Summary of Proceedings: FDA Transmissible Spongiform Encephalopathies Advisory Committee 17th Meeting 08 February 2005

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Summary of ProceedingsFDA Transmissible
Spongiform EncephalopathiesAdvisory
Committee17th Meeting 08 February 2005

• FDA Blood Products Advisory Committee
• 82nd Meeting
• 17 March 2005
• Gaithersburg MD
• David M. Asher, MD
• ltasher_at_cber.fda.govgt
• Laboratory of Bacterial, Parasitic and
  Unconventional Agents
• Division of Emerging Transfusion-Transmitted
  Diseases
• Office of Blood Research Review
• Center for Biologics Evaluation Research
• US Food Drug Administration

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• Worldwide BSE update (Lisa Ferguson, APHIS, USDA)
• UK notifications of recipients plasma
  derivatives re possible vCJD risk (Kate Soldan,
  Anna Molesworth, UK CJD Incidents Panel) TSEs
  and surgical instrument decontamination (Lynn
  Sehulster, CDC)
• Developing a risk assessment model and initial
  risk estimates for exposure to agent of variant
  Creutzfeldt-Jakob disease (vCJD) via
  investigational use of UK factor XI in USA (Mark
  Weinstein, Dorothy Scott, Steven Anderson, FDA)
• Developing risk assessment models for exposure to
  vCJD agent via other coagulation factors (Steven
  Anderson, FDA)
• vCJD in France (Jean-Philippe Brandel,
  EpidemioSurveillanceNetwork, Paris presented in
  absentia and revised by Pedro Piccardo and Steven
  Anderson, FDA) and UK (Sheila Bird, MRC Biostat
  Unit, Inst of Public Health, Cambridge)
• Possible deferral of blood and plasma donors with
  history of prior transfusion in European
  countries besides UK (Alan Williams, FDA
• --------------------------------------------------
  --------------
• Decisional issues

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Cases of BSE Registered in Great Britain through
1999 (DEFRA)
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23 Countries with BSE in Native Cattleyr first
reported approx. total cases reported to OIE
thro 28 Feb 2005

• UK 1986 (gt183 000) 1202 01 1144 02 612 03
  338 04
• Ireland 1989 (1489)
• Switzerland 1990 (519)
• France 1991 (945)
• Portugal 1994 (950)
• Belgium 1997 (129)
• Netherlands 1997 (77)
• Luxembourg 1997 (2)
• Liechtenstein 1998 (2)
• Denmark 2000 (13)
• Germany 2000 (357)

• Spain 2000 (519)
• Italy 2000 (124)
• Greece 2001 (1)
• Czech Repub 2001 (15)
• Slovakia 2001 (15)
• Japan 2001 (15)
• Slovenia 2001 (5)
• Finland 2001 (1)
• Austria 2001 (1)
• Poland 2002 (22)
• Israel 2002 (1)
• Canada 2003 (1 ex UK4)
• USA 2003 (1 ex Canada)

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Total Reported UK Exports of MBM 1986
1995(unconfirmed review by UK authorities of
export records)
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Unique Pathology of vCJD (Chazot G al. Lancet
19963471181. Will RG al. Lancet
1996347921-5. Hill AF al. Lancet
1999353183-9)
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Variant CJD Reasons for Greater FDA
Concernabout Potential Infectivity of Blood

• Lymphoid tissues of patients with vCJD contain
  much more protease-resistant prion protein than
  do those of patients with conventional forms of
  CJD. Infectivity of those tissues is not yet
  clear. (Note Lymphoid tissues of some patients
  with conventional sporadic CJD sCJD have been
  infectious for non-human primates Brown P et al.
  Ann Neurol 199435513.)
• Implication Blood, containing lymphoid cells,
  might be more infectious in vCJD than in
  classical forms of CJD.
• vCJD differs markedly from sCJD distribution of
  infectivity in patients with sCJD might not be
  predictive for vCJD.
• vCJD is a new emerging disease not found in the
  USA except in one long-time UK resident.
• Actions of UK authorities implied lack of
  confidence in safety of blood of UK donors.
• --------------------------------------------------
  --------------------------
• Two cases of probable TT vCJD

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Final Guidance for Industry Revised
Precautionary Measures to Reduce the Possible
Risk of Transmission of Creutzfeldt-Jakob Disease
(CJD) Variant Creutzfeldt-Jakob Disease (vCJD)
by Blood and Blood ProductsJan 9,
2002www.fda.gov/cber/guidelines.htm

• Phase I (for implementation by May 31, 2002)
• Indefinitely defer all donors who
• have any form of CJD or are at increased risk of
  CJD
• (no change from previous FDA guidance)
• spent ?3 mo in UK from Jan 1, 1980 to Dec 31,
  1996
• or who ever had blood transfusion in UK from 1980
  to present
• or who ever injected UK bovine insulin prepared
  in or after 1980
• spent ? 5 yr in France from Jan 1, 1980 to the
  present
• spent ?6 mo on US military bases from Jan 1, 1980
  to end of 1990 north of Alps or end of 1996 south
  of Alps

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Final Guidance for Industry Revised
Precautionary Measures to Reduce the Possible
Risk of Transmission of Creutzfeldt-Jakob Disease
(CJD) Variant Creutzfeldt-Jakob Disease (vCJD)
by Blood and Blood ProductsJan 9,
2002www.fda.gov/cber/guidelines.htm

• Phase II (for implementation by October 31, 2002)
• Indefinitely defer all donors of Whole Blood but
  not donors of Source Plasma who spent ?5 yr in
  Europe from Jan 1, 1980 to the present (including
  time in spent in UK 1980-1996 and France
  1980-present)
• Exempt from deferral are
• Donors of Source Plasma who spent any period of
  time in Europe except UK and France
• Donors of plasma/serum to manufacture
  CBER-approved non-injectable products (specially
  labeled)

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170 Cases of vCJD Worldwide (end Feb 2005)

• UK 154
• France 9
• Republic of Ireland 2
• Italy 1
• USA 1
• Canada 1
• Saudi Arabia 1
• Japan 1
• -------------------------------------------------
  ------------
• Six cases of vCJD in France (6) and 1 in Italy
  had no history of travel to UK. Nine others were
  current or former UK residents/visitors. Case
  from Japan spent lt1 mo in UK (? 24 da) during
  BSE-high-risk period (1989).

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Variant CJD in UK each Year since 1994(from Will
RG, unpublished Oct 2003)New Cases
Deaths
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Nine cases of vCJD in France 1994-2004(Epidemiolo
gical data from J-P Brandel)
Onsets
Deaths
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1st Transfusion-Transmitted Case of vCJD (UK
Parliament 17 Dec 2003 CA Llewelyn al. Lancet
2004363417-421)

• March 1996
• Clinically healthy young blood donor donated
  Whole Blood to the UK National Blood Service.
• RBCnot leukoreducedtransfused into 63 yr-old
  surgical patient.
• About March 1999
• Three yr later, donor developed signs of variant
  CJD, died vCJD was confirmed by autopsy.
• UK Transfusion Medicine Epidemiology Review
  (TMER) enrolled recipient (with 49 other
  recipients of vCJD-implicated labile blood
  components from 16 donors later Dx with vCJD13
  now living gt5yr).
• December 2003
• The recipient died age 69 post-mortem diagnosis
  was typical vCJD (PRNP-129-met/met homozygous).
• The recipient's age-adjusted food-borne risk of
  vCJD estimated by UK authorities to have been
  115,000 to 130,000.

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2nd Transfusion-Transmitted Case of vCJD(Peden
AH al. Lancet 2004264527-529)

• 1999
• Clinically healthy young blood donor donated
  Whole Blood to the UK National Blood Service.
• RBCnot leukoreducedtransfused into a surgical
  patient.
• 2000
• Donor developed signs of variant CJD 18 mo
  later, died in 2001 vCJD confirmed by autopsy.
• UK Transfusion Medicine Epidemiology Review
  (TMER) enrolled recipient (with 49 other
  recipients of vCJD-implicated labile blood
  components from 16 donors later Dx with vCJD13
  now living gt5yr).
• 2003
• The recipient died of ruptured abdominal aortic
  aneurysm.
• No history of dementia and CNS, tonsils and
  appendix were normal.
• PrPsc was present in several areas of spleen,
  cervical lymph node.
• The recipient's age-adjusted food-borne risk of
  vCJD was estimated by UK authorities to have been
  115,000 to 130,000.
• Recipients genotype was PRNP 129-met/val
  heterozygous).

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General Approaches to Assessing Risk

• FDA is committed to
• risk-based regulatory decision making.
• --------------------------------------------------
  ---------
• Recent Example
• TSEAC Meeting 08 February 2005
• --------------------------------------------------
  ---------
• TSE Risk Assessment
• for Plasma Derivatives
• Steven Anderson, PhD, MPP
• Office of Biostatistics Epidemiology
• Center for Biologics Evaluation and Research
• U.S. Food and Drug Administration
• --------------------------------------------------
  ---------
• lthttp//www.fda.gov/ohrms/dockets/ac/05/transcript
  s/2005-4088t1.htmgt

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Risk of Product Contamination

• Source of raw materials
• Animal low-risk origin, low-risk tissue
• Certificate
• Test for contaminant or Dx (better ones needed)
• Human low-risk population
• Donor or surrogate questionnaire
• Donor screening test (needed)
• Manufacturing process
• Eliminate contaminating agent (validate method)
• Inactivation
• Removal
• Prevent cross contamination (downstream
  contamination)
• Cleaning
• Disinfection
• End use of product
• Route
• Dose (course, year, lifetime)

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Factor XI Risk Assessment Exposure Assessment
Overview
Input
Module
Output
SOURCE vCJD ID50 plasma pool

• Total i.c. ID50 per vCJD donation
• Total i.v. ID50 per plasma pool of 20,000
  donations

• Probability vCJD in UK
• Number vCJD donations per pool
• ID50 per ml plasma

PROCESS Reduction by manufacture

• Percentage pool used in production
• Log10 reduction ID50 during processing

• ID50 in FXI post-processing
• Yield FXI plasma pool
• Total ID50 per vial

USE Dose per surgery

• ivID50 per unit FXI
• ivID50 per vial
• Scenarios include a pre- and post-surgery dose
  20 50 u/kg

• Exposure estimate vCJD iv ID50
• Exposure estimates 3 scenarios

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UK vCJD prevalence affects the number of possible
vCJD donations per plasma pool to manufacture
Factor XI.
Prevalence of vCJD in UK Population Cases per million (epidemiological survey, ? worst-case data) Mean 95 confidence interval
Prevalence of vCJD in UK Population Cases per million (epidemiological survey, ? worst-case data) 237 49 to 692

Triangular distribution Parameters Mean Range
UK Plasma pool Number of vCJD donations per 20,000 donations 5 Most likely 2 0 to 14
1 50
2x104 106
Prevalence x
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UK FXI vCJD Exposure AssessmentPossible vCJD
infectivity in UK plasma pool

• Quantity of vCJD ID50 present per ml plasma
• Intracerebral (ic) ID50 per ml blood (animal
  ID50)
• Minimum 0.1
• Most likely 10
• Maximum 1,000
• Assume 58 associated with plasma (Gregori, et
  al. 2004)
• Adjust down 5-fold to 10-fold for reduced
  efficiency of intravenous (iv) vs ic route of
  exposure

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FXI vCJD Exposure AssessmentReduction during
manufacturing PROCESS

• Log10 reduction ID50 during plasma processing
• Reduction based on processing steps
• Variability in processing and reductions achieved

Assumption Minimum Most Likely Maximum

Log10 reduction vCJD agent infectivity 0 2.0 4.0
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Results of FXI Risk Assessment Model Exposure
to vCJD iv ID50(no conclusion about relationship
between exposure and infection)
 Scenario  Quantity of factor XI utilized  Mean vCJD iv ID50  5th percentile  95th percentile

A single unit FXI 1 u 2 x 10-5  6.8 x 10-7 7.0 x 10-5
One vial FXI 1,000 u 2 x 10-2    6.8 x 10-4 7.0 x 10-2
Scenario 1 1 treatment 60 kg person 3,000 u 6 x 10-2 2.1 x 10-3   0.21  
Scenario 2 3 treatments 60 kg person 9,000 u 0.17 6.2 x 10-3 0.6
Scenario 3 gt3 treatments 60 kg person 15,000 u 0.28   1.0 x 10-2   1.0
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Exposure RisksAdvantages of quantitative models

1. Transparent assumptions articulated and
   available for modification
2. Data gaps identified
3. Sensitivity Analysis (Importance Analysis) Most
   important elements driving overall risk
   identified, even without agreement on assumptions

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vCJD DATA GAP PREVALENCE Epidemiological
Models Predicting the Size of the UK vCJD
Epidemic (from R Will, thro Oct 2003)
(13.7 million)
(6.1 million)
(136,000)
(80,000)
(3,000)
(416)
(29)
(200)
(205)
(183)
(75)
(63)
(52)
(Cousens)
(Ghani)
(Ghani)
(Ghani)
(dAignaux)
(Valleron)
(Boelle)
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PrPsc in Appendix, Tonsils Association with
vCJD(Hilton DA et al. Brit Med J 2002 325
633-634, J Pathol 2004203733-739)
Postmortem vCJD 19/20
Preclinical vCJD 2/3
1st Surgical Survey 1/8318
2nd Surgical Survey 3/12,674
Estimated UK prevalence of abnormal PrP in
lymphoid tissues 1st survey 120/million (95 CI
0.5 900/million) 2nd survey 237/million
(95 CI 49-692/million)
1 yr, 2 yr,10 yr (neg) before onset of symptoms
3 yr, 4 yr, 11 yr (neg) before death
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vCJD Data Gaps Incubation periods, duration of
blood infectivity, amounts infectivity in blood,
human ivID50)

• Incubation
• Food-borne cases
• US 9-21 yr
• Canada 11-19 yr
• Japan 12 yr
• Ireland 5-10 yr
• Blood-borne cases
• First case 6 yr
• Second case gt 5 yr
• Blood infectivity before clinical vCJD ? 3 yr

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Sensitivity Analysis Risk DriversEstimates of
FXI vCJD Exposure Risk

• Two major factors influenced FXI vCJD risk
• Number of vCJD donations per plasma pool
• Risk reduction measuredonor deferrals
• Reduction of vCJD agent during manufacture
• Robustness (inactivationgtremoval)
• Orthogonality (two processes preferred)
• Additivity of process steps (must justify)
• Validity (and relevance) of experimental data

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Recipients surviving gt5 yrs post transfusion of
blood components from vCJD/CJD Donors(data from
UK TMER and US ARC look-back studies R
Dodd,presented by S. Anderson, FDA TSEAC 14 Oct
2004)
Infection No Infection
vCJD 2 13
CJD 0 116

• Fisher's Exact Test comparing rates of infection
  after transfusions from vCJD and CJD donors
  suggests a statistically significant difference
  between the two groups (?1.2 likelihood of
  difference by chance).
• Conclusion Risk of TT CJD is less than TT vCJD.

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Policies to Reduce Risk of Transmitting vCJD by
Blood Products by Donor SelectionGeneral
Approaches

• Reduce risk that donor was exposed to BSE agent
• Dietary exposure Lived in BSE country (or
  military base importing beef from UK)
  geographic deferrals
• Other exposure Use of UK bovine insulin
• Reduce risk that donor was exposed to vCJD agent
  of human origin
• Transfusion, UK after 1980
• Transfusion, other BSE countryespecially
  France
• Surgery in BSE country after 1980 suggested by
  TSEAC member (not addressed by FDA or TSEAC)

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Estimated vCJD Blood Risk Reduction and Donor
Loss from Possible Enhanced Deferral
Policies(from A Williams, FDA, TSEAC 14 Oct 2004)
Reduced Risk (in addn to current 91) Donor Loss (in addn to current 6.4)
UK 3 mo (80-96) ? to 1 mo 4 3
Transfusion in France (80-now) Uncertain but very small 1.4/10,000
Transfusion in Non-UK W Eu (80-now) Uncertain but very small (Problem EuroBlood) 3/10,000
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TSEAC Advice to FDA 14 October 2004

• Are measures currently recommended by FDA to
  reduce the risk of transmitting CJD and vCJD by
  blood products still justified?
• Yes 14, No 0
• Do recent scientific data on vCJD warrant
  consideration by FDA of any additional
  potentially risk-reducing measures for blood and
  blood products?
• Yes 1, No 13
• If so, please comment on the additional
  risk-reducing measures that FDA should consider
  at this time. Investigate vCJD cases outside UK
  for ? exposure to blood. Consider deferral of
  donors transfused in non-UK BSE countries.

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TSEAC Advice to FDA 08 February 2005

• Should FDA recommend deferral of Whole Blood
  donors transfused after the beginning of 1980?
• In France Yes 12, No 3, Abstain 1
• Other W Europe Yes 0, No 15, Abstain 1
• Should FDA recommend deferral of Source Plasma
  donors transfused in/after 1980?
• In France Yes 5, No 7, Abstain 4
• Other W Europe Yes 0, No 16, Abstain 0

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Limitation of deferral-based approachesto reduce
the risk of blood-borne vCJD

• Problem
• Many (? most) deferred donors are probably not
  infected with a TSE agent (needlessly deferred
  and alarmed).
• Possible solutions
• Develop validated and reliable screening tests to
  detect infected donors and re-enter/reassure
  uninfected donors.
• Develop validated and reliable methods to remove
  (inactivate or separate) infectious TSE agents
  from products.
• Current status
• No FDA-licensed/approved TSE test (for diagnosis
  or donor screening)
• No FDA-licensed method validated to remove TSE
  infectivity from red cells, platelets and plasma

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