something similar to what we have seen
16 here which is a diverging trend, a trend for the
17 creatinine to be rising or to be more negative, if
18 you will, in the continued cyclosporine and Rapa as
19 opposed to the rapamycin, itself.
20 Let's assume that the qualified yesses I
21 heard some of turn out to be the majority opinion.
22 I don't know quite what I am asking here but what I
23 am trying to get across is that it would seem to me
24 this is one area where it is absolutely crucial
25 that these patients be followed long-term in an
1 intent-to-treat fashion so we find out whether
2 these early changes do, in fact, mature into a
3 difference in graft survival, which is what we are
4 looking for.
5 I think that this is one of the places
6 where whether you speak about this in terms of
7 accelerated approval with ultimate validation later
8 on or however you want to term it, we have got to
9 assure that if there is an indication given, we
10 have to confirm what this means in the long haul.
11 DR. CAVAILLE-COLL: Are you suggesting
12 that, before we take any kind of decision, that we
13 should be looking at the analysis you are proposing
14 at these folks up to 24 months as they are entering
15 their third year and that that should be the
16 intent-to-treat analysis including all the patients
17 that were in the study that still have a kidney to
19 DR. HUNSICKER: It is not going to be a
20 trivial issue because there are some patients who
21 are going to be lost because they have failed, and
22 that is obviously an informative failure and you
23 have got to figure out how you are going to analyze
24 that, whether you do it by medians, or whatever.
25 But I believe that. I am going to assume
1 you are going to get some recommendation. All of
2 what we do, all of what my colleagues do because I
3 don't vote today, is a recommendation to you
4 anyway. What I am suggesting is that, however this
5 comes out, my feeling is that I would not want to
6 act, were I voting, until I saw the results of a
7 really well-done slope analysis because I think we
8 are trying to bet a known, maybe not too great,
9 negative today against a promise of something that
10 may be substantial and I want to have that promise
11 of what is substantial in terms of creatinine be
12 tied down as best I can.
13 But, no matter how you do it or we do or
14 anybody does it today or tomorrow or the day after,
15 the proof of the pudding is going to be in what
16 happens five years from now. I think that one of
17 the things that is essential is that there be an
18 understanding that, if there an approval given of
19 some form, that this approval has to be validated,
20 if you will, downstream by seeing whether these
21 differences in function, in fact, translate
22 ultimately into differences in graft survival.
23 DR. ALBRECHT: If I may go ahead and sort
24 of paraphrase what I think you said and, really, in
25 a sense, review some of the options that actually
1 are available to us. I think the issue you raise
2 about, let's say, five-year follow-up data in the
3 setting of a regulatory decision earlier than that,
4 under the regulatory options available to us, we
5 could take such a course if we were to approve and
6 indication and then request a phase-IV commitment
7 for data long-term.
8 That is certainly one approach and that
9 would be the kind of approach where we felt that a
10 decision at this time was based on adequate
11 information and one that we could comfortably
12 reach. Clearly, this is why we are asking you to
13 assist us with making this decision and that, in
14 fact, the long-term data is just to confirm and
15 make us comfortable that the hypotheses and
16 decisions we made early are, in fact, confirmed.
17 However, if, to take it to the next stage,
18 if we are dealing with--we are construing surrogate
19 endpoints where we believe they are likely to
20 predict the long-term outcome but we really don't
21 have the data on which to make that conclusion,
22 then there is, under the regulation, a section
23 called Subpart H in 314.500 where what we say is
24 this is an approval based on a surrogate which we
25 believe will have predictive value long-term
1 clinically but we are not certain.
2 As part of that action, the company is
3 required to continue clinical trials--in this case,
4 the long-term follow up for example--and provide
5 such information to, in fact, confirm or show that
6 these results are not consistent over time and then
7 the regulatory action would follow based on those
9 Having gone over those two, I think what
10 we would like to ask you, as the committee, as you
11 are discussing and voting on this, is to provide us
12 your best advice on whether you believe the
13 findings now, the likelihood is that what we would
14 be doing long-term is confirming--or whether the
15 information is such that, at this point, it would
16 premature for you to expect that these results are
18 In fact, the final option really would be
19 to say the information we have is so preliminary
20 that we do need further data before we can even
21 reach a decision. So I think those are the three
22 options before us and we look to you for guidance
23 on which of those really you believe scientifically
24 and clinically are supported by the data presented.
25 DR. ENGLUND: Are there any comments
1 before we proceed with voting on No. 1?
2 DR. SHAPIRO: I have a question for John.
3 Do you think that, if you had more time, more
4 follow up, maybe an additional trial that would
5 strengthen and sort of amplify in the data that you
6 have presented, that that would make your position
7 a little bit stronger but, perhaps, also, more
8 generalizable and would it be worth it from Wyeth's
9 point of view to try to do that to increase
10 everybody's confidence in your claim?
11 Right now, everybody is sort of saying,
12 "Yeah, well, for a very small subset of patients
13 who are doing really well, this is probably a good
14 thing but they represent not a huge number of
15 patients whom we are transplanting today in real
17 The question is, if you had more
18 information, would it be stronger from the
19 company's point of view to have a stronger
21 DR. NEYLAN: Let me address that in two
22 parts. One, yes. Wyeth is, in fact, even now,
23 undertaking a variety of studies which further
24 explore this issue, the issue of the use of a
25 reduced calcineurin inhibitor, the issue of
1 continued exploration of a withdrawal strategy.
2 In fact, in that latter point, we are now
3 initiating one of the largest clinical trials in
4 the maintenance population that has ever been
5 undertaken and that is a randomized comparative
6 analysis for the maintenance population of a
7 continuance of calcineurin inhibitors versus a
8 conversion and taking patients with all ranges of
9 renal function.
10 We are building into that protocol
11 biopsies and a variety of what I believe are going
12 to be very important elements to help the community
13 better understand these issues as they relate to
14 the long-term care of recipients.
15 So the commitment is there. It is
16 ongoing. What we have with these two studies,
17 however, is now two-year data for 310, emerging
18 three-year data, and a commitment to go to five.
19 At each of these time points, these twelve-month
20 time points, we are seeing a consistency or a
21 confirmation, if you will, of the elements that
22 have come before.
23 So, while the commitment to continue this
24 study and continue the reporting of its results is
25 there, I think it would be difficult for us to
1 start from scratch at this point already having put
2 in so much time and effort. I think it would be a
3 disappointment if we were not able to move forward
4 with the indication today.
5 DR. ENGLUND: Dr. Hunsicker?
6 DR. HUNSICKER: Could I respond to your
7 comments, which were very clarifying for me. You
8 know that I am not going to vote but I can still
9 give you my opinion and that is, if I can start
10 with the last one and move forward, I think it
11 would be unjust to the sponsor to say that we just
12 don't know anything.
13 There are issues of how to apply what we
14 have here. We don't know quite who the population
15 is at this point and that has got to be addressed
16 as a separate issue. But if you take the
17 population that we have seen, the data that we have
18 are fairly convincing that the cost is small but
19 real and it appears that the long-term benefit is
20 going to be real.
21 That remains to be qualified by what I
22 have said. I want you people to do a proper, and
23 to agree on a proper, analysis of this issue that
24 is--intention-to-treat and all that. I have said
25 that, so I don't have to go over it again.
1 But if, in fact, the outcome were to show
2 that there is this initial improvement in function
3 and that, in fact, over time, that difference in
4 function between the cyclosporine and the other arm
5 widens rather than constricts so that there is a
6 presumption that the creatinine is getting better
7 in time relatively speaking, the sirolimus-only
8 arm, it seems to me you have as good data as you
9 are going to have that there is likely to be a
10 long-term benefit short of actually doing the
12 So I would not feel, given the
13 restrictions that I have said about what the
14 population is, that it would be just to say that
15 these folks haven't shown you anything.
16 On the other hand, if we go to the other
17 extreme, is this already cold-cocked? No; it can't
18 be because no one yet has done an interventional
19 study in which they have said, "I am going to do
20 something to lower the creatinine," some
21 intervention to lower to creatinine, and show that
22 this transforms ultimately into prolonged graft
24 I think the rationale behind it is strong.
25 I have written about that. I have talked about
1 that. I believe it. I think that it is reasonable
2 to think that but it has never been shown. I would
3 go on further to say that our obligation to make
4 sure we know what the outcome is of an intervention
5 that lowers the serum creatinine or preserves GFR
6 acutely and to see whether this translates is very
7 important because, as Dr. Neylan said, you are
8 likely to see a whole mess of this coming down the
9 pike an we have got to settle this once and for
11 Is the presumption that a lowering of
12 creatinine and widening of things leads to better
13 graft survival in fact supported--in fact
14 supported--by our data at the end of time. So I
15 don't think that you can say that it has been shown
16 because it hasn't. Nobody has shown that.
17 So I find myself very much in the middle
18 here, as Marc knows that I have for years. I think
19 that this is something for which there is very
20 strong presumption, a basis, perhaps, for early
21 approval but with the requirement that this
22 assumption that an early improvement in function
23 will translate into longer graft survival must be
25 MR. LAWRENCE: A point of clarification,
1 if I could. We are about to vote on Question 1 but
2 I am not sure what Question 1 says. The company is
3 asking for language that says that cyclosporine
4 should be withdrawn, or should be considered to be
5 withdrawn, after two to four months. Is that what
6 we are voting on, that they have shown us
7 sufficient data to say that that is--
8 DR. ENGLUND: We are not voting on the
9 wording. We are not voting on the "should" or
10 "may." We are voting on does the--and we can ask
11 for clarification, but we are voting, does the data
12 support the contention that withdrawing
13 cyclosporine is safe and effective.
14 DR. ALBRECHT: That's correct. The
15 question is not how we should label the product but
16 whether the committee does believe that the data
17 that Wyeth has presented show that this regimen is
18 safe and is effective.
19 Actually, if I may comment a little
20 further, having heard the discussion, I find that
21 it would probably be reasonable to paraphrase the
22 second part of that question to, if the answer is
23 yes, not just the population or subpopulation that,
24 perhaps, could be discussed but I also got the
25 sense that, perhaps, as part of that question, if
1 the committee does believe yes is the direction in
2 which the members would like to vote, what
3 additional information would be needed before that
4 yes could take place.
5 DR. ENGLUND: So the FDA is letting us ask
6 for more information.
7 DR. ALBRECHT: The more information could,
8 of course, be more analyses.
9 DR. ENGLUND: From what we already have.
10 At this point, what I would like to do is briefly
11 summarize. I am putting, perhaps, my perspective
12 but I will try to be global. Then, at this point,
13 I would like us to vote on question 1 because I
14 think we have to vote on question 1 before we can
15 decide if we are going to answer a. or b. We are
16 not going to answer both of them because it depends
17 on how question 1 goes.
18 I think, at this point, I have several
19 comments. Number one, I think we need to
20 congratulate the pharmaceutical company for
21 proposing and carrying out a relatively complicated
22 study in the withdrawal of immunosuppressives. To
23 my knowledge, this is the first study that I have
24 seen that has been carried out with 100 percent
25 compliance. In the era--in my field of more
1 antivirals, I never get that. I think this is
2 amazing and they are to be congratulated and that
3 we appreciate the work that has gone to give us
4 this kind of numbers.
5 I also think that the theory and the
6 theoretical concerns as to what they are using as
7 our endpoints are good. The fact that they can't
8 tell us for sure what elevated creatinine means at
9 one year is not--they should not be penalized for
10 that because that is the state of the art.
11 So I think we, on the committee, recognize
12 some of the good work that has gone into this but,
13 in reviewing the comments from the different
14 speakers, I think we have, as a group and as a
15 committee, certain sincere difficulties and I am
16 going to just briefly go over them.
17 We have, as a group, a very big issue with
18 the population. To my knowledge, we did not show
19 living related donors in Americans. That is,
20 perhaps, going to be a very big population that we
21 would be concerned about. We have different
22 ethnicities that have not been addressed, at least
23 in our country, and these are big issues from my
24 point of view that the pediatric data, of course,
25 is still barely getting started. I feel that is an
2 So we have patient-population concerns.
3 And then I think we have some big analysis concerns
4 that, with the help of our statisticians and
5 pharmacology colleagues, we really have some
6 concerns about what is intention-to-treat, what is
7 a really appropriate comparison.
8 I have concerns about the toxicity and
9 safety. I mean, what is a low potassium? I don't
10 care of people's platelet count is 10,000 less. I
11 care if they are thrombocytopenic and I wasn't
12 able to get good values as to what some of our
13 toxicities really were. So I think that there is
14 some more analysis, that I think the data is here.
15 I think the committee as a whole has raised some of
16 these issues.
17 Last, but not least, is the use of
18 surrogate endpoints which we, as a committee, and
19 with our specialties, have to realize that that is,
20 in fact, the state of the art today. I think that
21 is important for us to realize. As much as we do
22 want more, that is what we have today.
23 So, with that, I have tried to summarize a
24 lot of people's concerns and comments, at the risk
25 of adding a little bit of my personal
2 With that, I think I would like to take a
3 vote and I would like to start at this end of the
4 table because we have started at that end of the
5 table first. For this vote, we really have to say
6 yes or no to question 1, or abstain, I guess.
7 But, do the data presented support the
8 effectiveness and safety of cyclosporine withdrawal
9 two to four months after kidney transplantation in
10 patients treated originally with a combination
11 regimen of sirolimus, cyclosporine and
13 Could you please say your name before you
14 vote so it can be taken down in the minutes.
15 Dr. Johnson?
16 DR. JOHNSON: Lynt Johnson. I guess I
17 would say no with a qualifier. But I guess it gets
18 registered as a no and it relates to the lack of
19 data representing the African-American population
20 which may, in turn, be a group that has benefit
21 from this regimen. As I got the sense of it, it
22 seems like it was more leaning towards yes with the
23 restriction of a population. I would hate to
24 restrict that population which may have benefit. I
25 just don't know.
1 So, with the absence of that data, it is
2 very hard for me to support question No. 1.
3 DR. ENGLUND: Dr. Shapiro?
4 DR. SHAPIRO: Ron Shapiro. Yes, but with
5 many of the same qualifications.
6 DR. SUTHANTHIRAN: Suthanthiran. I
7 actually think you can't split question 1 from 1a
8 because we are really saying yes or no to the first
9 question. I would say that I would say a qualified
10 yes in the sense--if the proposed indication is as
11 stated by the sponsor, we can't vote yes. I can't
12 vote yes on it.
13 But, if that is modified to say that "may"
14 be considered for withdrawal in certain low-risk
15 patients, I would vote yes. So I think, in my
16 mind, Question 1 and 1a and 1b are so inextricably
17 linked, I would find it difficult to--
18 DR. ENGLUND: Okay; so you are a yes
19 qualified as opposed to a no qualified.
20 DR. SUTHANTHIRAN: With the modification
21 in the proposed indication.
22 DR. ENGLUND: Steve Ebert?
23 DR. EBERT: Steve Ebert. To the question
24 that is posed, my answer is yes. I will hold off
25 on comments with the follow up.
1 DR. ENGLUND: Dr. DeGruttola.
2 DR. DeGRUTTOLA: Victor DeGruttola. I
3 would say that this is a gray zone. It appears
4 that there are patients who would benefit from this
5 regimen. It also appears the answer to the
6 question depends on the clinical importance of
7 acute rejection which, I understand, has been used
8 as an endpoint in some trials.
9 Given that concern, I would give this a
10 qualified no but, again, emphasize that there does
11 appear to be benefit in some populations and if
12 that can be further specified, then I think that
13 that fact should be taken into consideration when
14 FDA makes its decision.
15 I know that is a long vote, but--
16 DR. ABERNETHY: Darrell Abernethy. No. I
17 need more data and more analysis. So, at this
18 point in time, I cannot say anything other than no.
19 DR. ENGLUND: Dr. Auchincloss.
20 DR. AUCHINCLOSS: Auchincloss. No. I
21 think study 212 might as well be thrown out. I
22 don't ever think it is going to be useful. I think
23 they need longer and more analysis of the 310
24 study. I think they are going to need some
25 additional data from an additional study. So, no;
1 I don't think that this is ready for a label change
2 even though, as I have indicated, I will probably
3 go home and do it on a patient.
4 DR. ENGLUND: Mr. Lawrence?
5 MR. LAWRENCE: William Lawrence. My vote
6 would be yes but with the same reservations
7 expressed by Dr. Suthanthiran and Dr. DeGruttola.
8 I have serious reservations about applying this too
9 broadly but I think the answer is more yes than no.
10 DR. ENGLUND: I am sitting hedging because
11 what I am hearing is yes, not all, but we are
12 hearing a lot of yes, buts and no, buts, which is
13 difficult. But I think I would say no, but. The
14 reason for that is that if I were having to say
15 what would be the patient population to select, I
16 can't do it.
17 If they are going to expect my help, our
18 help, but my help, in designing who would benefit
19 from it, I know it is good. I know it is going to
20 work. But I don't know who to give it to and I
21 feel that is, at this point--and, perhaps, further
22 analysis could help us with that. So I am a no,
24 But, having said that, there are four
25 yesses, five nos.
1 DR. ABERNETHY: So it was a tie-breaker.
2 DR. ENGLUND: The problem is I would say
3 that questions 1a and 1b are actually closely tied
4 in with question No. 2 in the sense that we need
5 more studies. I don't care what they are called,
6 but we need more studies.
7 For the yes people, how would you define
8 the patient population, if we could just briefly go
9 through the people who said yes. How would you
10 define it based on the data available?
11 DR. SUTHANTHIRAN: I am strictly going by
12 the data that I have. I know what patients to
13 exclude from entering in the study which would
14 include patients who had advanced to vascular
15 rejection. It would include patients who have
16 dialysis dependency. And it would include patients
17 who have more than 400 micromoles of creatinine.
18 These four patients, the four groups of
19 patients, cannot be entered into the study at this
20 time because we have no data to support that these
21 patients can be weaned off from cyclosporine. So
22 those patients can be excluded from the study.
23 We have no data on African-Americans so
24 those patients should not be included in the study.
25 DR. ENGLUND: I'm sorry; you mean--
1 DR. SUTHANTHIRAN: In cyclosporine
2 withdrawal. I am listing the group of patients for
3 whom we do not have data to make a recommendation.
4 So I have five groups of people who should not be
5 entered in a cyclosporine-withdrawal protocol at
6 this time.
7 I also know that related and living-donor
8 transplants are not--well, I am not that worried
9 about that patient population because usually, if
10 you can treat cadaveric patients, you can usually
11 get away in a living donor. So that is not an
12 exclusion criteria for me.
13 So, for my qualified yes, I would call all
14 these patients as high-risk patients, these
15 patients for whom I have no data, and I would allow
16 other patients to be entered in this. Potentially,
17 we can consider it for this protocol.
18 But I want to go back to what was said by
19 Mr. Lawrence about--I wouldn't put the word
20 "should." This is why I thought 1 and 1a are
21 inextricably linked. I think "should" gives a very
22 different connotation to the clinician. I think it
23 should be "may" or "might" be considered and I
24 would also add the line "in certain low-risk
1 DR. ENGLUND: Mr. Lawrence?
2 MR. LAWRENCE: Dr. Hunsicker and I were
3 discussing this point. This is who we thought
4 should be included. You say who should not. "May
5 be considered in low-risk patients," with an
6 asterisk to define that. "No delayed graft
7 function. No type III rejection. Adequate renal
8 function. There is too little data to address
9 blacks, Hispanics, Asians."
10 So, when I voted yes, I was voting yes
11 based on these people. If I had a chance to vote
12 no on the rest, I would vote no on the rest. But I
13 want to encourage withdrawal of immunosuppressive
14 drug. The flavor of that is a very attractive
15 flavor to people like me.
16 DR. ENGLUND: Dr. Shapiro?
17 DR. SHAPIRO: I wouldn't have much to add.
18 First, maybe second, transplant patients who have
19 kept their first kidney for a long time, low PRA,
20 low panel-reactive antibody level, if they have had
21 a rejection and easily treated, mild or
22 mild-to-moderate rejection with complete reversal,
23 preferably either no delayed graft function or
24 minimal delayed graft function, I think those
25 patients would fit into the category of patients
1 who might be candidates for a successful
2 calcineurin inhibitor withdrawal.
3 I guess, like everybody else, I would be
4 more concerned without more data.
5 DR. ENGLUND: I guess just as a response
6 to you is I would be very concerned about putting
7 something like--putting some of the things that
8 people have said here on a label when there is
9 actually nothing known about it. I agree, I think
10 that is what people will do and will do it at my
11 institution, but to put it on the label or to say
12 that that is who we are giving it to without any
13 data--we don't even have much living related data
14 even though I believe it is good. So this is my
16 DR. ENGLUND: I just want to echo what you
17 just said in that--and part of my comment was just
18 that. I tried to answer this as directly as
19 possible whether the data support the effectiveness
20 and that was the basis for my vote. But, as you
21 said, whether you are going to try to put
22 something--translate that into modifying the
23 labeling, I think is a much slipperier slope.
24 Whether this is something that should be
25 noted by practitioners and should be incorporated
1 into their daily practice as a "off-label" use in
2 selected individuals or whether this should be, as
3 you said, something that would be incorporated into
4 the labeling. I think those are two very different
6 DR. ENGLUND: We have two other questions
7 actually that are not to be voted upon but really I
8 think we should bring up for discussion.
9 DR. AUCHINCLOSS: Did the FDA feel like
10 they got their answer to the question? Do they
11 feel like they know what question we were
12 answering? I was just struck by the comment that I
13 heard over here because I think you were a yes
15 DR. ENGLUND: Yes was "yes, but."
16 DR. AUCHINCLOSS: But you wouldn't rewrite
17 the label?
18 DR. ENGLUND: Again, I agree with the
19 chair in that I don't think that there is enough
20 information available in a wide enough patient
21 population that I would feel strongly enough to
22 modify the labeling.
23 DR. AUCHINCLOSS: Because it was really
24 sort of that question that I used as the way to
25 hinge my vote one way or another.
1 DR. ALBRECHT: I think as I heard those
2 last comments about perhaps uncertainty whether the
3 information available was such that some of the
4 members felt comfortable about putting them in
5 labeling. The question that came to my mind is
6 what would be the information that you would
7 recommend or would like to see that would actually,
8 then, make you comfortable about this kind of
9 information being part of the label.
10 Again, not to go into the specific wording
11 but some of the ideas that you were voicing about
12 certain patient subsets or populations, what would
13 be the data that you would like to see before you
14 would be comfortable having this in the label?
15 Again, I ask that really just for completeness of
16 discussion, not to try to actually pin down the
17 criteria because, again, this is a very hard issue.
18 DR. ENGLUND: I would just like to
19 summarize. I think intention-to-treat data would
20 be the echo of our committee, without having to
21 call on everyone.
22 MR. LAWRENCE: Dr. Albrecht, I just have
23 to ask you again. When you say what would you have
24 to see before this would go in the label, I don't
25 know what "this" is. I have been trying to clarify
1 what "this" is. If "this" is that this should be
2 done generally, my answer is no, we haven't
3 seen--if the answer is that this is that this can
4 be contemplated by physicians based on the clinical
5 picture of the patient that they see and in certain
6 circumstances, then the answer is yes.
7 But you are not going to put that on the
8 label. So question 1 is not actually crafted in
9 terms of getting a yes or a no answer because the
10 qualifications are so manifest that everybody at
11 the table voted yes, but or no, but. I am not sure
12 the vote that you got today is worth much.
13 Obviously, there are serious reservations.
14 And, obviously, in some cases, it is appropriate
15 and should be encouraged. If you are going to put
16 that on the label, I will look for that.
17 DR. ALBRECHT: I think, as I said earlier,
18 there are the two aspects of making a regulatory
19 decision. The first is the burden of is the drug
20 safe and effective and that is what is specified in
21 the Food, Drug and Cosmetic Act.
22 Then the second aspect is how the
23 information about the safety and efficacy of the
24 drug is placed into the package insert so that it
25 can be understood by the individuals that would be
1 using the product.
2 I think we really are just asking you to
3 vote on the first issue of is the drug safe, is it
4 effective, and then the details of the words that
5 we will use to communicate that information, I
6 think, is the next level and some of the comments
7 that we are hearing, I think, indicate to me that
8 that is going to be a very challenging area.
9 DR. ABERNETHY: In terms of the further
10 information, I would suggest that--I think I need
11 to see a U.S. study that reflects the U.S.
12 transplant population. I would like to see
13 patients randomized at the time of transplant so
14 that we get a much better feel for where these risk
15 stratifications should be with regard to benefit
16 and then an intention-to-treat analysis.
17 DR. AUCHINCLOSS: Why is that? If the
18 issue is cyclosporine withdrawal versus no
19 withdrawal, why don't you randomized at the moment
20 of withdrawal? Then you can do all the
21 stratification you want at that point. It seems to
22 me they terribly muddied their picture by
23 randomizing up front and then withdrawing two
24 months later. By then, a whole series of events
25 had happened to the alternate population that
1 weren't comparable.
2 DR. DeGRUTTOLA: I would echo that. If
3 you could randomize at the time you would withdraw,
4 if that were a consideration, then I think that
5 would get most directly at the question.
6 I think one of the issues we are
7 struggling with is that, as Dr. Albrecht mentioned,
8 the regulations talk about the effectiveness and
9 safety of a drug, but we are really talking about
10 the effectiveness and safety of a strategy to
11 withdraw a drug which is a little bit more
12 complicated. I think that Dr. Auchincloss'
13 suggestion of randomizing at the time that you
14 would reduce the cyclosporine, that choice is an
15 interesting one to try and get most directly at
17 DR. ENGLUND: That was the 310.
18 DR. AUCHINCLOSS: It is the 310. But we
19 are now asking for a United States study.
20 DR. ENGLUND: Right.
21 DR. ALBRECHT: May I actually add a few
22 more comments about foreign studies because I think
23 that this is an issue that is important to us. As
24 you know, drug companies do conduct studies in the
25 United States and abroad. As I indicated earlier,
1 the Code of Federal Regulations does allow foreign
2 studies to be used.
3 But if I understand, your concern is that
4 in the United States, there are a substantial
5 number of patients who have living, related-donor
6 transplants. In the studies that have been
7 submitted--in fact, it was 90 to 100 percent
8 cadaveric. So the concern is that we cannot
9 extrapolate the data from those studies to U.S.
10 patients--because I think it is just as important
11 to recognize that, in the area of international
12 drug development, we try not to stymie development
13 across the world but, rather, the concern is when
14 the patient population studied abroad cannot be
15 extrapolated to the patient in the United States
16 and, therefore, we cannot, then, effectively label
18 So was that the concern, that the patients
19 being studied in these studies would not reflect
20 the U.S. population?
21 DR. ABERNETHY: I think you are saying it
22 in a, perhaps, too gracious way. The concern I
23 believe is that it is clear that when this study
24 was conducted, there was no commitment or no
25 possibility of including a population that is of
1 great interest here. Then, secondly, the concern
2 is is the practice pattern going to be the same in
3 one setting versus another.
4 I understand what you are saying about
5 harmonization on the one hand. On the other hand,
6 we are talking about getting an appropriate
7 practice for patients in the United States.
8 MR. LAWRENCE: A point of information.
9 Last year was the first time in this country that
10 living donors outnumbered cadaveric donors for
11 kidneys. So that is a material question.
12 DR. AUCHINCLOSS: I agree that there are
13 lots of potential concerns about an abroad
14 population. I don't think that the living-donor
15 issue is my primary one. I really would fairly
16 strongly believe that if this kind of thing works
17 for your cadaver-donor population, it is going to
18 be okay for your living-donor.
19 DR. ENGLUND: I believe that. Wouldn't
20 you like to see one or two patients?
21 DR. AUCHINCLOSS: Yes; I would like to see
22 one or two patients but that is not, by any means,
23 my primary concern about the patient population
25 DR. SHAPIRO: Actually, the living donor
1 would be sort of a positive in that those are
2 patients who tend to do, as a group, better. I
3 think there is a sense that the American transplant
4 recipient population is more heterogeneous and that
5 the need for doing a study in the United States to
6 reflect that would be important.
7 DR. SUTHANTHIRAN: I think there is
8 another issue we need to address in terms of
9 randomization because we are going to be asked a
10 question, whatever the regimen or whatever the
11 protocol, is it safe and effective. The question
12 is being asked is it safe and effective for
13 transplant patients.
14 Now, at the time of randomization, certain
15 groups of patients are excluded from randomization
16 and they go into Arm C or nonrandomized. We are
17 always going to have this problem. We always have
18 this problem, it is safe but we cannot comment
19 about population A, B or C who were not excluded in
20 the randomization plan.
21 The only way to avoid the problem is to
22 really enter all patients into randomization.
23 Otherwise, we are going to revisit the issue all
24 the time. It is kind of a Catch 22. If you start
25 patients at zero time, all your transplant
1 patients, and then, let's say, at one month or two
2 months, you randomize, but you are really not
3 randomizing A B. You also have a group C because
4 of whatever notion that group C is a high-risk
5 patient population.
6 Now, when we are asked to answer the
7 question, is this protocol fine for transplant
8 patients, we are always going to say it is fine for
9 the transplant-patient population minus group C.
10 DR. AUCHINCLOSS: But that is true of many
11 studies. You have exclusion criteria and then the
12 results apply only to those that were not excluded.
13 DR. SUTHANTHIRAN: Right.
14 DR. ENGLUND: But the problem here is we
15 have not just those exclusion criteria but we also
16 have the exclusion criteria for all the people that
17 they didn't even--that weren't even enrolled in the
18 first place.
19 DR. DeGRUTTOLA: I think the point is
20 exclusion criteria, per se, shouldn't necessarily
21 be a concern. If it is not appropriate to withdraw
22 cyclosporine from some patients, then it is
23 appropriate to exclude them both from the study and
24 mention that in the label.
25 I think the issue is do you always want to
1 do the reduction of cyclosporine at three months so
2 that is specified then, or could there be a more
3 variable time at which you say, now is the time we
4 might consider reducing the cyclosporine. It might
5 be later, for example, in some patients. I think
6 maybe you could get at the issue that way in
7 allowing the randomization only to happen at the
8 time that you want to consider withdrawing it, not
9 necessarily fixed at three months by protocol but
10 allowing some latitude with that.
11 DR. SHAPIRO: If I could just defend the
12 selectivity on the part of the sponsor, you
13 want--this is pretty radical to stop a calcineurin
14 inhibitor and you want to load the dice to come up
15 with a trial that is going to give you--one, that
16 is going to give you a trial that is going to be
17 relatively safe to do and one that is not going to
18 fall on its face.
19 I think that they have succeeded extremely
20 well in doing a study like that, at least at a
21 first pass, in a relatively low-risk population. I
22 think to have done an allcomer study at the
23 beginning, one would have risked a result that
24 would have been harder to understand and, two,
25 would have been very difficult to do.
1 So I think that the rationale for looking
2 at selected populations initially was the right
4 DR. ENGLUND: I would like us to move on
5 to what additional studies would we want, would we
6 ask for. I have heard from Dr. Abernethy.
7 DR. SHAPIRO: I would echo that. You
8 would need to do a large-scale American trial with
9 both living donor and cadaveric recipients and not
10 restrict entry on the basis of ethnic group. You
11 might want to restrict entry in terms of transplant
12 number and PRA to at least give it a shot of being
13 reasonable, just from a tactical point of view.
14 DR. ENGLUND: Would you consider
15 randomization at time of transplant or at a period
16 following transplant?
17 DR. SHAPIRO: The ideal thing would be to
18 randomize pretransplantation. But you are going to
19 increase your dropout rate enormously if you do
20 that. At some level, that is the cleanest. The
21 way to stack your trials so that they come out the
22 way you want them to is to randomize after you know
23 that you have got kidneys that are functioning in
24 patients who are doing well.
25 The ideal thing would be to randomize
2 DR. ENGLUND: Dr. Johnson?
3 DR. JOHNSON: I am not sure that I would
4 agree that they would have to redo the entire study
5 in the U.S. population. I think that--you know, my
6 main concern is that the African-American
7 population represents such a large proportion here
8 in the United States and I think that we need to
9 have some data. That data may come back and say,
10 yes, it is okay in certain conditions and they may
11 say it is worse.
12 But that is the information that I would
13 like to have because I think that, from the
14 question that was asked, can we extrapolate this
15 data, there is some extrapolation that I can do
16 with this data but I can't, based upon prior data
17 and based upon my knowledge of this group,
18 extrapolate it to that subpopulation.
19 So, in my opinion, I am not sure they
20 would need to redo the whole study. But I think
21 that they need to provide supplemental data in
22 African Americans in the United States in some
23 fashion so that we can make a judgment one way or
24 the other whether or not we need to provide a basis
25 to exclude or include them in this labeling in some
2 DR. ENGLUND: Any other comments about the
3 phase IV studies? I have heard that the pediatric
4 studies--I have heard about those and I think those
5 sound good and sufficient and I am pleased to see,
6 actually, the numbers that are being discussed for
7 the pediatric studies.
8 DR. SUTHANTHIRAN: I would add a biomarker
9 to the study. I think it would be terrific if
10 there is nice improvement in creatinine, there
11 appears to be a nice improvement in renal function,
12 it seems to hold out over time--I think it would be
13 very nice of a biopsy is really part of the
14 protocol and the patients get biopsied at defined
16 I know logistically there are some
17 problems associated with it, but I think the study
18 would be improved so much if a biopsy is done in
19 all the patients and we can see a structural
20 correlation and a structural counterpart to this
21 improved renal function.
22 DR. ENGLUND: Dr. Shapiro?
23 DR. SHAPIRO: I would also point out that,
24 while protocol biopsies are very nice and I have
25 written about them and we have performed them and
1 we have published on them, and I have also been
2 slammed for them, or our paper has been, as being
3 of uncertain significance.
4 That is the problem with protocol biopsies
5 in the world today. The transplant community has
6 some people who are very interested in them and
7 think that they are wonderful and a large number of
8 people who think that they are nonsense.
9 DR. ENGLUND: I would just like to add,
10 from my experience in clinical trials, that it
11 makes recruiting in minority populations greatly
12 difficult. It makes some of the recruiting more
13 difficult in some of the populations, and I think
14 that is something to consider.
15 DR. SHAPIRO: It depends how you sell it.
16 DR. ENGLUND: You are better at it than we
18 DR. ENGLUND: I don't really want to open
19 a can of worms on this, but I think, if additional
20 phase IV studies were going to be done, one might
21 also want to consider having a subset of patients
22 which, rather than doing prospective
23 concentration-controlled dose modification may want
24 to just start out immediately at a dose of, whether
25 it is 8 milligram a day, 10 milligrams a day,
1 whatever have you, and try to see whether, in fact,
2 doing dose titration really, in fact, does improve
3 on outcomes compared with just arbitrarily giving a
4 certain dose.
5 DR. AUCHINCLOSS: I know that the company
6 is thinking about different ways of using their
7 drug in combination with other drugs and they have
8 thought, not just about cyclosporine withdrawal but
9 they have thought about steroid withdrawal, et
10 cetera, et cetera, et cetera.
11 But I do think it is worth their while to
12 rethink again whether this is really their top
13 priority, cyclosporine withdrawal. To me, as I
14 looked at the 212 data which I found interesting
15 even though I don't think it is a good study, it
16 seems to me the message there is that high-dose
17 sirolimus with very low-dose cyclosporine is a
18 fantastic combination that is destroyed when you
19 withdraw the cyclosporine.
20 So I just wonder whether they want to
21 think again about whether their endpoint actually
22 should be cyclosporine withdrawal or cyclosporine
24 DR. ENGLUND: Let me go, then, to question
25 No. 3 which I think we have kind of addressed, but
1 let's make sure we have gone through all of our
2 questions. Question No. 3 states, do we have any
3 additional comments or recommendations regarding
4 the study design and/or endpoints for controlled
5 clinical trials intended to support the safety and
7 In particular, one of the things which we
8 have, I think, discussed, but for a maintenance and
9 a maintenance withdrawal regimen which is going to
10 be coming up before this committee again, one
11 hopes, what comments do we, as a committee have?
12 What would we like to be seeing in these trials?
13 Any comments in addition to what has
14 already been stated? Perhaps our statistician?
15 DR. DeGRUTTOLA: I think points have
16 already been made about longer-term follow up and
17 the ability to relate some of the markers to longer
18 follow up. I actually think that randomizing at
19 the point when people would reduce the dose rather
20 than up front is probably better for the reason
21 that was mentioned, if you are going to have
22 dropouts and people that can't be entered into the
23 study. So I think that the design is actually more
25 DR. ENGLUND: Any comments or questions
1 from the FDA?
2 DR. ABERNETHY: It may have already been
3 said abundantly, but I think viewing this kind of a
4 study as essentially an equivalence study, your new
5 regimen of having one less medicine is really--you
6 are testing equivalence to the currently accepted
7 regimen and taking that point of view from day 1
8 and really understanding what that means would
9 certainly make the interpretation at this end much
11 DR. DeGRUTTOLA: Yes; prespecifying what
12 equivalence means. I guess it is as little
13 confusing in that this study was intended to show
14 equivalence for some outcomes but superiority for
15 other outcomes, I guess prespecifying what the
16 criteria are for equivalence or noninferiority, as
17 was mentioned.
18 I also thought that Dr. Hunsicker made an
19 interesting comment about doing intent-to-treat
20 analyses of some of the toxicity results which is
21 not standard. Typically, that is done on-therapy
22 or as-treated. But, for the reasons that were
23 discussed, I think that that is something that
24 should be considered here as well.
25 DR. AUCHINCLOSS: You make a comment about
1 how you balance two what are, in effect, surrogate
2 endpoints when we are not sure that either is okay.
3 One is going to go up and one is going to go down.
4 I think that the outcome here was pretty much as
5 you might have predicted, a slight increase in
6 acute rejections and an improvement in renal
7 function. We are not quite sure how important
8 either one of those things are.
9 DR. DeGRUTTOLA: I think that that is
10 always a challenge in any study and there are a
11 couple of ways to approach it. One is if you
12 believe that you can predict or develop a
13 predictive model, as I believe Dr. Neylan gave one
14 example, so that you can essentially weight the
15 improvement or lack of improvement by the expected
16 clinical consequences.
17 What that presupposes is that you have
18 information to allow to relate the markers to the
19 clinical consequences and you know that that
20 relationship is not affected by the drug that
21 people are on because, in fact, that relationship
22 could differ by drug. So, it is a challenging
23 thing to do but I think that that is probably the
24 only way, really, to evaluate what the consequence
25 is going to be for the patient.
1 Other kinds of analyses that people might
2 do in this setting are quality of life. But,
3 because the surrogates that are being discussed
4 don't seem to have a direct clinical impact. At
5 least the acute rejection, from what I understood
6 did not. The creatinine, I am not so sure. It
7 wasn't discussed. Presumably not.
8 But, having some way to relate these
9 endpoints to their clinical effect on patients I
10 think is the only way to really address that
12 DR. ENGLUND: With that, I would--
13 DR. CAVAILLE-COLL: One moment please. I
14 would like to get as much as we can out of this
15 question 2. I know this is about the last time we
16 are going to hear recommendations as well as
17 clinical-study designs and endpoints.
18 This has been going on the past year at
19 different meetings organized by AST and ASTS. But
20 I would still like to, before we leave here, get
21 the panel's opinion about whether they believe or
22 not that bettering renal function is important in
23 clinical studies in renal transplantation and
24 should every effort be done to attain
25 intent-to-treat information on renal function in
1 patients who discontinue study drug, for example,
2 as well as patients who stay on study? This is for
3 future studies.
4 DR. SHAPIRO: Yes.
5 DR. ENGLUND: Yes.
6 [Chorus of yesses].
7 DR. ENGLUND: With that, I would like to,
8 once again, thank the committee, nonvoting guests.
9 I thank everyone for their participation. Thank
10 you for your presentation. And I adjourn this
12 [Whereupon, at 3:50 p.m., the meeting was
14 - - -