ESA 101 Erythropoietin Stimulating Agents for Novices

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ESA 101Erythropoietin Stimulating Agents for
Novices
November 15 2007 Marti Nelson Cancer Foundation
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Primary resources

• FDA Briefing information
• Document http//www.fda.gov/ohrms/dockets/ac/07/b
  riefing/2007-4301b2-02-FDA.pdf
• Errata http//www.fda.gov/ohrms/dockets/ac/07/bri
  efing/2007-4301b2-02-01-FDA-Errata-2-Bckgrnd-ESA.h
  tm
• Slides http//www.fda.gov/ohrms/dockets/ac/07/sli
  des/2007-4301s2-07-FDA-Juneja.ppt
• All meeting material for May 10 2007 meeting
  available at http//www.fda.gov/ohrms/dockets/ac/
  cder07.htmOncologicDrugs

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Erythropoietin Definition

• EPO (erythropoietin) is a hormone (a type of
  protein) produced by specialized cells in the
  kidneys. These cells are sensitive to the oxygen
  concentration in the blood, and increase the
  release of EPO when the oxygen concentration is
  low.
• Since oxygen is carried by red blood cells, too
  few red blood cells (anemia) will result in
  erythropoietin release. EPO acts on stem cells in
  the bone marrow to increase the production of red
  blood cells.
• http//www.nlm.nih.gov/medlineplus/ency/article/00
  3683.htm

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ESA names
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ESA Approval Timeline
This is not complete see FDA briefing for
complete list of FDA actions
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Overview of the issue

• Since the first approval of an ESA for treatment
  of chemotherapy-associated anemia in 1993, data
  continue to accumulate regarding the increased
  risks of mortality and of possible tumor
  promotion from the use of ESAs.
• As of March 2007, increased mortality has been
  observed when ESA treatment strategies were
  designed to achieve and maintain hemoglobin
  levels above 12 g/dL.

FDA briefing document
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And the bottom line

• While the risks of treatment strategies in which
  ESAs are used to achieve and maintain hemoglobin
  levels in excess of that needed to avoid
  transfusions have been clearly demonstrated to be
  unacceptable, there are insufficient data from
  adequate and well controlled studies designed to
  assess effects on survival or tumor promotion
  employing the recommended doses of ESAs.

FDA briefing document
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In other words

• We know that risks outweigh benefits when ESAs
  are used at higher doses
• We do NOT know if benefits outweigh risks when
  ESAs are used at approved doses

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Benefits of ESAs

• Clinical benefits of ESAs were demonstrated in
  anemic pts receiving chemo who were able to avoid
  RBC (red blood cell) transfusions their
  concomitant risks
• Use of ESAs reduced proportion of pts receiving
  RBC transfusions their concomitant risks

FDA slide 16
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Effects of ESAs

• Improved QOL, fatigue, and other symptoms
  associated with anemia NOT established in
  properly conducted, randomized, double-blind,
  placebo-controlled trials.
• Improved survival or improved tumor control NOT
  established

FDA slide 22 QOL Quality of Life
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Risks of ESAs

• Increased thrombovascular events (TVEs)
• Increased Morbidity, Potential Increased
  Mortality
• Decreased Survival
• Increased Tumor Promotion
• Decreased Locoregional Control
• Decreased Progression-Free Survival?

FDA slide 23
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Concern raised in 1993

• At the time of approval for treatment of anemia
  associated with cancer chemotherapy, the FDA
  noted that Procrit could potentially serve as a
  growth factor for malignant tumors.

FDA briefing document
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Concern not resolved by 2007

• Im concerned that this compound is a stimulant,
  a tumor fertilizer, for epidermal tumors. Im
  interested in squamous-cell cancer of the lung as
  well as squamous-cell cancer of the head and
  neck. Im also interested in adenocarcinoma of
  the lung, since we have seen adenocarcinoma
  breast data.
• Otis Brawley, MD
• ODAC member
• May 10 2007 ODAC meeting

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Amgen post-marketing commitment in 1993

• Because of this concern, Amgen agreed to conduct
  a study (N93-004), which was designed to rule out
  a detrimental effect of Procrit on the response
  rate in patients with limited or extensive stage
  small cell lung cancer.

FDA briefing doc
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Study N93-004 (SCLC)

• ORR was determined w/o central review of images
• 17 of patients had missing tumor response data
• Confirming ORR by repeat imaging was not required
  
• ORR not a sensitive detection method for tumor
  promotion

FDA slide 35
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In other words

• Results from N93-004 were inconclusive on the
  issue of tumor promotion

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2 other trials added to concerns

• BEST (Stg IV Breast Ca) ? survival for pts on
  ESA arm
• ENHANCE (Head/Neck Ca) ? survival ?
  locoregional control for pts on ESA arm

FDA slide 42
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Concerns culminated in 2004 ODAC
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ODAC 2004 Recommendations

• Double Blind, Placebo-Controlled Trials
• Preferred Primary Endpoint Survival
• Adequately powered trials to detect survival
  differences
• Routine Assessment of Tumor Progression
• Homogeneous Tumor Type
• Tumor biopsies to assess for EPO receptors was
  optional
• Studies conducted outside of US would be
  generalizable to the US cancer population
• Assessment of TVEs should be prospectively
  defined endpoint.
• Case report forms should be designed to capture
  clinically symptomatic TVEs.
• TVEs should be assessed at prespecified intervals.

FDA slide 45 TVE thrombovascular event
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At 2004 ODAC

• Amgen and JJ presented studies which were
  initiated and accruing at the time of the May
  2004 ODAC meeting (see following slides).
  Therefore FDA did not have the opportunity to
  modify the protocols nor to ensure that each
  study contained the study design elements that
  were recommended by the ODAC. FDA did provide
  comment on an additional study EPOANE 3010, which
  was proposed by Johnson Johnson.

Adapted from briefing document
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(No Transcript)
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(No Transcript)
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From 2004 2007, trials mentioned at the 2004
ODAC meeting
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Summary (as of May 2007)

• 12 studies presented at ODAC 2004 by JJ and
  Amgen as capable of addressing ESA tumor
  promotion risks.
• 10 of these 12 studies are not adequately
  designed with respect to ODAC 04s
  recommendations
• (FDA slide 83)
• In other words
• When ESAs are used as prescribed on the label, we
  still dont know
• If the risk of thrombovascular events outweigh
  the benefit of not getting a transfusion
• If overall survival is decreased by use of ESAs
• If ESAs promote tumor growth

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Summary (as of May 2007)

• Primary data from 5 completed epoetin studies
  with no reported safety signals not submitted to
  FDA.
• These studies finished accrual as long as 6 years
  ago
• (FDA slide 83)
• In other words
• Some data exists which may shed light on this
  however, the sponsors do not have control of all
  the data. Thus FDA does not currently have
  access to the primary data. The sponsors (Amgen,
  JJ) are working to get the data to FDA.

FDA slide 83
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Note the arrowed trials are the trials for
which FDA was unable to get data prior to the May
2007 ODAC.
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Primary Data vs Summary Result

• Primary Data database from clinical trial with
  efficacy data (i.e. OS, RR), safety data (i.e.
  TVE), all data captured on CRFs submitted to
  FDA
• FDA independently analyzes database/verifies
  result
• Summary Result descriptive data analyzed by
  investigators submitted to FDA
• Examples journal abstract/ publication/ report
• FDA cannot perform independent analysis cannot
  verify results
• FDA cannot detect flaws in data

FDA slide 29
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Status of Data

• Per query of FDA, data is now coming forward.
• Per presentation on May 9 by JJ, there are
  specific commitments on trials (see next slide)

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Status of ongoing research per JJ slide
presentation May 2007 http//www.fda.gov/ohrms/doc
kets/ac/07/slides/2007-4301s2-05-Amgen-Zukiwski.pp
t326,5,Slide 5
Primary data not available to FDA per slide 83 /
FDA
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Conclusions (from May 2007)

• Efficacy of ESAs ? RBC transfusions
• Post-approval studies ? OS, ? locoregional
  control, ? TVE risk
• ESAs do NOT ? survival, and may ? tumor growth
• Since 1993 ? RBC transfusion infectious risk vs
  ? ESA risk
• Reconsideration of riskbenefit ratio of ESAs
• No completed or ongoing trial has addressed
  safety issues of ESAs in cancer pts w/chemo
  associated anemia using currently approved dosing
  regimens in a generalizable tumor type

FDA slide 84
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July 2007 CMS Action

• National Coverage Decision
• Limits reimbursement of ESAs
• Reimburse only if starting HgB
• See decision memo for additional limitations of
  ESA use
• http//www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id
  203

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Amgen response

• Legislation introduced which asks CMS to revisit
  the National Coverage Decision
• House Joint Resolution 54
• Senate Joint Resolution 22
• Sense of the Senate Resolution 305
• Pharmacovigilence Program announced 10/2007
• Trials to be defined

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FDA Label Update 11-8-2007

• No use of ESAs when HgB 12
• Use minimum ESA possible to increase HgB
• Clear statement that data does not exist which
  shows ESAs are safe when HgB levels are between
  10 and 12.
• Clear language about consistent safety trends
  across 6 studies (see next slide for table
  contained in label)

http//www.fda.gov/cder/foi/label/2007/103234s5158
lbl.pdf
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Text from FDA Label for ESAs
http//www.fda.gov/cder/foi/label/2007/103234s5158
lbl.pdf
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FDA Patient Info 11-8-2007

• Cancer patients
• You may have an increased chance of dying sooner
  or your tumor (cancer) may grow faster if you
  take this drug.
• Your doctor should use the lowest dose of
  PROCRIT needed to help youavoid red blood cell
  transfusions.
• Once you have completed your chemotherapy course,
  PROCRIT treatment should be stopped.
• All patients
• PROCRIT treatment increases your chance of a
  blood clot. If you are scheduled for surgery,
  your doctor may prescribe a blood thinner to
  prevent blood clots.

http//www.fda.gov/cder/foi/label/2007/103234s5158
ppi.pdf
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Issue FDA and CMS appear to be in conflict

• CMS wont reimburse unless starting Hg
• FDA says use minimum dose possible to get Hg no
  higher than 12