Safety and Supply of plasma-derived hemophilia products

Presented to the European Haemophilia Consortium

Vilnius, Lithuania, September 2009

Albert Farrugia

Plasma Protein Therapeutics Association

www.pptaglobal.org

• Tremendous and rapid advances in fractionation in the 1960’s and 70’s enabled concentrate manufacture to emancipate haemophiliacs

Plasma-derived & Recombinant Both Important

• Robust record of safety for both

• Supply of either alone insufficient

• Range of product cost

• Therapeutic benefit

– Treatment for rare factor deficiencies & vWD

– Patient or physician assessment

• Maintain flexibility

• Adverse event risk

Choice of Treatment Products

www.pptaglobal.org

Pathogens transmitted by factor concentrates

• HIV

• HCV

• HBV

• HAV

• HPB19

www.pptaglobal.org

Blood infections in US hemophiliac birth cohorts

CDC survey

HBV (▪), HCV ( ), and HIV-1 ( )▴ ◯ The proportion was zero for HIV after 1984, for HCV after 1992, and for HBV after 1993.

www.pptaglobal.org

The road to SAFE hemophilia products

Through:

•Mandated – legally binding – measures

•Voluntary industry standards

www.pptaglobal.orgwww.pptaglobal.org

Standards and CertificationR

elat

ive

risk

From the general public to the patient

Finished product

Virus inactivation / removal steps

Dilution by pooling

NAT testing

Testing donations

Inventory Hold

Donor selectionDonor population

www.pptaglobal.orgAugust 30, 2006 NBA, Australia

PPTA Standards Programs

Quality Standards of Excellence, Assurance and Leadership (QSEAL)

• Program for final therapies• Inventory Hold• Nucleic Acid Amplification Testing (NAT)• Parvovirus B19 testing

International Quality Plasma Program (IQPP)• Program for source plasma collectors• Qualified donor standard• Viral marker standard

Both programs include independent audits

www.pptaglobal.org

Selection

• Reduction of risk: approx. 100-fold

PPTA: voluntary standard

plus: QSEAL certification

Kreill 2006

Industry standards

www.pptaglobal.orgM Busch, JAMA 2003 Kreill 2006

Testing• Reduction of risk: approx. 100-fold

– (B19V PCR:up to 100,000-fold reduction of load)

www.pptaglobal.org

• B19 Viral load of plasma pools: • reduction by PCR

1,0E+00

1,0E+01

1,0E+02

1,0E+03

1,0E+04

1,0E+05

1,0E+06

1,0E+07

1,0E+08

1998 2001

Parv

o B

19 [

IU/m

l]

average reduction of viral load by > 5 log10

www.pptaglobal.org

Emerging Pathogens West Nile Virus

• Incubation period ranges from 3-14 days

• Most infected individuals have no symptoms--20% develop only mild ones

• Individuals are most viremic in asymptomatic state; however, viremia usually is transient and people clear the virus very quickly

• Approx. 1 in 150 (<1%) of those infected result in severe and sometimes fatal illnesses (meningitis, encephalitis, paralysis)

• Among those with severe illness, mortality rate is 3-15%

www.pptaglobal.org

Organ Donor

Kidney recipientWNME (fatal)

Kidney recipientWNME

Liver recipientWNF

Heart recipientWNME

Blood components 63

donors

Organ Donor

36 hours

F/U: 1 seroconverting donor;Retrieved, stored plasma – WNV PCR-positive

WN virus infection in organ donor and four organ recipients, August 2002

WNV PCR-neg

WNV IgM-neg

WNV PCR-pos

WNV culture-pos

WNV IgM-neg

www.pptaglobal.org

Treatment of AHF-M with 10% SD chemicals

0 10 20 30 40 50 60

0

2

4

6

8

limit of detection

WNV run 2

WNV run 1

BBBB

BVDV

BB

B

duration of SD treatment [min]

log

10 [

TC

ID5

0/m

l]

WNV Inactivation in FVIII

www.pptaglobal.org

Risk of vCJD

• Infectious disease affecting the brain

• Transmitted from cows with a related condition – BSE

• Mostly affected people living and consuming beef in UK

• Can be transmitted by blood transfusion

www.pptaglobal.org

vCJD abnormal prion protein found in a patient with haemophilia at post mortem

•70 years old PWH died of a condition unrelated to vCJD

•No symptoms of vCJD prior to his death

•vCJD abnormal prion protein identified during post mortem research tests

•New finding will not change the way patients with haemophilia are treated

•Final view as to how prion protein was transmitted has yet to be reached

•Investigations are continuing

•Patient had been treated with UK sourced clotting factors before 1999

•Patient's treatment had included one batch of Factor VIII that was

manufactured using plasma from a donor who went on to develop

symptoms of vCJD six months after donating the plasma in 1996

www.pptaglobal.org

The road to SAFE hemophilia productsvCJD

Geographical deferrals

Test not available, under development

Processes can clear infective agent

VCJD risk reduction and donor loss estimates FDA/CDC Risk-weighted exposure day model

Policy Risk reduction %

Donor loss % EfficiencyRisk reduction/donor loss

A 68 2.2 31

B 82 2.2 20

C 92 7.8-9.1 9.7-8.4

D 91 4.6-5.3 15.7-13.6

Selection – deferral policies have modest results and will not affect significantly the potential of contaminating a plasma manufacturing pool

Australian TGA RA (Similar to all others)Probability that a unit of medical product contains TSE infectious units is given by:

P = (d*r*v*i) / (u*l)Where d = number of blood / plasma donations

pooled in production processr = rate of TSE infection in Australia blood

donorsv = volume of blood / plasma donationi = number of infectious TSE units per ml

plasmau = number of units of product from

production processl = log reduction in number of TSE infectious

units during production process

Estimating vCJD risk in factor concentrate

1 log manufacture reduction of vCJD agent2 FVIII used per year (IU/Y,person3 Prevalence of UK vCJD (cases/million)4 efficiency of i.c vs i.v route5 Infectivity in blood (ID50/ml)6 Yield of FVIII from plasma (IU/L plasma)7 Efficiency of donor deferral policy

7 6 5 4 3 2 1

Factors decreasing risk

Factors increasing risk

TSE Clearance in FVIII concentratesPPTA companies

Product

Step MAB column

Q-Sepharose chromatography

Total

ALog reduction(s), ID50 4.6 3.5

8.1

Step 3.5% PEG pptn

Heparin chromatography

Saline pptn + final

filtrations

ALog reduction(s), ID50

3.32 >3.45 2.28 >9.05

Step Subsequent pptn

steps

Pptn+polishing+sterile filtration

ALog reduction(s), ID50

3.5 – 3.9 2.9 – 4.0 6.4 – 7.9

WFH April 2009

“Although this case suggests that those

patients exposed to contaminated

products in the past may be at risk for vCJD, it

does not mean that current plasma-derived

products on the market today carry such risk”

RISK OF HIV INFECTION FROM PLASMA FACTOR CONCENTRATE

www.pptaglobal.org

Source: WFH Global Survey 2001-2007

Factor VIII IU Per Capita

Meanwhile, the vast majority of the world’s potential recipients of

haemophilia productslive a short life filled with pain and suffering

www.pptaglobal.org

How much FVIII for the world?•The World Federation of Hemophilia (WFH) claims that unconstrained demand, including prophylaxis, would result in a FVIII consumption of 6.9 IU per capita

•This level is attained or exceeded currently by only 4 out of 104 countries reporting to WFH.

www.pptaglobal.org

Less joint damage

Less joint hemorrhages

Less total hemorrhages

www.pptaglobal.org

1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012

1,438 1,4811,612

1,8371,719

1,878

1,663

2,124 2,111 2,115

2,304 2,3502,421 2,493

0

500

1,000

1,500

2,000

2,500

WORLDWIDE DEMAND FOR FACTOR VIII 1986 - 2012Plasma-derived, Million International Units

• Between 1998 and 2006, the global factor VIII demand grew by about 3% per year.

• By 2012, the global factor VIII demand is forecast to reach 2.5 billion international units (+2.5% per year from 2006).

• In the industrialized countries, the factor VIII demand will be primarily be met by recombinant products.

www.pptaglobal.org

www.pptaglobal.org

Plasma for manufacture

www.pptaglobal.org

Plasma in the EU – Some realities

• The EU is composed of 27 countries with a population of 500 million

• Of these, two countries with a population of 91 million collect source plasma for manufacture, much of which is processed by the for profit sector

• In addition, one country of 10 million population is on the verge of becoming a supplier of plasma for export

www.pptaglobal.org

• The total plasma for fractionation from all parts of the sector – for profit/for export and “self-sufficiency” is 4812 thousand litres

• If fractionated to FVIII assuming a yield of 180 IU/litre – the best yield achievable by the low purity products – it generates 1.73 IU/capita

• Are the people with haemophilia in Europe willing to accept this level of therapy?

Plasma in the EU – Some realities

www.pptaglobal.org

Conclusions

Safety• Industry and authorities have

worked together to make plasma protein therapies the safest of medicines

• These measures have proven effective against known and unknown agents

• Nevertheless, constant vigilance is required and the industry is actively doing this

Supply• Treatment of haemophilia is

still lacking for most patients with the condition

• For adequate access to treatment, barriers based on economic or ideological interests affect patient care

• As the safety problems recede, barriers to access must engage the attention of patients, industry and decision makers