The audience was welcomed by the chairman who introduced the meeting and outlined the programme.

Completed Reports 1996/1997. I.R. Peake.

Collaborative study on assays of activated FIXa by E. Gray et al., Thrombosis and Haemostasis 1996, 76, 1114-1117.

Final Stages:

Nijmegen modification of the Bethesda assay. A. Giles et al.

Revision of viral safety protocol. F. Hill, North American registry of immune tolerance protocols. D. DiMichele (not yet submitted).

Final Report:

The use of porcine FVIII in infants and children - J. Lusher. To be produced after inclusion of further material from the UK.

Reports of On-going Activities:

The pharmacokinetics of factor VIII and IX in infants - J. Lusher. Protocol produced. More recruitment needed.

Viral transmission by blood products in noninfected patients by PCR technology - E. Berntorp, one year to go before final recommendation would be possible.

New Proposals:

Registry of factor VIII/IX concentrates - C. Kasper. No report given. Chair has received a draft. Final form next year.

Protease inhibitors and bleeding in haemophilia - E. Briët.

Case report presented. Participant meeting arranged for p.m. to consider recommendations and reporting.

Recommendations on the use of PUPs and PTPs - G. White.

Proposal forwarded to study PTP instead of PUP in clinical immunogenicity trials. Comments to Dr. White within four weeks. Proposal to be written.

Risk Factor Assessment for Inhibitor Development:

Product-related Risk. Y. Sultan, chairman.

Incidence of FVIII inhibitors in PUPs treated with recombinant FVIII: Introduction - Y. Sultan. Dr. Sultan summarized recent French data on inhibitor occurrence.

Data from France and USA - C. Rothschild. Dr. Rothschild gave a detailed report on a French study of 53 PUPs treated with rVIII. D. DiMichele reported on local US and PR cohort comparing two rVIII treated groups with patients shifted from plasma-derived factor VIII to recombinant.

Proposal for a French-American-International Registry - L. Aledort, Y. Sultan. The questionnaire was outlined by Dr. Aledort. Additions to include genetic information and patients treated with a plasma-derived product. Current and past inhibitors should be requested also. Dr. C. Hay also outlined preliminary data on UK PUPs.

Inhibitors in mild and severe haemophilia - F. Rosendaal. Reviewed Dutch patients estimating the spontaneous occurrence of inhibitors and those related to particular product.

Genetic Risk. L. Hoyer, Chairman

Kogenate inhibitor study - J. Lusher. Outlined proposed study which will commence soon.

Recombinate inhibitor study - A. Goodeve. Detailed the present genetic information on the Recombinate study.

Immunogenetic risk - C. Hay. Outlined situation and stressed that ethnic differences make studies very difficult.

Risk and Assay Variability. D. DiMichelle, Chairman

Inhibitor assay variability in Canada - A. Giles. A positive inhibitor result may be influenced by methodology adopted, type of equipment, and type of deficient plasma. Chemically depleted FVIII deficiency plasma should not be used.

Inhibitor assay variability in UK - S. Kitchen, E. Preston. Dr. Kitchen reported the UK NEQAS study that showed wide variation.

Summary and Proposed Inhibitor Risk Guidelines. I. Peake, F. Rosendaal.

Discussion followed. Nijmegen modification of the Bethesda assay to be endorsed by the SC. Attempts to reduce cost of materials to be explored by Dr. Giles. Working group to meet soon to study in detail the possibility of preparing guidelines and definitions of inhibitors for possible publication to assist in the prediction of inhibitor development. Commercial companies to be asked to contribute.

Standardization Issues. C. Prowse (UK), K. Mertens (NL), chairmen.

FIX Standards. Dr. M. Weinstein reported on the finalized work on a new FDA/EP standard for Factor IX concentrate, and Dr. E. Gray reported on the development of a new activated FIX standard (FIXa) (potency not yet established).

FVIII Standards. Dr. M. Weinstein reported on the ongoing work with a new factor VIII concentrate MEGA standard (MEGA II). Multicentric potency estimation to be performed. Dr. T. Barrowcliffe reported that new WHO standards for plasma and concentrate FVIII will be prepared during 1998 for final release during 1999.

Discussion followed. Members expressed hope that harmonization between US and WHO standards could be reached.

Collaborative Studies: results of SSC studies.

Report of 1996/1997 studies. S. Raut reported on two FVIII studies (SSC3 & SSC4) of FVIII at two different potency levels. Recombinant & intermediate purity concentrate show a wide inter-laboratory variation. Factor VIII concentrate study to be continued for another 12 months.

Plasma and Concentrate Units and in vivo Recovery.

Summary of the Problem. T. Barrowcliffe. The problem was outlined. Post-infusion Factor VIII:C levels are subject to variation dependent of the method adopted to measure FVIII (one-stage or chromogenic substrate method).

A Fractionater's View. M. Mikaelsson. Data presented indicating that concentrate added to haemophilia plasma (e.g., after injection) does not compare well with a plasma standard but compares more accurately with a concentrate standard.

A Clinician's View. C. Lee. Data presented (UK Hemofil M & Recombinate pharmakokinetic study) illustrated that potency assessment of a concentrate as well as the quantitation of VIII:C in post-dosage samples gave higher values with chromogenic substrate methods than one-stage procedures.

Discussion. Dr. J. Lusher stressed the importance of assay discrepancies as demonstrable in pharmacokinetic analysis, showing data signifying an increased peak FVIII:C value as well as an apparently prolonged in vivo half-life value when the chromogenic assay was used. Dr. Lusher further suggested a clinical review of databases of PUP and PTP recombinant studies to search for a bleeding/dosage relationship.

Recommendations. Dr. T. Barrowcliffe argued that the reasons for assay discrepancies are not understood and proposed to the SC

1. that recovery should be based on one-stage assays until more information is obtained;

2. that post-infusion samples should be assayed against the concentrate standard, preferably the same material as was infused; and

3. that the concentrate standard should be diluted in hemophilic plasma (preferably from the patient).

In conclusion, it was hoped that further studies would help to overcome these problems. The possibility of dosage/effect studies will be explored.

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