Prostate Cancer End Points Workshop
`June 21-22, 2004
`Bethesda Marriott - Bethesda, MD
`
`AGENDA
`
`Monday, June 21, 2004, AM
`
`
`
`Introductory Overview: End Points to Measure Therapeutic Efficacy in
`Prostate Cancer
`
`8:00 ! 8:20
`
`Regulatory Perspective
`
`8:20 ! 8:55
`
`Relevance of Prostate Cancer Clinical
`States to End Points and PSA End Point
`Application Methodologies
`
`Richard Pazdur
`
`Howard Scher
`
`8:55 ! 9:10
`
`Statistical Issues in the Validation of
`Surrogate Endpoints
`
`Stuart Baker
`
`9:10 ! 9:20
`
`Prostate Cancer Specific Mortality !
`Issues in its Use in Surrogate Validation
`
`Peter Albertsen
`
`9:20 ! 9:30
`
`Clarification Questions to Presenters
`
`
`
`9:30 ! 9:45 Bone Scan ! Issues in Application for
`Disease Assessment
`
`Steve Larson
`
`9:45 ! 9:55
`
`Bone Scan ! Application Experience in
`Clinical Trials
`
`Kevin Carroll
`
`9:55 ! 10:05
`
`Break
`
`
`
`10:05 ! 10:25 Patient Reported Outcomes
`
`Derek Raghavan
`
`10:25 ! 10:35 Clarification Questions to Presenters
`
`
`
`10:35 ! 11:40 Formal Questions for Discussion
`
`
`11:40 ! 12:10 Audience Questions
`
`12:10 ! 12:55 Lunch
`
`
`
`Discussion Leaders:
`Anthony D"Amico,
`Howard Scher &
`Peter Scardino
`
`
`
`
`
`dds/6-18-04
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`
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`

`Prostate Cancer End Points Workshop
`June 21-22, 2004
`Bethesda Marriott - Bethesda, MD
`
`AGENDA
`
`Monday, June 21, 2004, PM
`
`
`
`End Points for Clinical Trials in Primary Treatment
`(Neoadjuvant & Adjuvant) of M0 Disease & Hormone Sensitive M1 Disease
`
`12:55 ! 1:10 Hormone Sensitive Disease ! Regulatory
`End Point History of Approved Therapies
`
`George Benson or
`Donna Griebel
`
`1:10 ! 1:30
`
`Early disease: It!s Scope & Associated
`End Point Issues
`
`Peter Scardino
`
`1:30 ! 1:50
`
`Increasing PSA after Primary Treatment
`
`Anthony D"Amico
`
`1:50 ! 2:00
`
`Clarification Questions to Presenters
`
`
`
`2:00 ! 2:20
`
`Examination of End Points " Increasing
`PSA after Primary Treatment Including
`Adjuvant
`
`Howard Sandler
`
`2:20 ! 2:30
`
`Clarification Questions to Presenter
`
`
`
`2:30 ! 2:50
`
`Examination of End Points in the
`Adjuvant Casodex EPC Trials Experience
`
`Kevin Carroll
`
`2:50 ! 3:00
`
`Clarification Questions to Presenter
`
`3:00 ! 3:10
`
`Break
`
`
`
`
`
`3:10 ! 3:30
`
`Examination of End Points in Advanced
`Disease (D2) " Casodex Experience
`
`Laurence Collette
`
`3:30 ! 3:40
`
`Clarification Questions to Presenter
`
`
`
`3:40 ! 3:50
`
`Examination of End Points in the Primary
`Hormonal Treatment of Advanced
`Disease (D2) " SWOG Experience
`
`Cathy Tangen
`
`3:50 ! 4:00
`
`Clarification Questions to Presenter
`
`
`
`4:00 ! 5:15
`
`Formal Questions for Discussion
`
`
`Discussion Leaders:
`Mario Eisenberger,
`Barry Kramer, &
`Howard Sandler
`
`5:15 ! 5:45
`
`Audience Questions
`
`
`
`
`
`dds/6-18-04
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`
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`

`

`Prostate Cancer End Points Workshop
`June 21-22, 2004
`Bethesda Marriott - Bethesda, MD
`
`AGENDA
`
`
`
`Tuesday, June 22, 2004, AM
`
`Hormone Refractory Disease
`(M0 with PSA Rising Post Hormone Therapy and M1)
`
`8:00 ! 8:30
`
`Introductory Comments and Overview of
`Regulatory End Point History of Approved
`Therapies
`
`Bhupinder Mann
`
`8:30 ! 8:50
`
`End Points and Trial Design for
`Evaluating Second-Line Chemotherapy !
`Post Docetaxel
`
`Mario Eisenberger
`
`8:50 ! 9:00
`
`Clarification Questions to Presenter
`
`
`
`9:00 ! 9:20
`
`Examination of End Point Applications in
`the Abbott Atrasentan Trials
`
`Perry Nisen
`
`9:20 ! 9:40
`
`Examination of End Points in the Aventis
`Docetaxel Trial
`
`Martin Roessner
`
`9:40 ! 10:00
`
`Examination of End Points in the SWOG
`Docetaxel Trial
`
`Daniel Petrylak
`
`10:00 !10:20 Clarification Questions to Abbott, Aventis, &
`SWOG Presenters
`
`10:20!10:30
`
`Break
`
`10:30!12:15
`
`Formal Questions for Discussion
`
`
`
`
`
`
`Discussion Leaders:
`Steven George,
`Philip Kantoff, &
`Derek Raghavan
`
`
`
`
`
`
`
`
`
`12:15!12:45 Audience Questions
`
`12:45 ! 1:30
`
`Lunch
`
`1:30 ! 3:00
`
`Optional Discussion Period:
`Wrap-Up Topics of Remaining Interest
`from Workshop Days 1 and 2
`
`3:00
`
`Adjourn
`
`
`
`dds/6-18-04
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`
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`

`

`Prostate Cancer End Points Workshop
`June 21-22, 2004
`Bethesda Marriott - Bethesda, MD
`
`PANELISTS & SPEAKERS
`
`
`Peter C. Albertsen, MD
`Division of Urology
`University of Connecticut Health Center
`Farmington, CT 06030-3955
`Urol
`
`E. David Crawford, MD
`Prof. of Surgery & Radiation Oncology
`Head, Urologic Oncology
`Univ. of Colorado Hlth Sci Ctr
`Aurora, CO 80010
`Urol
`
`Anthony V. D’Amico, MD
`Chief, Genitourinary Radiation Oncology
`Assoc. Professor of Radiation Oncology
`Depts. of Cancer Onc and Rad Onc
`Brigham and Women’s Hospital
`Dana Farber Cancer Institute
`Boston, MA 02115
`Rad Onc
`
`Mario A. Eisenberger, MD
`Professor, Oncology & Urology
`Johns Hopkins Univ
`Baltimore, MD 21231
`Int Med, Med Onc
`
`Stephen L. George, PhD
`Dir., Biostatistics &Information Systems
`Duke University Medical Center
`Durham, NC 27710-0001
`Biostats/Epid
`
`Philip W. Kantoff, MD
`Chief, Division of Solid Tumor Oncology
`Dir of the Lank Ctr for GU Oncology
`Dana Farber Cancer Institute
`Dir, Prostate Cancer Prog. & Prostate
`Cancer SPORE at Dana Farber
`Harvard Cancer Center
`Professor of Medicine
`Harvard Medical School
`Boston, MA 02115-6013
`Med Onc
`
`Eugene Kazmierczak ! patient rep
`Sierra Vista, AZ 85650
`
`Eric A. Klein, MD
`Head, Section of Urologic Oncology
`Cleveland Clinic Foundation
`Cleveland, OH 44195
`Urol/Surg
`
`Barry Kramer, MD, MPH
`National Institutes of Health (NIH)
`Office of the Director
`Office of Disease Prevention
`Rockville, MD 20852
`Med Onc
`
`Alison Martin, MD
`National Cancer Institute (NCI), NIH
`Cancer Therapy Evaluation Program
`Rockville, MD 20892-7436
`Med Onc
`
`Judd Moul, MD
`Director, Dept of Defense
`Center for Prostate Disease Research
`Rockville, Maryland 20852
`Urol
`
`Derek Raghavan, MD, PhD, FACP (Co-chair)
`Chair & Director
`Cleveland Clinic Taussig Cancer Center
`Cleveland Clinic Foundation
`Cleveland, OH, 44195
`Med Onc/Hem
`
`Mack Roach III, MD, FACR
`Professor Rad Onc and Urology
`Vice Chair Radiation Oncology,
`Director of Clinical Research
`Department of Radiation Oncology
`UCSF Comprehensive Cancer Center
`San Francisco, CA 94143-1708
`Int Med, Med Onc, Rad Onc
`
`
`
`dds/6-18-04
`
`
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`

`

`Prostate Cancer End Points Workshop
`June 21-22, 2004
`Bethesda Marriott - Bethesda, MD
`
`PANELISTS & SPEAKERS
`
`Steven Hirschfeld, MD, PhD
`Division of Clinical Evaluation &
`Pharmacology/Toxicology, OCTGT,
`CBER
`
`
`Patricia Keegan, MD
`Division Director
`Division of Therapeutic Biological
`Oncology Products, CDER
`
`
`Bhupinder Mann, MBBS
`Medical Officer
`Division of Oncology Drug Products,
`CDER
`
`Richard Pazdur, MD (Co-chair)
`Division Director
`Division of Oncology Drug Products,
`CDER
`
`Daniel Shames, MD
`Division Director
`Division of Reproductive and Urologic
`Drug
`Products, CDER
`
`Rajeshwari Sridhara, PhD
`Acting Statistical Team Leader
`for Division of Oncology Drug Products,
`CDER
`
`
`Grant Williams, MD
`Deputy Director
`Division of Oncology Drug Products,
`CDER
`
`
`Howard M. Sandler, MD
`Clinical Div Dir and Residency Dir
`Assoc Prof, Dept of Rad Onc
`University of Michigan Medical Center
`Ann Arbor, MI 48109-0010
`Rad Onc
`
`Peter T. Scardino, MD
`Chairman, Dept. of Urology
`Mem. Sloan-Kettering Cancer Ctr.
`New York, NY 10021
`Urol/Surg
`
`Howard I. Scher, MD
`Chief, Genitourinary Oncology Service
`Sidney Kimmel Ctr for Prostate and
`Urologic Cancers
`Mem. Sloan-Kettering Cancer Ctr.
`New York, NY 10021-6094
`Med Onc, Int Med
`
`Siu-Long Yao, MD ! Industry Rep
`Aventis Pharmaceuticals, Inc.
`Clinical Onc
`Bridgewater, NJ 08807
`Med Onc, Hem, Int Med
`
`
`FDA Representatives:
`
`George Benson, MD
`Urology Team Leader
`Division of Reproductive and Urologic
`Drug Products, CDER
`
`
`Susan Ellenberg, PhD
`Director
`Office of Biostatistics and Epidemiology,
`CBER
`
`
`Donna Griebel, MD
`Deputy Director
`Division of Reproductive and Urologic
`Drug Products, CDER
`
`
`
`dds/6-18-04
`
`
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`

`

`Prostate Cancer End Points Workshop
`June 21-22, 2004
`Bethesda Marriott - Bethesda, MD
`
`PANELISTS & SPEAKERS
`
`
`
`Speakers*
`(not on the Panel)
`
`
`Daniel P. Petrylak, MD
`Assoc Prof of Med, Presbyterian Hosp
`Director of GU Oncology Program
`Columbia Presbyterian Medical Center
`New York, NY 10032
`(AM: TUESDAY, JUNE 22; Presenter #5)
`
`Martin Roessner, MS
`Head of Statistics, Oncology
`Aventis
`Bridgewater, NJ 08807
`(AM: TUESDAY, JUNE 22; Presenter #4)
`
`Cathy Tangen, DrPH
`SWOG Statistical Center
`Fred Hutchinson Cancer Research Ctr
`Seattle, WA 98109-1024
`(PM: MONDAY, JUNE 21; Presenter #8)
`
`==============================
`
`Science Writer: Eleanor Mayfield
`
`
`
`Stuart Baker, ScD
`Mathematical Statistician
`NIH / NCI / Div of Cancer Prevention
`Biometry Research Group
`Bethesda, MD 20892-7354
`(AM: MONDAY, JUNE 21; Presenter #3)
`
`Kevin Carroll
`Global Statistical Leader, AZ Oncology
`AstraZeneca
`Alderley Park
`Macclesfield, UK
`(AM: MONDAY, JUNE 21; Presenter #6)
`(PM: MONDAY, JUNE 21; Presenter #6)
`
`Laurence Collette, MSc
`Biostatistician & Coordinator for External
`Research Project
`European Organisation for Research
`and Treatment of Cancer (EORTC)
`Brussels, Belgium
`(PM: MONDAY, JUNE 21; Presenter #2)
`(PM: MONDAY, JUNE 21; Presenter #7)
`
`Steven M. Larson, MD, PhD
`Chief, Nuclear Medicine Service
`Department of Radiology
`Memorial Sloan Kettering Cancer Ctr
`New York, NY 10021
`(AM: MONDAY, JUNE 21; Presenter #5)
`
`Perry Nisen, MD, PhD
`Divisional Vice President
`Global Oncology Development
`Abbott Laboratories
`Abbott Park, IL 60064-6145
`(AM: TUESDAY, JUNE 22; Presenter #3)
`
`
`
`*see Workshop Agenda for complete speaker list
`
`dds/6-18-04
`
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`

`

`Prostate Cancer End Points Workshop
`June 21-22, 2004
`Bethesda Marriott - Bethesda, MD
`
`Questions for Discussion
`
`
`
`Monday, June 21, 2004, AM
`
`
`The first session: Bone scan and PSA
`
`Explore questions regarding these modalities. For instance:
`
`Bone Scan
`
`as components of an end point?
`
`(cid:120) What are the pros and cons with using bone scan findings
`(cid:120) What are the recommended end point definitions using bone
`
`scan for:
`
`-Recurrence?
`
`-Response?
`
`-Progression?
`
`(cid:120) When must bone scan findings be verified by other clinical
`(cid:120) What is the optimal scheduling for bone scan follow-up?
`(cid:120) Do PSA findings help with interpretation of bone scan
`
`investigations?
`
`findings?
`
`
`PSA
`
`(cid:120) What are the pros and cons with using PSA, and/or its
`
`time-dependant derivatives, as an end point to
`demonstrate drug effectiveness?
`
`(cid:120) What are PSA end points that are worthy of consideration
`
`for use in oncology trials?
`
`For:
`
`-Recurrence?
`
`-Response?
`
`-Progression?
`
`validated in any setting?
`
`(cid:120) Should any of the PSA end points be considered as
`(cid:120)
`
`If not, what studies or what data are needed to validate
`PSA as an end point in various settings?
`
`Discussion Leader
`
`Anthony D!Amico
`
`Howard Scher
`
`Peter Scardino
`
`Anthony D!Amico
`
`Howard Scher
`
`Peter Scardino
`
`Anthony D!Amico
`
`Howard Scher
`
`Peter Scardino
`
`dds/6-18-04
`
`
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`

`

`Prostate Cancer End Points Workshop
`June 21-22, 2004
`Bethesda Marriott - Bethesda, MD
`
`Questions for Discussion
`
`
`Other End Points
`
`(cid:120)
`
`Is the state of the art of assessing patient-reported
`outcomes sufficiently developed to make it a major
`parameter in assessment of new agents for prostate
`cancer?
`
`
`Monday, June 21, 2004, PM
`
`
`The second session: Early Disease
`
`(cid:120) How should DFS be defined using existing modalities?
`(cid:120)
`(cid:120)
`(cid:120)
`
`Discussion Leader
`
`Anthony D!Amico
`
`Mario Eisenberger
`
`Barry Kramer
`
`Howard Sandler
`
`Barry Kramer
`
`Derek Raghavan
`
`Steven George
`
`Philip Kantoff
`
`Derek Raghavan
`
`Is the DFS definition different for adjuvant therapy post
`surgery versus adjuvant therapy post radiation therapy
`
`Is DFS a surrogate for survival in any setting?
`
`Is DFS a sufficient end point for drug approval in any
`setting?
`
`
`
`Tuesday, June 22, 2004, AM
`
`
`The third session: Advanced Disease
`
` (cid:120) How do you define response and PFS?
`
`
`
`
`-role of bone scan
`-role of PSA, and/or its time-dependant derivatives
`
`(cid:120) How do you deal with dropouts due to PSA?
`(cid:120) Are symptom end points useful?
`
`-Is time to symptomatic progression a practical end point?
`
`(cid:120) Are composite end points useful (e.g. skeletal-related
`
`events)?
`
`
`
`dds/6-18-04
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`

`

`FDA Public Workshop on Clinical Trial Endpoints in Prostate Cancer
`
`1
`
`FDA Public Workshop on Clinical Trial Endpoints in Prostate Cancer
`
`June 21-22, 2004 (cid:16) Bethesda, Maryland
`Monday, June 21 (cid:16) Morning session
`
`Summary
`
`INTRODUCTORY OVERVIEW: ENDPOINTS TO MEASURE THERAPEUTIC
`EFFICACY IN PROSTATE CANCER
`
`Dr. Pazdur welcomed everyone in attendance and noted that the purpose of this meeting
`was to have a wide-ranging discussion about the positive and negative aspects of various
`endpoints for trials of drugs to treat prostate cancer. This workshop is the third in a series
`evaluating potential endpoints for drug approvals in the most common cancers. Previous
`workshops have considered endpoints in lung cancer and colon cancer. Issues highlighted
`at these workshops are subsequently discussed at meetings of the Oncology Drugs
`Advisory Committee (ODAC), the FDA(cid:127)s statutory advisory body on issues related to
`oncology drugs. By statute, FDA can take advice related to oncologic drugs only from
`ODAC.
`
`Dr. Pazdur noted that time had been allocated on the agenda specifically for questions
`and comments from the audience. He encouraged those in attendance to make their views
`known or to contact him via email after the workshop.
`
`The meeting began with a presentation by Dr. Pazdur on the regulatory background to the
`issue of endpoints in trials of cancer drugs. The panel then heard presentations on specific
`issues relating to endpoints for drug approvals in the prostate cancer setting. Members of
`the panel then discussed the issues raised by the speakers and offered a wide range of
`viewpoints.
`
`Regulatory Background (Richard Pazdur, MD, FDA)
`
`Dr. Pazdur reviewed the regulatory process by which the FDA makes drug approval
`decisions. Drug approval in the United States requires adequate and well-controlled
`studies demonstrating that a drug is both safe and effective for the indication for which
`approval is sought. The safety requirement comes from the Federal Food, Drug, and
`Cosmetic Act of 1938; the efficacy requirement from a 1962 amendment to that Act.
`
`There are two routes to new drug approval. The traditional route(cid:650)regular approval, also
`called full approval(cid:650)requires the demonstration of either clinical benefit or an effect on
`an established surrogate for clinical benefit. Clinical benefit is usually considered to be
`tangible benefit of obvious worth to the patient, such as prolongation of survival, relief of
`pain, or measurable improvement in tumor-related symptoms. FDA has interpreted the
`1962 amendment to require, in most cases, at least two trials for drug approval.
`
`FDA has sometimes accepted surrogates for clinical benefit as the basis for regular
`approval, usually after much clinical experience with the surrogate and widespread
`acceptance of it by both patients and physicians. For example, reductions in blood
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`MYLAN PHARMS. INC. EXHIBIT 1125 PAGE 9
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`

`pressure and cholesterol are accepted surrogates for clinical benefit in the heart disease
`setting. On occasion, however, assumptions of clinical benefit based on a surrogate have
`later been proven wrong.
`
`The second route to drug approval is accelerated approval (AA), which can be based on a
`surrogate endpoint that is considered reasonably likely to predict clinical benefit,
`provided that post-marketing clinical trials are conducted to substantiate the purported
`benefit. AA is discussed at greater length below.
`
` A
`
` basic dilemma in oncology drug development is that of marginal activity accompanied
`by high toxicity. To generate confidence that a drug is producing a true treatment effect,
`subjective bias must be minimized. Blinding of oncology trials is difficult because drugs
`are often given on different schedules and produce different toxicities; in addition,
`patients are often reluctant to enter a blinded trial. In the absence of blinding, FDA
`considers it important to have trial endpoints that minimize the opportunity for subjective
`interpretation of results by the investigator.
`
`The presence of a true treatment effect can be substantiated by the magnitude of the
`statistical significance of the finding; by the internal consistency of results in subgroups;
`and by consistency among secondary endpoints (e.g., an improvement in survival
`accompanied by an increased response rate and/or a longer time to disease progression).
`External substantiation (e.g., duplication of results in a second trial) provides additional
`confirmation that a true treatment effect exists.
`
`Surrogate Endpoints
`
`FDA has defined a surrogate endpoint as !a measurement or sign used as a substitute for
`a clinically meaningful endpoint that measures directly how a patient feels, functions, or
`survives. Therapeutic changes on a surrogate are expected to change the clinical
`endpoint." It is important to note that a correlate is not necessarily a surrogate. The
`Prentice criteria for a surrogate endpoint require not only that a surrogate endpoint be
`correlated with the clinical outcome, but also that the surrogate endpoint fully capture the
`net effect of treatment on the clinical outcome.
`
`Meta-analyses of clinical trials data can contribute to the validation of surrogate
`endpoints. However, the most important aspect of validation of a surrogate endpoint is
`gaining a comprehensive understanding of the causal pathways of the disease process and
`of the intervention(cid:129)s intended and unintended mechanisms of action.
`
`FDA has been relatively liberal in its acceptance of surrogate endpoints for drug
`approvals. Although there are few established surrogates for clinical benefit in oncology,
`in consultation with ODAC the agency has accepted response rate and time to
`progression (TTP) as surrogate endpoints in regular approvals of hormonal agents to treat
`breast cancer. Complete response rates have been accepted as established surrogates for
`agents to treat leukemias.
`
`With increasing frequency, FDA is accepting surrogates that are reasonably likely to
`predict clinical benefit as the basis for AA. For example, a 10% response rate in
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`MYLAN PHARMS. INC. EXHIBIT 1125 PAGE 10
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`

`

`refractory lung cancer was the basis for AA of gefitinib (Iressa); a partial response rate in
`refractory multiple myeloma was the basis for AA of bortezomib (Velcade).
`
`Unproven surrogates are those that are used for exploratory or hypothesis-generating
`purposes. With more data, an unproven surrogate can become a surrogate that is
`reasonably likely to predict clinical benefit. Similarly, as confirmatory studies uphold the
`validity of surrogates now regarded as reasonably likely to predict clinical benefit, these
`endpoints can attain the status of established surrogates.
`
`Although it is widely believed that FDA will accept only overall survival as an endpoint
`for drug approval, a recent analysis of drugs approved since 1990 showed that survival
`was the approval endpoint in a minority of approvals; 73% (48/66) of all approvals were
`not based on survival. When AAs were excluded, 67% (37/55) of all approvals were not
`based on survival (Johnson et al. J Clin Oncol 2003;21(7):1404-1411).
`
`Improvement in tumor-related symptoms has been the basis for approval of a number of
`oncology drugs.
`
`metastases on the basis of improvement in patients’ bone pain.
`
` (cid:120) Mitoxantrone was approved for use in patients with symptomatic prostate cancer
`(cid:120) Approvals of two bisphosphonate drugs (pamidronate and zoledronate) were based on
`(cid:120)
`
`a composite bone-morbidity endpoint (skeletal-related events).
`In several clinical settings, tumor-related symptoms plus objective tumor responses
`provided mutually supportive evidence that led to drug approval. In diseases with
`cutaneous manifestations, such as Kaposi’s sarcoma and cutaneous T-cell lymphoma,
`improvements in cosmesis, cutaneous signs, and cutaneous symptoms have provided
`such evidence.
`In cancers obstructing esophageal or bronchial passages, approvals have been based
`on both improvement in symptoms of lumenal obstruction and objective responses of
`intralumenal tumors. Such evidence supported the approval of photodynamic therapy
`for the palliation of obstructing esophageal and endobronchial cancers.
`
`(cid:120)
`
`
`Accelerated Approval
`
`AA can be granted for drugs that treat serious or life-threatening diseases when the new
`drug appears to provide benefit over available therapy. AA can be granted on the basis of
`a surrogate endpoint that is reasonably likely to predict clinical benefit. After receiving
`AA, the applicant is required to perform a post-marketing study to confirm that treatment
`with the drug does indeed provide clinical benefit.
`
`It is important to note that the quality and amount of evidence required for AA is not
`different than that required for regular approval. The applicant must show substantial
`evidence of the measured effect from well-controlled clinical trials. Borderline evidence
`is not acceptable. The difference is that the evidence may focus on a surrogate endpoint
`that is only reasonably likely to predict benefit rather than on an accepted clinical benefit
`endpoint.
`
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`MYLAN PHARMS. INC. EXHIBIT 1125 PAGE 11
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`

`Survival vs. TTP: Pros and Cons
`
`FDA is keenly aware of the pros and cons of survival vs. TTP as trial endpoints. Unlike
`TTP, survival is 100% accurate and its importance is unquestioned. However, trials that
`use survival as their endpoint take longer to perform and must enroll larger numbers of
`patients. In addition, the true survival effect of a treatment may be obscured by secondary
`treatment and crossover.
`
`However, the use of TTP as a trial endpoint presents several challenging study design
`issues. TTP is a difficult endpoint to measure; meticulous care must be taken
`prospectively to ensure that a TTP endpoint has validity. When possible, trials should be
`blinded. Tumor assessments must be symmetrical on all study arms. Tumor progression
`must be prospectively defined and prospective methods must be in place for handling
`missing data. If progression is to be determined radiographically, independent radiology
`review plays a key role in the analysis and interpretation of trial results. Review of
`radiographic progression by blinded radiology panels provide credence to the endpoint.
`
`The clinical significance of TTP must also be considered. If a trial is powered to detect a
`difference in overall survival, a relatively trivial improvement in TTP (e.g., 10 days, 2
`weeks) may be statistically significant although its clinical significance is questionable.
`On the other hand, smaller studies powered to detect only improvement in TTP are likely
`to be underpowered to detect a difference in survival. Asymmetric assessments and
`missing data can call into question the reliability and precision of a claimed improvement
`in TTP. Another issue that continues to be debated is whether a delay in TTP is itself a
`clinical benefit to the patient or a surrogate for clinical benefit.
`
`Response Rate
`
`Response rate is a unique endpoint in that the treatment is entirely responsible for any
`observed reduction in tumor size. By contrast, the endpoints of survival and TTP
`comprise in part the effect of the disease(cid:127)s natural history as well as any observed effect
`of treatment. However, the duration and magnitude of the response must also be
`considered. Measurement of response rate excludes patients whose disease is stable or
`whose level of response does not meet the threshold to be considered a partial response.
`
`Several methods exist for measuring response rate. FDA is less concerned with which
`method is used than with whether a single method is adopted and uniformly applied.
`
`Palliation and Patient-Reported Outcomes
`
`The credibility of palliation and patient-reported outcomes as endpoints is enhanced
`when trials are blinded. FDA has advised sponsors to use simple, hypothesis-driven
`instruments to measure these endpoints and to avoid the use of multiple endpoints.
`Because many patients enter clinical trials without symptoms, it can be difficult to
`measure palliation and delay in symptom development.
`
`The use of these endpoints has been most successful in diseases in which symptoms are
`the hallmark of the disease"for example, bone pain in advanced prostate cancer (the
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`basis for the approval of mitoxantrone), dysphagia in esophageal cancer (the basis for the
`approval of photodynamic therapy).
`
`FDA is interested in health-related quality of life (QOL) as a potential trial endpoint
`because it captures the patient(cid:127)s perspective on the success of treatment. However, the
`design of trials based on this endpoint poses many challenges. The interpretation of
`results is complicated by lack of blinding, missing data, and multiple endpoints. The
`clinical significance of small changes in QOL scores is often unclear. Also unclear is
`whether the use of QOL as an endpoint provides additional information or simply a more
`systematic recording of toxicity and symptom data.
`
`Conclusion
`
`Regulatory decision-making is a two-stage process. In stage one, the question to be
`answered is whether the drug has a convincing effect, which can be adequately
`characterized, on an endpoint. In stage two, the question is whether the observed effect is
`clinically relevant. This second question can only be asked if the first question is
`answered in the affirmative. One cannot discuss the clinical relevance of an uncertain or
`poorly characterized finding.
`
`Relevance of Prostate Cancer Clinical States to Endpoints and PSA Endpoint
`Application Methodologies For Prostate Cancer (Howard I. Scher, MD)
`
`The management of prostate cancer differs in several ways from the management of other
`malignancies, said Dr. Scher. In prostate cancer, unlike other tumors, the untreated
`history of the disease can span 10 years or more; treatment is often deferred at diagnosis,
`at recurrence, or at relapse; slowing tumor growth may be equivalent to curing the
`disease; and comorbidities produce a high risk of non(cid:127)prostate-cancer death.
`
`At initial presentation patients are classified using the Tumor Node Metastasis (TNM)
`staging system. However, TNM staging is only relevant to the untreated patient and does
`not inform trial designs for the patient for whom initial therapy has failed. The clinical
`states model was developed to address the shortcomings of the TNM staging system. The
`advantages of using this model are that it describes patients at any point in the disease
`continuum, is applicable to both treated and untreated patients, and provides a framework
`in which specific issues related to clinical trial design can be addressed.
`
`The clinical states model that Dr. Scher and his colleagues have proposed begins by
`considering the patient who presents for a prostate cancer evaluation. Most patients today
`who undergo biopsies have clinically localized disease. If the disease recurs following
`local treatment, the sole manifestation of recurrence may be a rising PSA level.
`Detectable metastatic disease is differentiated on the basis of its sensitivity to hormonal
`therapy and on the presence or absence of castrate levels of testosterone in the patient(cid:129)s
`blood.
`
`The model is applied clinically by considering at each patient encounter the
`manifestations of disease at that point in time and the probability that an asymptomatic
`patient will experience a clinically significant event within a given time frame; offering
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`appropriate therapy to eliminate clearcut manifestations of disease or to prevent the
`occurrence of clinically significant events; and/or deferring treatment if the probability of
`clinically significant events is low.
`
`Applying the clinical states model to prostate cancer clinical trials, the critical questions
`are: (1) What is the objective? (2) What are the disease manifestations of the patient
`group (state) that will receive the intervention? (3) What change in those disease
`manifestations will be used to assess treatment effects? and (4) How will it be determined
`whether or not the intervention achieved a clinical benefit?
`
`Objectives will vary according to the patient(cid:127)s clinical state. For the patient who initially
`presents with a high risk for prostate cancer, the clinical objective is prevention. For the
`patient with localized disease, the objective is to determine whether the disease is
`indolent and treatment can be deferred, whether local therapy alone is likely to achieve a
`cure, or whether a combined therapeutic approach is needed because the patient is at high
`risk for developing metastatic disease. For the patient with a rising PSA, the objective is
`to prevent metastasis. For patients with metastases, the objective may be to eliminate
`symptoms, prevent future symptoms, or prevent death from prostate cancer.
`
`Irrespective of clinical state, assessments should be quantitative and reproducible.
`Outcome measures, like objectives, vary with clinical state; appropriate outcome
`measures when rising PSA is the sole manifestation of disease are very different from
`those that are appropriate when the patient has symptomatic metastases. Outcomes for
`each disease manifestation should be reported separately and should include both the
`proportion of patients showing the outcome (degree and proportion) and the durability of
`the outcome. Global categorizations such as complete response, partial response, or stable
`disease, which vary by disease manifestation and disease state, should be avoided.
`
`PSA Endpoint Application Methodologies
`
`PSA-based endpoints were originally proposed because of the difficulties involved in
`assessing outcomes by means of bone scans. Determinations of PSA level are both
`reproducible and quantitative. Natural history studies have shown that, across the disease
`continuum, rising PSA values precede other manifestations of progression. The use of
`PSA-based endpoints expands the opportunity for trial participation beyond the subset of
`patients who have measurable disease. Because changes in PSA levels can be monitored
`quickly, PSA-based endpoints may accelerate both the development of promising agents
`and the discontinuation of inactive ones. The central issue with regard to post-therapy
`PSA changes is whether the endpoint that is used relates to a specific biologic effect on
`the tumor.
`
`Of the drugs currently approved for treatment of clinical metastases in castrate disease,
`none was approved solely on the basis of tumor regression or PSA endpoints. Androgen
`ablation, bisphosphonates, bone-seeking radiopharmaceuticals, and
`mitoxantrone/prednisone chemotherapy were approved on the basis of symptomatic relief
`with no improvement in survival. Bone-seeking radioisotopes and bisphosphonates have
`been shown to delay or prevent
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`symptoms. Agents such as GnRH analogs, anti-androgens, bicalutamide, and
`bisphosphonates have been approved based on reduced toxicities. The first agent to show
`a survival benefit in this disease state, docetaxel used in combination with prednisone,
`was approved in May 2004.
`
`The fact that such a range of endpoints have been found to provide clinical benefit in one
`disease state illustrates that different criteria for approval decisions are necessary
`depending on the relevant disease state, the question being addressed, the type of drug,
`and the drug(cid:127)s mechanism of action. No decision criterion can stand alone; all
`manifestations of disease must be monitored concurrentl