Pathogen Reduction: American

Red Cross Experience with

Implementation

Roger Y. Dodd, PhD

Adjunct Associate Professor

Johns Hopkins University, Baltimore, USA

SANBTC, Sun City, S.A.

August 30th, 2017

Disclosure

• My travel was supported by Cerus Corporation.

US environment for blood supply

• Private, not-for-profit

• Multiple independent groups and centers

• Funded through direct payment from hospitals

• Hospitals reimbursed by government and/or private

insurance

• Government policies tend to define reimbursement

• In-patient reimbursement via DRGs

• Hospitals under pressure to reduce costs

• Competitive environment for blood providers

• Most blood providers currently operating at a loss

US regulatory environment

• Blood regulated as a Biologic by FDA

• Regulation by law and by Guidance

• Compliance through inspection

• Tools for blood activities also licensed as Biologics or

Devices

• FDA can require implementation of measures

• Blood centers are free to exceed requirements but can

only avoid them by demonstrating equivalent safety

• In some circumstances, non-licensed measures can be

implemented under IND or IDE and users may engage in

cost-recovery

Regulation and PR

• Selected PR methods have been licensed for use in USA

• INTERCEPT: platelets and plasma

• Octaplas: plasma

• Guidance for Zika

• Licensed PR acceptable as a substitute for NA testing

• Draft Guidance* for bacterial safety of platelets

• Primary culture

• Secondary testing at 3 days and within 24 hours before use

• These measures may be replaced by PR

* Combination of published and anticipated Guidance

Drivers and barriers - platelets

• Management of bacterial contamination

• Earlier release of platelets

• No need for irradiation

• (Generic safety)

• Cost

• Impact on platelet availability

• Decision devolves to hospitals

• (Adverse effects)

• Essentially no uptake of PR plasma

Cerus INTERCEPT product insert, US

Cerus INTERCEPT

product insert,

US

Bacterial outgrowth

• Bacteria grow during storage at room temperature

• Fast-growing bacteria may grow to levels that exceed

inactivation capacity within 36 hours (or less)

• If inactivation is delayed much beyond 24 hours, viable

bacteria may remain in the treated product

• Treatment should therefore be performed within 24 hours

Cerus INTERCEPT product insert, US

11

Conventional Platelets Amotosalen/UVA Platelets

YearUnits Transfused

(n)

Transfusion

Transmitted Sepsis

(Fatalities)

Units Transfused

(n)

Transfusion

Transmitted Sepsis

(Fatalities)

2006 231,853 4 (0) 6,420 0 (0)

2007 232,708 9 (2) 15,393 0 (0)

2008 239,349 6 (1) 15,544 0 (0)

2009 241,634 9 (0) 21,767 0 (0)

2010 253,149 2 (1) 22,632 0 (0)

2011 267,785 2 (1) 22,392 0 (0)

2012 275,834 7 (2) 24,849 0 (0)

2013 281,288 4 (1) 24,954 0 (0)

2014 278,788 2 (0) 26,676 0 (0)

2015 272,836 4 (1) 33,666 0 (0)

FRANCE total 2,575,224 49 (9) 214,293 0 (0)

2011 6,613 0 (0) 26,454 0 (0)

2012 - - 34,265 0 (0)

2013 - - 34,750 0 (0)

2014 - - 35,328 0 (0)

2015 - - 36,403 0 (0)

SWITZERLAND total 6,613 0 (0) 167,200 0 (0)

2009 41,346 0 27,564 0 (0)

2010 41,597 2 (0) 27,731 0 (0)

2011 41,392 2 (0) 27,594 0 (0)

2012 41,668 2 (0) 27,779 0 (0)

2013 41,880 0 (0) 27,920 0 (0)

2014 38,221 3 (0) 28,834 0 (0)

BELGIUM total 246,104 9 (0) 167,422 0 (0)

Total 2,827,941 58 (9) 548,915 0 (0)

HV Data on Bacteria Sepsis from Three National HV Programs (~1:50,000)

Pathogen Reduced Platelets…

years in the making

12

Dec 2014 PI licensed in US

April 2015 Implementation Project formed

Feb 2016 ARC/Cerus sign contract

July 2016 PR Ops trial

Sept 2016 1st Hospital Customer

Jan 2017BLA submission

Starting Jan 2018General Availability

CHIKV in PR Donors

• 557 collections Apr 4-Aug 14

2014

• Neg for ID markers including

DENV RNA by TMA

• Screened by CHIKV TMA

95% detection 16 copies/mL

Singlet => dilutions to 10^8

• No donor reported PDI up to

12 days post donation

• 3 (0.54%, 1:186) TMA RR and

confirmed by orthogonal

methods

(3 pos and 3 neg controls)

1/3 reported PDI from call

back

Chiu et al., EID 2015:21(8). Genomic assays for

Identification of CHIKV in Puerto Rico 2014

copies/mL: 2.9x105 – 9.1-

107

Puerto Rico Executive Order Summary

• In response to the CHIKV epidemic declared in Puerto Rico, Governor issued an Executive Order in July 2014 requiring additional pre-donation screening questions and deferral• Targeted symptoms => past 7 days• Exposure to someone with DENV or CHIKV => past 7

days• 28-day deferral if a “yes” response

• 3-day “required” platelet hold and call-back of donors for evidence of symptoms (RBCs 7-day passive hold)• Products discarded if symptoms are reported or if contact was

not established

• The Red Cross elected to suspend platelet collections in Puerto Rico in August 2014• Platelets to meet patient need supplied from the US mainland

15

Pre-donation question remains, within last 7 days… if yes, defer 28 days

Quarantine platelets (3-5 days)/red cells (7 days) with post-donation information

provided to

all donors informing them to call back if symptoms arise. Release of platelets

requires a “no symptom response”; red cells = passive

There are technologies used in Europe, Asia and some parts of the Americas for

pathogen inactivation of platelets and plasma. These technologies have recently

been approved by FDA for use in the US under regulations applicable to medical

devices known as Treatment Use Investigational Device Exemptions. Their use

entails strict compliance with FDA regulations. Blood collectors who are

registered with the FDA as one of those approved for implementation will have

to…. Notify assistant Secretary of Health; waives quarantine period

INTERCEPT Blood System17

• FDA approved (Dec 2014) pathogen reduction

system

• Intended to be used for the ex vivo preparation of

pathogen-reduced, whole blood derived,

apheresis plasma, or apheresis platelets in order

to reduce the risk of transfusion-transmitted

infection (TTI), including sepsis

• Potentially reduce the risk of transfusion-

associated graft versus host disease (TA-GVHD)

• Uses amotosalen and UV light to crosslink

nucleic acids and prevent replication

TReatment Use IDE - Trial Objectives

• Primary objective to provide access to treated platelets for patients at risk of TT-CHIKV or DENV in Puerto Rico

• 12-18 month study

• Platelets collected in 100% plasma (not PAS-3)

• Safety and efficacy of INTERCEPT-treated platelets supplied for routine clinical transfusion practice assessed

• FDA requested interventions be introduced in response to the 2013-2014 CHIKV outbreak; only CERUS responded

TRUE Overall Trial Design

• Prospective, open-label, multi-center, observational, treatment-use study designed to monitor the safety and efficacy of INTERCEPT-treated platelets

• Pilot Phase (Validation)

• Patients sign informed consent to have study data collected following transfusion with conventional PCs

• Evaluate study logistics and data collection methods

• Sites enroll at least one patient

• INTERCEPT Treatment-Use Phase

• Patients sign informed consent to receive INTERCEPT–treated platelets, to provide blood samples for study, and for collection of study data

• Hospitals carry inventory of conventional platelets (US mainland) for patients not enrolled

Subject Study-Specific Blood Sample Collection

• Recipient blood samples are collected and archived for future testing. Study-specific blood samples are collected at: • Study entry

• Before each platelet transfusion cycle, and

• Prior to hospital discharge (or on day 5 following each platelet transfusion cycle)

• All donor and recipient blood samples are:• Frozen and archived

• To be tested for RNA and/or viral serology if CHIKV or DENV TT infections are suspected

• Determine CHIKV/DENV RNA donor prevalence and whether associated breakthrough infections in transfused patients occur

• Testing of the donor repository is linked to the Roche cobas8800 CHIKV/DENV IND

Study results

• 90 patients received a total of 257 PCs

• 33 unrelated AEs, 19 unrelated SAEs

• 2 FNHTRs, 1 allergic reaction, unrelated

• Rates of AEs within expectations for patient population

• No suspected cases of CHIKV or DENV infection

• 1056 donor specimens tested nonreactive for DENV and

CHIKV RNA

Process Changes

• 100% of Puerto Rico apheresis platelet production treated with INTERCEPT process

• Standard products received from mainland to support hospitals or patients not participating in study

• Treated platelets ordered, stored, packed, and shipped separately from standard products

• No longer perform

• Bacterial culture (potentially yields at least one additional day of dating)

• Gamma irradiation

• CMV testing not required

• Continue to perform CMV due to existing configurations in ePROGESA

22

INTERCEPT Platelets Workflow

23

12 4 6 10 12 4 6 10

Day 0

TIME 10 2 8 2 8 12 2

Day 1

4 6 8 10 12

Bac

teria

l

Dete

ctio

n

Hold / Triage

Collection,

Receipt

4 62 8

Day 2

10 12 2 4

IncubationBac

T Release

INT

ER

CE

PT

Wo

rkflo

w O

ptio

ns

Infectious Disease Testing

8

Approach used in PR: INTERCEPT

treatment performed on Day 1 with a 16- 24

hour CAD.

*Minimum CAD times based on suspension medium

(100% Plasma)

Collection,

Receipt

Triage

P

I16hr CAD*

Infectious Disease Testing Release

Positive Outcomes

• Use of INTERCEPT and elimination of bacterial

culture reduced nearly one day of processing time

• Collaboration between the Red Cross and Cerus

resulted in reduced implementation period• Teamwork used effectively during development of procedures and

training, creation of validation plan, and delivery of training

• Phased implementation, relatively small staff, and

highly attentive trainers established some excellent

work habits• Platelet yield reduction was lower than originally anticipated (< 5%)

24

Challenges

• Limited resources and competing priorities for hospitals in Puerto Rico

• Implemented under a “study” (i.e., informed consent, patient data capture and monitoring)

• Conversion to PAS to simplify study requirements

• Main challenge to broader participation is education of hospital staff

• Physicians are unfamiliar with the technology, benefits and worldwide experience

25

American Red Cross PI program

• Driven by hospital demand: strategy is to support

requests

• Perceived drivers are management of bacterial

contamination of platelets

• Replacement of selected activities

• Irradiation

• CMV testing

• Others to come?

• Perceived value for emerging infections

• Some value for known infections

• Apheresis platelets only

Benjamin et al; accepted Transfusion

n=156,773 2.52x10^6 1.3x10^6 306,970 252,809 2.3x10^6

82.9

35.6

5.4

16.3

19.

0

ARC = 10

27

ARC Data Summary: bacteria in PCs

• BacT detection rates:

• 1:2500, prior to routine testing

• 1:5000, 2008 to present, overall – no change

• 1:3000-1:5000, false-negative rate (reculture, Gram-stain or Verax at

outdate)

• STR rates:

• 1:36,000 prior to routine testing

• 1:109,000, 2008 to present, overall – no change

28

29

6312

10

16

Options to meet FDA guidance on bacterial contamination

Pathogen Reduction RBT

Combination of Both Undecided

*RBT (rapid bacterial-test) aka POI (point-of-issue)

D e m a n d S n a p S h o t

• Hospitals are well informed on the FDA Draft

guidance and options

• A ready-to-use, singular approach to meeting

regulatory requirements and patient

transfusion needs

• Pathogen-reduction was the favoured choice

• Price of PR is well known

• FDA guidance is a key influencer in select

markets

• Some hospitals will remain committed to PR

regardless of guidance timelines

Demand Analysis…

.

INTERCEPT for platelets

Illuminator

PR Site Selection: First Implementers

Pomona

Oakland

Charlotte

Baltimore

Norfolk

Farmington

West HenriettaSt. Paul

St. Louis

32

Nashville

PAS – A Stepping Stone to PRT

• Successful PRT implementation requires robust PAS collections • ARC collects apheresis platelets using the Amicus device• Intercept is only licensed on Amicus with PAS 3 (Intersol)

• PRT manufacturing needs sufficient PAS starting material to select from • Not all PAS collections are eligible for PRT due to the volume guard bands and

triple bag collections not yet being approved

• PRT platelets must be illuminated within 24 hours of collections so importing PAS collections is unworkable in most sites

• ARC is expanding PAS capacity system wide• Converting several collections sites to PAS to augment PRT supply• Need to maintain a strong PAS customer base independent of PRT for product

that cannot be pathogen reduced• Depending on site, hospitals may need to transition to PAS then PR

33

PI: Year One Successes

34

Deployed illuminators and began

pathogen inactivation in ten

manufacturing sites

10Currently distributing pathogen-

reduced platelets to seventeen

early adopter hospital customers

17

Of total 164 apheresis collections

sites targeted to be 100% PAS

75Estimated current demand for

pathogen-reduced platelets

20%

Sites Customers

Total platelet distributions Fixed sites

C o n t i n u e d g r o w t h a n d i n v e s t m e n t i s p r e d i c a t e d o n t h e s t a t e d h o s p i t a l d e m a n d a n d a b i l i t y t o i n c r e a s e P R

s u p p l y

…

Risk & Issue Summary

• Current ARC SDP collections practice to maximize

potential for triple restrict the amount of collections eligible

for PRT treatment based on current INTERCEPT input

specifications

• Cerus will not have a PR kit for triples until late 2018 at

the earliest

• ARC has noticed an increase in number of invalid residual

platelet counts (>100% residual count)

• Slow ramp of demand has led inefficient data to calculate

maximum number of products that can be produced at

each site

35

Qualifying a Pathogen-reduced Platelet

• Historical and ongoing strategy to focus on triple

collections limits potential for units to qualify for PR• Of the units collected, 30% are from triples leaving doubles/singles

to qualify

• Due to guard bands more than half of the units will fail

• Targets

• Set Points

• Default values for first time donors

• Limited number of units qualify for PR out of the original

units collected

• Further reductions in percentage of eligible PR unts:

• HLA/ABO RH

• Competing demand for PAS units in certain markets

<30.0%

Singles

<15.0%

Doubles

Successful

36

Qualifying a Pathogen-reduced Platelet

• Of the units collected, 30% are from triples leaving doubles/singles to qualify

• Due to guard bands more than half of the units will fail

• Targets

• Set Points

• Default values for first time donors

• Limited number of units qualify for PR out of the original

units collected

• The following are the Cerus INTERCEPT guard bands that are used to qualify

apheresis platelets in PAS for pathogen reduction:

~55%

Singles

46%

Doubles

Successful

38

ParameterSmall

Volume Set

Large Volume

SetDual Storage

Platelet Yield (×1011) 2.9 - 5.0 3.0 - 6.0 6.1 - 8.0Volume (mL) 255 - 325 325 - 390 375 - 420*Plasma/PAS volume

0

100

200

300

400

500

600

700

800

900

0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0

Vo

lum

e

Yield

PR eligible units - All Sites

PR Eligible

Not PR Eligible

Increase Eligibility of Units Qualifying for PR

• Red Cross has developed a series of mitigations to increase percentage of units that qualify for PR without reducing the number of split products

Lower Split Point for Doubles

• Operation trial underway to determine if ARC split point for PR doubles can be reduced from current 7.3 yield to a point as low as 6.6 • Conservative split point set based on advice from Cerus and data gathered

during True Study in Puerto Rico

• Data analysis indicates that if successful, the mitigation could increase number of eligible PR units by 4.5%

40

Increase Eligibility of Units Qualifying for PR (cont.)

• Volume Reduction

• Evaluating feasibility of removing volume product from a homogenous mixture of PAS platelets in order to meet Cerus guard bands.

• Initial analysis indicates a potential 39% increase in single units and 6% double units that are eligible for PR

• Mitigation to Absence of Triple Kit

• Evaluating feasibility of splitting units prior to PR and using various mixes of Cerus kits to treat all products from a triple

• Configuration of ePROGESA and revised procedures required• Initial analysis indicates a potential 34% increase in units that are eligible for

PR

41

Additional Mitigations

• Embarked on process to routinely gather data

• Creating sustainable approach to gathering and analyzing data to monitor performance, trends, and results of mitigations

• Using Lean engineering team to assess process flow and batch sizes in order to

• Optimize use of illuminators

• Ensure sufficient time to meet 24 hour post collection requirement to PR including addition of mitigation steps in manufacturing

• Assessing approach to programming Amicus devices to blend high potential split rate with increasing percentage of units eligible for PR while maintaining donor comfort

42

Hospital Adoption Timeline

Engagement/ Education• Transfusion MD

• Grand Rounds

• Department meetings

Approvals • Transfusion

Practice Committee

• Medical Executive Committee

• Budget

• Contracting

Implementation• Hospital Readiness

Planning

• Transfusion Policy Changes

• BB IT changes

• Billing Systems

• BB Inventory Management

• Ordering processes

• Nursing In-service

6 – 9 months 3+ months

Educating, forecasting, building capacity, contracting, implementing checklist

Blood Center Readiness

• Success of PI hinges on the partnership between Blood Center and hospital

• Realistic expectations on availability and timing must be established as we launch

– Hospitals will need to transition to PAS prior to PR platelets

– Need standalone PAS customers after PR platelets are introduced in market

– 100% light switch conversion to PR is not possible, need cooperation from hospital to develop steady ramping schedule to desired levels

– Plan to manage dual inventory

– Prepare that some portion of inventory may require RBT

• Hospital implementation for PR platelets is involved, start early

Early Learning

Hospital

Demand

PASLocation of

Manufacturing PRT

Perspective

• Current approach of continued new testing is not

sustainable

• Pathogen reduction is a proactive solution

• Particular current focus on bacteria

• Costly, but has the potential for eliminating many existing

tests/processes

• Active interest from a proportion of hospital customers

• Current constraints need resolution of guard-band issue

and implementation of program for triple-bag collections

Acknowledgements

• I am grateful to the following for support and for slides

• Susan Stramer

• David Reeve

• Rachel Smith