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Safety and Supply of hemophilia products


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Presented to the European Haemophilia Consortium
Vilnius, Lithuania, September 2009

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Safety and Supply of hemophilia products

  1. 1. Safety and Supply of plasma-derived hemophilia products Presented to the European Haemophilia Consortium Vilnius, Lithuania, September 2009 Albert Farrugia Plasma Protein Therapeutics Association
  2. 2. <ul><li>Tremendous and rapid advances in fractionation in the 1960’s and 70’s enabled concentrate manufacture to emancipate haemophiliacs </li></ul>
  3. 3. <ul><li>Plasma-derived & Recombinant Both Important </li></ul><ul><li>Robust record of safety for both </li></ul><ul><li>Supply of either alone insufficient </li></ul><ul><li>Range of product cost </li></ul><ul><li>Therapeutic benefit </li></ul><ul><ul><li>Treatment for rare factor deficiencies & vWD </li></ul></ul><ul><ul><li>Patient or physician assessment </li></ul></ul><ul><li>Maintain flexibility </li></ul><ul><li>Adverse event risk </li></ul>Choice of Treatment Products
  4. 4. Pathogens transmitted by factor concentrates <ul><li>HIV </li></ul><ul><li>HCV </li></ul><ul><li>HBV </li></ul><ul><li>HAV </li></ul><ul><li>HPB19 </li></ul>
  5. 5. 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.
  6. 6. The road to SAFE hemophilia products <ul><li>Through: </li></ul><ul><li>Mandated – legally binding – measures </li></ul><ul><li>Voluntary industry standards </li></ul>
  7. 7. Standards and Certification Relative risk From the general public to the patient Finished product Virus inactivation / removal steps Dilution by pooling NAT testing Testing donations Inventory Hold Donor selection Donor population
  8. 8. PPTA Standards Programs <ul><li>Quality Standards of Excellence, Assurance and Leadership (QSEAL) </li></ul><ul><ul><li>Program for final therapies </li></ul></ul><ul><ul><li>Inventory Hold </li></ul></ul><ul><ul><li>Nucleic Acid Amplification Testing (NAT) </li></ul></ul><ul><ul><li>Parvovirus B19 testing </li></ul></ul><ul><li>International Quality Plasma Program (IQPP) </li></ul><ul><ul><li>Program for source plasma collectors </li></ul></ul><ul><ul><li>Qualified donor standard </li></ul></ul><ul><ul><li>Viral marker standard </li></ul></ul><ul><li>Both programs include independent audits </li></ul>August 30, 2006 NBA, Australia
  9. 9. Industry standards Selection <ul><li>Reduction of risk: approx. 100-fold </li></ul><ul><ul><li> PPTA: voluntary standard </li></ul></ul><ul><ul><li> plus: QSEAL certification </li></ul></ul>Kreill 2006
  10. 10. M Busch, JAMA 2003 Kreill 2006 Testing <ul><li>Reduction of risk: approx. 100-fold </li></ul><ul><ul><li>( B19V PCR : up to 100,000-fold reduction of load) </li></ul></ul>
  11. 11. <ul><li>B19 Viral load of plasma pools:  </li></ul><ul><li>reduction by PCR </li></ul>average reduction of viral load by > 5 log 10
  12. 12. <ul><li>Emerging Pathogens </li></ul><ul><li>West Nile Virus </li></ul><ul><li>Incubation period ranges from 3-14 days </li></ul><ul><li>Most infected individuals have no symptoms--20% develop only mild ones </li></ul><ul><li>Individuals are most viremic in asymptomatic state; however, viremia usually is transient and people clear the virus very quickly </li></ul><ul><li>Approx. 1 in 150 (<1%) of those infected result in severe and sometimes fatal illnesses (meningitis, encephalitis, paralysis) </li></ul><ul><li>Among those with severe illness, mortality rate is 3-15% </li></ul>
  13. 13. Organ Donor 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 Kidney recipient WNME (fatal) Kidney recipient WNME Liver recipient WNF Heart recipient WNME
  14. 14. WNV Inactivation in FVIII
  15. 15. Risk of vCJD <ul><li>Infectious disease affecting the brain </li></ul><ul><li>Transmitted from cows with a related condition – BSE </li></ul><ul><li>Mostly affected people living and consuming beef in UK </li></ul><ul><li>Can be transmitted by blood transfusion </li></ul>
  16. 16. vCJD abnormal prion protein found in a patient with haemophilia at post mortem <ul><li>70 years old PWH died of a condition unrelated to vCJD </li></ul><ul><li>No symptoms of vCJD prior to his death </li></ul><ul><li>vCJD abnormal prion protein identified during post mortem research tests </li></ul><ul><li>New finding will not change the way patients with haemophilia are treated </li></ul><ul><li>Final view as to how prion protein was transmitted has yet to be reached </li></ul><ul><li>Investigations are continuing </li></ul><ul><li>Patient had been treated with UK sourced clotting factors before 1999 </li></ul><ul><li>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 </li></ul>
  17. 17. The road to SAFE hemophilia products vCJD Geographical deferrals Test not available, under development Processes can clear infective agent
  18. 18. VCJD risk reduction and donor loss estimates FDA/CDC Risk-weighted exposure day model Selection – deferral policies have modest results and will not affect significantly the potential of contaminating a plasma manufacturing pool Policy Risk reduction % Donor loss % Efficiency Risk 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
  19. 19. 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 process r = rate of TSE infection in Australia blood donors v = volume of blood / plasma donation i = number of infectious TSE units per ml plasma u = number of units of product from production process l = log reduction in number of TSE infectious units during production process Estimating vCJD risk in factor concentrate 1 log manufacture reduction of vCJD agent 2 FVIII used per year (IU/Y,person 3 Prevalence of UK vCJD (cases/million) 4 efficiency of i.c vs i.v route 5 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
  20. 20. TSE Clearance in FVIII concentrates PPTA companies Product Step MAB column Q-Sepharose chromatography Total A Log reduction(s), ID 50 4.6 3.5 8.1 Step 3.5% PEG pptn Heparin chromatography Saline pptn + final filtrations A Log reduction(s), ID 50 3.32 > 3.45 2.28 > 9.05 Step Subsequent pptn steps Pptn+polishing+sterile filtration A Log reduction(s), ID 50 3.5 – 3.9 2.9 – 4.0 6.4 – 7.9
  21. 21. WFH April 2009 <ul><li>“ 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” </li></ul>
  23. 23. 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
  24. 24. How much FVIII for the world? <ul><li>The World Federation of Hemophilia (WFH) claims that unconstrained demand, including prophylaxis, would result in a FVIII consumption of 6.9 IU per capita </li></ul><ul><li>This level is attained or exceeded currently by only 4 out of 104 countries reporting to WFH. </li></ul>
  25. 25. Less joint damage Less joint hemorrhages Less total hemorrhages
  26. 26. <ul><li>Between 1998 and 2006, the global factor VIII demand grew by about 3% per year. </li></ul><ul><li>By 2012, the global factor VIII demand is forecast to reach 2.5 billion international units (+2.5% per year from 2006). </li></ul><ul><li>In the industrialized countries, the factor VIII demand will be primarily be met by recombinant products. </li></ul>
  27. 28. Plasma for manufacture
  28. 29. Plasma in the EU – Some realities <ul><li>The EU is composed of 27 countries with a population of 500 million </li></ul><ul><li>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 </li></ul><ul><li>In addition, one country of 10 million population is on the verge of becoming a supplier of plasma for export </li></ul>
  29. 30. <ul><li>The total plasma for fractionation from all parts of the sector – for profit/for export and “self-sufficiency” is 4812 thousand litres </li></ul><ul><li>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 </li></ul><ul><li>Are the people with haemophilia in Europe willing to accept this level of therapy? </li></ul>Plasma in the EU – Some realities
  30. 31. Conclusions <ul><li>Safety </li></ul><ul><li>Industry and authorities have worked together to make plasma protein therapies the safest of medicines </li></ul><ul><li>These measures have proven effective against known and unknown agents </li></ul><ul><li>Nevertheless, constant vigilance is required and the industry is actively doing this </li></ul><ul><li>Supply </li></ul><ul><li>Treatment of haemophilia is still lacking for most patients with the condition </li></ul><ul><li>For adequate access to treatment, barriers based on economic or ideological interests affect patient care </li></ul><ul><li>As the safety problems recede, barriers to access must engage the attention of patients, industry and decision makers </li></ul>