Draft Quantitative Risk Assessment of

1

• Draft Quantitative Risk Assessment of
• vCJD Risk Potentially Associated with
• the Use of Human Plasma-Derived
• Factor VIII Manufactured Under United
• States (US) License From Plasma
• Collected in the US
• Steven Anderson, PhD, MPP
• Office of Biostatistics Epidemiology
• Center for Biologics Evaluation and Research
• U.S. Food and Drug Administration
• December 15, 2006
• TSEAC Meeting

2
Background Draft Risk Assessment for U.S. Factor
VIII and vCJD

• Emergence of vCJD transmission via red cell
  transfusion in December 2003
• Concerns vCJD may potentially be transmitted
  through plasma-derived products including
  clotting factors
• Clotting factors such as plasma-derived FVIII
  (pdFVIII) made from human plasma are used in
  large quantities by many US patients
• Transmission of vCJD via FVIII is a potential
  hazard but magnitude of potential risk was
  unknown
• Fall 2004 FDA began developing a risk assessment
  of potential vCJD risk via pdFVIII manufactured
  from plasma collected in US

3
Background Draft Risk Assessment for U.S. Factor
VIII and vCJD

• FDA presented conceptual vCJD-FVIII risk
  assessment model at February 8, 2005 TSEAC
• FDA sought Committee discussion and advice on
  several risk assessment inputs at October 31,
  2005 TSEAC
• Peer review of FDA Risk Assessment model and
  document by 3 external experts
  in Summer 2006
• Presentation of Draft Quantitative Risk
  Assessment of
• vCJD Risk Potentially Associated with the Use
  of Human Plasma- Derived Factor VIII Manufactured
  Under United States (US) License From Plasma
  Collected in the US at December 15, 2006 TSEAC
• FDA risk communication activities

4
Advice from TSEAC on vCJD-pdFVIII risk assessment
data inputs
TSEAC Oct 31, 2005
UK vCJD prevalence estimate 1. Epidemiological Model Estimate (mean 1.8 in 1 million) 2. Tissue Surveillance method (mean 1 in 4,225)
Efficiency of vCJD deferral 85 - 99
Quantity of infectivity present in blood 5th Percentile 2 Minimum 0.1 Most likely 10 Maximum 1,000 95th Percentile 30 i.c ID50/ml
Adjustment for efficiency of transmission i.v. vs i.c. 0.1 - 1
Infectivity presence in blood Last half of incubation period
Clearance of vCJD agent during manufacturing 3 Categories stratified by clearance 7-9 log10, 4-6 log10, 2-3 log10
FVIII usage 1. CDC Sponsored 6 state surveillance study 1993-1998 2. CDC UDC project used to estimate patient population sizes
5
Risk Assessment Framework used by FDA (NAS, 1983)

• 1. Hazard identification
• Establishes causality between hazard and adverse
  effects
• 2. Dose response (Hazard characterization)
• Probability of response infection or illness
• 3. Exposure assessment
• Frequency and level of exposure
• Estimates potential DOSE vCJD ID50
• 4. Risk characterization
• Probability of occurrence, severity of adverse
  effects
• Uncertainty
• Sensitivity analysis

6
FDA Risk Assessment Scope and Type of risk
assessment

• Risk Assessment Problem Statement
• What is the potential vCJD risk for recipients
  of pdFVIII manufactured from plasma collected
  in US?
• Scope of FDA pdFVIII Risk Assessment
• Estimates potential vCJD risk for US pdFVIII
  recipients
• Severe Hemophilia A
• Severe von Willebrand disease (vWD) (Type 3)
• Potential vCJD risk estimated for one-year
  treatment period in 2002
• Model results generally applicable to current
  year
• General Analytic Approach
• Quantitative risk assessment (QRA)
• Input data incorporated into model as
  statistical distributions
• Probabilistic computer-based model
• Monte Carlo methods

7
FDA Risk Assessment BackgroundpdFVIII product
usage in clinical setting

• Factor VIII (FVIII) a plasma protein necessary
  for blood clotting
• Two types of bleeding disorders associated with
  deficiency of FVIII
• Hemophilia A (HA)
• Deficiency of FVIII,
• Severe HA patients have lt1 FVIII activity
• von Willebrand disease (vWD)
• Deficiency of von Willebrand factor (glycoprotein
  carrier of FVIII)
• Severe vWD patients have reduced levels of FVIII
• Clinical usage of pdFVIII
• Human pdFVIII used by 25 HA patients
• Recombinant FVIII available since early 1990s
• vWD patients use pdFVIII no recombinant vWF,
  some pdFVIII
  contains vWF

8
Hazard Identification Potential vCJD risk via
pdFVIII

• 3 vCJD infections probably acquired through
  red-cell transfusions in UK since 2003
• Potential presence of vCJD agent in human plasma
  (and plasma-derived products including pdFVIII??)
  may be a hazard to human health
• Hemophilia A and vWD patients who used pdFVIII
  over long treatment period may have been exposed
  to vCJD agent
• To date no cases vCJD identified in recipients
  of plasma-derived clotting factors

9
Hazard Identification vCJD Risk issues
associated with pdFVIII

• Plasma pooled from thousands of donors
• Increased chance plasma pools contain vCJD
  donations compared to single donors
• HA vWD patients may use large amounts FVIII
  over lifetime
• TSE clearance during manufacturing
• Clearance likely decreases potential vCJD
  infection risk by decreasing exposure to vCJD
  agent
• FVIII products vary in level of reported
  clearance
• Challenge to evaluate and study clearance

10
Dose-response for Human vCJD

• Challenges for determining dose-response
  
• Human data absent
• Quantity agent in human blood? Plasma?
• Present throughout incubation period?
• Genetics susceptibility of humans
• Threshold? Or not?
• Accumulation of agent in humans?
• Use of animal data Approximate human vCJD well?
• FDA risk assessment model assumes
• vCJD agent present in last half incubation period
• Linear dose-response (below 2 ID50), no threshold
• Accumulation of infectious agent in the body

11
Exposure Assessment Overview Potential vCJD risk
via pdFVIII
12
Monte Carlo Method used in FDA Risk Assessment
model

• Tool for combining input data as distributions
  rather than using and propagating data as summary
  statistics
• Without Monte Carlo methods process of combining
  more than 2
  distributions of possible values of variables
  would be challenging
• Method
• Draws randomly from defined distributions
• Performs the programmed mathematical functions
  and stores number each time
• Process repeated thousands of times or
  iterations
• Results displayed as a new, aggregate
  distribution

13
Monte Carlo Analysis Example calculation i.v.
ID50 per ml plasma
Result of 10,000 iterations
Distribution i.v. ID50 per ml plasma
2 10 30
Perform Multiplication 10,000 times
Mean 5.2
i.c. ID50 per ml Blood
x
58
Percent ID50 in plasma
x
(5th)
(95th)
0.1 1.0
Actual distribution used in FDA risk assessment
included a range of 0.1 to 1,000 i.c.ID50/ml
Adjustment i.c. to i.v.
14
Exposure Assessment Module 1Prevalence of vCJD
in United Kingdom

• A. Epidemiological modeling vCJD cases
• Clarke and Ghani 2005
• Predicted 70 (10 190 95 CI) vCJD cases,
  2002-2080
• Prevalence vCJD 1.8 per million UK population
• B. Tonsil/appendix tissue surveillance in UK
  patients
• Hilton, et al. 2004
• 3 prion positive samples in 12,674 samples tested
• Mean of 1 positive in 4,225 individuals, or 237
  per million
• Mostly in 20 30 yr old patients
• UK prevalence is Critical model input used to
  estimate vCJD prevalence for France, other
  Europe, Military bases in Europe, Plasma donors
  in United States

15
Exposure Assessment Module 1 vCJD Prevalence in
United Kingdom (cont.)

• Uncertainties of Estimating UK vCJD Prevalence
• Epidemiological modeling based on vCJD cases in
  UK
• All vCJD cases-MM codon 129 PrP individuals (40
  population)
• Assumptions incubation period, time of
  infection, effectiveness feed ban, etc
• Tonsil/appendix surveillance data
• Prion protein in appendix but may not have
  agent in blood or develop disease
• Sample size relatively small for rare disease
• Underestimate vCJD prevalence - in one vCJD
  infection no agent found in appendix
• Tissue surveillance lacks controls (survey of
  non-BSE exposed population), patient outcomes
  unknown

16
Exposure Assessment Module 2 vCJD Prevalence in
US plasma donors

• Modeling Approach for Module 2
• Estimation of US vCJD donor risk
• Estimate size of US plasma donor population
  travel history to UK, France or other countries
  Europe since 1980
• Model donor/traveler risk using survey data blood
  donors
• Adjust travel risk by several factors (duration
  of stay, year, etc.)
• Estimate probability of infection in individual
  donors
• Add up potential number infections for US plasma
  donor groups
• Apply effectiveness of donor deferral policy
• Calculate total number potential vCJD infected
  donors donations

17
Exposure Assessment Module 2 vCJD Prevalence in
US plasma donors (cont.)

• Relative Risk metric was used to estimate
  probability
  vCJD infection (prevalence)
  in US donors
• Estimates vCJD prevalence in donors who traveled
  to France and other countries of Europe relative
  to UK vCJD prevalence
• Relative Risk estimated in year 2001 using
  country-specific info on BSE cases, amt imported
  UK beef, number vCJD cases, etc.

Adjustment for Relative Risk Prevalence
UK 1 PvCJD-UK
France 0.05 PvCJD-France 0.05 ? PvCJD-UK
Other Countries in Europe 0.015 PvCJD-EU 0.015 ? PvCJD-UK
Military Bases in Europe 0.35 PvCJD-DOD 0.35 ? PvCJD-UK
18
Exposure Assessment Module 2vCJD Prevalence in
US plasma donors (cont.)

• FDA Model estimated relative risk for US plasma
  donors with travel history to UK, France or other
  Europe since 1980
• Model proportionally adjusted relative risk for
  vCJD for US donors over 23 year period (1980
  2002) based on
• Duration of Travel
• Relative risk is adjusted on a per month or per
  day basis
• Specific year(s) of travel
• Accounts for variation in BSE epidemic / exposure
• Age of donor
• To apply age specific rates for vCJD in UK
  (median age 28yrs)
• Age specific donation rates
• Type of Donor Source and Recovered

19
Exposure Assessment Module 2 vCJD Prevalence
in US plasma donors (cont.)

• Model estimates two sources residual risk for US
  donors
• (1) Donors with deferrable criteria but not
  deferred because limitations in screening
• (2) Not deferrable short-term travel
• Approximately 90 vCJD risk eliminated for US
  donors by current donor
  deferral policy for travel
• UK 1980-1996, gt 3 mos
• France since 1980, gt 5 years
• Other Europe since 1980, gt 5 years (recovered
  plasma donors only)
• Military Bases in Europe 1980-1996
• Efficiency of deferral 85-99

20
Exposure Assessment Module 2 vCJD Prevalence
in US plasma donors (cont.)

• Module outputs for Module 2
• Potential vCJD infected US plasma donors
• Potential donations with vCJD agent
• Uncertainties in the data
• No travel data for source plasma donors-source
  plasma donors may travel less than whole blood
  donors (group surveyed)
• Estimation deferral effectiveness a challenge
  self-deferred population unknown
• MV and VV at codon 129 PrP individuals Potential
  disease attack rate and incubation period unknown
• Percentage infections that become symptomatic
  disease

21
Exposure Assessment Module 3Factor VIII
Processing

• Modeling Approach for Module 3
• Estimate probability plasma pool contains vCJD
  donation
• Estimate quantity vCJD ID50 per ml plasma and per
  pool
• Efficiency of exposure through i.v. vs i.c. route
  
• Log10 reduction in quantity i.v. ID50

22
Exposure Assessment Module 3Factor VIII
Processing (cont.)

• Infectivity clearance in product plasma pools
• Each product has different purification steps
  and clearance
• Product specific data not available for all
  products and process steps
• Data in published literature available only for
  some purification steps, variation among
  studies
• FDA model stratified by 3 clearance levels
  7-9 log10, 4- 6
  log10, 2-3 log10
• FDA believes that most pdFVIII products have at
  least 4 log10 of clearance

23
Exposure Assessment Module 3Factor VIII
Processing (cont.)

• Model output from Module 3 predicts
• Percentage plasma pools with vCJD agent
• Percentage vials with vCJD agent
• Quantity vCJD agent per vial

24
Exposure Assessment Module 3Factor VIII
Processing (cont.)

• Uncertainties in the data
• Quantity of infectivity in plasma and plasma
  pools
• Detection of low level infectivity difficult
• Infectivity in animal blood may not be
  representative of infectivity in human blood
• Infectivity clearance
• No standard method for clearance study spiking
  materials
• No standard method for animal study selection of
  donor and recipient animals
• Reduction in laboratory scale with high
  concentration spiked infectivity may not reflect
  reduction in real processing systems
• Reduction in different purification steps
  additive?

25
Exposure Assessment Module 4Utilization of
Factor VIII (cont.)

• Modeling Approach for Module 4
• Inputs
• Percentage vials with vCJD agent
• Quantity vCJD agent per vial
• Annual utilization / dose Factor VIII per patient
• Model output to predicts
• Annual potential dose vCJD ID50 per patient
• Prediction of risk of vCJD infection based on
• animal dose-response information

26
Exposure Assessment Module 4 Utilization of
FVIII (cont.)

• Factors considered for utilization
• Type of disease
• Severe Hemophilia A,
• Severe von Willebrand disease (vWD)
• Treatment regimens Prophylaxis and Episodic
• Inhibitor and immune tolerance
• Data Sources
• CDC UDC data to estimate size of HA vWD
  populations
• CDC sponsored 6 states hemophilia surveillance
  study, 1993-1998 (total records 17,848)
• Information on age, sex, factor of deficiency,
  baseline level of factor, product and amount
  used, inhibitor and immune tolerance

27
Risk CharacterizationIntegration of information
from Exposure Assessment and Dose-Response

• Exposure assessment of FDA model provides
  estimate of
• potential vCJD ID50 DOSE
• FDA assumed a LINEAR DOSE-RESPONSE relationship
  for vCJD
• (TSEAC recommendation vCJD ID50 is a linear
  dose-response)

Dose Probability of infection
1 ID50 50
0.1 ID50 5
etc. etc.
28
Risk Characterization (contd)

• Uncertainty- 2 major sources
• (1) Arises from lack of information
• Inadequate quantity / quality of data
• Express outcomes uncertainty with confidence
  intervals
• 95 CI , 5th and 95th percentiles, etc.
• Outcomes expressed with measures central
  tendency mean, median, etc.
• (2) Inaccuracies of models
• Peer-review to identify errors or omissions, etc.

29
Risk Characterization (contd)Factor VIII Risk
Assessment
Table 4.5 Annual Percentage plasma pools
containing vCJD donation
LOWER PREVALENCE Epidemiological model prevalence 1.8 in 1million LOWER PREVALENCE Epidemiological model prevalence 1.8 in 1million HIGHER PREVALENCE Surveillance prevalence 1 in 4,225 HIGHER PREVALENCE Surveillance prevalence 1 in 4,225
 Scenario Source Mean (5th - 95th) Recovered Mean (5th - 95th) Source Mean (5th - 95th) Recovered Mean (5th - 95th)
Percent pools with vCJD agent 0.01 (0 0) 0.10 (0 0) 0.96 (0 5.88) 9.12 (0 40.17)
Average percent pools containing vCJD agent 0.027 (0 0 ) 0.027 (0 0 ) 2.41 (0 10 ) 2.41 (0 10 )
Results from the model as shown but considerable
UNCERTAINTY is associated with estimates !
30
Risk Characterization (contd) Table 5.2A
Individual vCJD risk- severe Hemophilia A FVIII
Manufacture reduction of 4-6 log10 clearance
LOWER vCJD Case Prevalence 1.8 in 1 million HIGHER vCJD Prevalence 1 in 4,225
Treatment regimes Inhibitor status Mean annual vCJD risk (5th -95th) Mean annual vCJD risk (5th -95th)
Prophylaxis No Inhibitor 1 in 4.0 million (0-0) 1 in 54,000 (0 - 1 in 12,000)
Prophylaxis With Inhibitor No Immune Tolerance 1 in 4.8 million (0-0) 1 in 41,000 (0 - 1 in 9,000)
Prophylaxis With Inhibitor With Immune Tolerance 1 in 1.3 million (0-0) 1 in 15,000 (0 - 1 in 3,700 )
Episodic No Inhibitor 1 in 9.4 million (0-0) 1 in 105,000 (0 - 1 in 24,000 )
Episodic With Inhibitor 1 in 8.0 million (0-0) 1 in 48,000 (0 - 1 in 12,000 )
31
Risk Characterization (contd) Table 5.2B
Population vCJD risk for severe Hemophilia A
Manufacture reduction of 4-6 log10 clearance
LOWER PREVALENCE Epidemiological model prevalence 1.8 in 1million HIGHER PREVALENCE Surveillance prevalence 1 in 4,225
Total number patients Mean Total quantity FVIII used by all patients per yr Mean annual vCJD risk (5th -95th) Mean annual vCJD risk (5th -95th)
1,800 243 million IU 1 vCJD infection in 3,077 years (0 - 0) 1 vCJD infection in 35 years (0 - 1 in 8)
Results from the model as shown but considerable
UNCERTAINTY is associated with estimates !
32
Risk Characterization (contd) Table 5.3A Range
of vCJD risk-severe Hemophilia A
7 - 9 Log10 Reduction 7 - 9 Log10 Reduction 4 6 Log10 Reduction 4 6 Log10 Reduction 2 3 Log10 Reduction 2 3 Log10 Reduction
LOWER vCJD Prevalence 1.8 in 1 mill HIGHER vCJD Prevalence 1 in 4,225 LOWER vCJD Case 1.8 in 1 mill HIGHER vCJD Prevalence 1 in 4,225 LOWER vCJD Prevalence 1.8 in 1 mill HIGHER vCJD Prevalence 1 in 4,225
Treatment Regimen Inhibitor Status Mean potential vCJD risk per person per year (5th - 95th perc) Mean potential vCJD risk per person per year (5th - 95th perc) Mean potential vCJD risk per person per year (5th - 95th perc) Mean potential vCJD risk per person per year (5th - 95th perc) Mean potential vCJD risk per person per year (5th - 95th perc) Mean potential vCJD risk per person per year (5th - 95th perc)
Prophylaxis No Inhibitor 1 in 4.1 billion (0-0) 1 in 50 mill (0 - 1 in 11 mill) 1 in 4 mill (0-0) 1 in 54,000 (0- 1 in 12,000) 1 in 15,000 (0-0) 1 in 82 (0 - 1 in 17)
Prophylaxis With Inhibitor No Immune Tolerance 1 in 3.5 bill (0-0) 1 in 40 mill (0 - 1 in 8.8 mil) 1 in 4.8 mill (0-0) 1 in 41,000 (0- 1 in 9,000) 1 in 12,000 (0-0) 1 in 65 (0 - 1 in 13 )
Prophylaxis With Inhibitor With Immune Tolerance 1 in 551 mill (0-0) 1 in 15 mill (0 - 1 in 3.4 mill) 1 in 1.3 mill (0-0) 1 in 15,000 (0- 1 in3,700) 1 in 2,700 (0-0) 1 in 24 (0 - 1 in 3 )
Episodic No Inhibitor 1 in 3.2 bill (0-0) 1 in 100 mill (0 - 1 in 24 mill) 1 in 9.4 mill (0-0) 1 in 105,000 (0- 1 in 24,000) 1 in 21,500 (0-0) 1 in 159 (0 - 1 in 34 )
Episodic With Inhibitor 1 in 4 bill (0-0) 1 in 50 mill (0 - 1 in 11 mill) 1 in 8 mill (0 - 0) 1 in 23,000 (0- 1 in 12,000) 1 in 23,000 (0-0) 1 in 73 (0 - 1 in 16)
33
Risk Characterization (contd) Table 5.3A Model
results of Range of vCJD risk-severe Hemophilia A
Excerpt Excerpt 7 - 9 Log10 Reduction 7 - 9 Log10 Reduction 4 6 Log10 Reduction 4 6 Log10 Reduction
LOWER vCJD Prevalence 1.8 in 1 mill HIGHER vCJD Prevalence 1 in 4,225 LOWER vCJD Case 1.8 in 1 mill HIGHER vCJD Prevalence 1 in 4,225
Treatment Regimen Inhibitor Status Mean potential vCJD risk per person per year (5th - 95th perc) Mean potential vCJD risk per person per year (5th - 95th perc) Mean potential vCJD risk per person per year (5th - 95th perc) Mean potential vCJD risk per person per year (5th - 95th perc)
Prophylaxis No Inhibitor 1 in 4.1 billion (0-0) 1 in 50 mill (0 - 1 in 11 mill) 1 in 4 mill (0-0) 1 in 54,000 (0- 1 in 12,000)
Prophylaxis With Inhibitor No Immune Tolerance 1 in 3.5 bill (0-0) 1 in 40 mill (0 - 1 in 8.8 mil) 1 in 4.8 mill (0-0) 1 in 41,000 (0- 1 in 9,000)
Prophylaxis With Inhibitor With Immune Tolerance 1 in 551 million (0-0) 1 in 15 mill (0 - 1 in 3.4 mill) 1 in 1.3 mill (0-0) 1 in 15,000 (0- 1 in 3,700)
34
Risk Characterization (contd) Table 5.2A Range
of vCJD risk severe vWD Manufacture reduction of
4-6 log10 clearance
Excerpt YOUNG vWD (lt 15 yrs of age) YOUNG vWD (lt 15 yrs of age)
  LOWER vCJD Prevalence 1.8 in 1,000,000 HIGHER vCJD Prevalence 1 in 4,225
Mean potential vCJD risk per person per yearb (5th - 95th perc)c Mean potential vCJD risk per person per yearb (5th - 95th perc)c
Prophylaxis 1 in 4.7 million (0 - 0) 1 in 52,000 (0 - 1 in 13,000)
Episodic 1 in 48 million (0 - 0) 1 in 971,000 (0 - 1 in 293,000)
ADULT vWD ( gt 15 yrs of age) ADULT vWD ( gt 15 yrs of age) ADULT vWD ( gt 15 yrs of age)
Prophylaxis 1 in 4.1 million (0 - 0) 1 in 46,300 (0 - 1 in 11,000)
Episodic 1 in 10 million (0 - 0) 1 in 1 million (0 - 1 in 24,000)
35
Risk Characterization (contd) Table 5.2B
Population vCJD risk for severe vWD Manufacture
reduction of 4-6 log10 clearance
LOWER PREVALENCE Epidemiological model prevalence 1.8 in 1million HIGHER PREVALENCE Surveillance prevalence 1 in 4,225
Total number patients Mean annual vCJD risk (5th -95th) Mean annual vCJD risk (5th -95th)
250 1 vCJD infection in 28,450 years (0 - 0) 1 vCJD infection in 405 years (0 - 1 in 76)
Results from the model as shown but considerable
UNCERTAINTY is associated with estimates !
36
Risk Characterization (contd)Sensitivity and
Importance Analysis

• Analyses identify key inputs or drivers of vCJD
  risk
• (1) Conducted by varying value of input and
  observing impacts on risk estimate
• (2) Importance analysis
• Ranks inputs according to level of influence on
  final risk estimate
• (3) Most important model inputs
• Clearance of vCJD agent during manufacture
• Quantity of pdFVIII used by patients
• Prevalence of vCJD in UK
• Efficiency i.c. vs i.v. route

37
Risk Characterization (contd)Importance Analysis
Fig 2.A. Importance Analysis ranking influential
factors for predicted vCJD exposure (yr) using
prevalence estimates from 0.7 to 700 cases per
million
_

38
Uncertainties and Data Gaps

• More data are needed on
• Clearance of vCJD agent during manufacturing
  steps
• Prevalence of vCJD in UK, USA, etc.
• Utilization How do patients use pdFVIII? By lot?
  Several lots per year?
• Amount vCJD agent present in human blood plasma
• Progression of vCJD and variability of levels of
  infectivity in blood plasma
• Dose response relationship in animal models
• Many other parameters

39
Risk Characterization

• It is not possible to precisely estimate
  potential vCJD risk for pdVIII recipients because
  of uncertainties in data and knowledge of vCJD
• vCJD risk from use of pd FVIII may not be zero,
  but most likely extremely small
• FDA risk assessment results consistent with
  absence of observed vCJD cases in clotting factor
  recipients
• Current donor deferral greatly reduced the risk
  by deferring individuals with history of extended
  travel to UK, France and other countries in
  Europe since 1980
• Risk assessment shows that manufacturing
  processes shown to reduce the Infectivity is the
  most influential factor in model for reducing
  vCJD risk
• Risk assessment highlights data gaps in level of
  clearance, product usage, vCJD prevalence and
  dose-response

40
Acknowledgements

• OD
• Jesse Goodman
• Karen Midthun
• Diane Maloney
• Peer Reviewers
• David Gaylor (Gaylor Assoc.)
• Mark Powell (USDA)
• Sonja Sandberg (Univ. Framingham)

• OBE
• Hong Yang
• OBRR
• David M. Asher
• Jay Epstein
• Jonathan Goldsmith
• Dorothy Scott
• Mark Weinstein
• Alan Williams