WFH GLOBAL FORUM · they don’t know what causes AIDS. Another suggested that although prions are...

WFHGLOBAL FORUM

on the Safety and Supplyof Hemophilia Treatment Products

Montreal, CanadaJanuary 21-22, 2002

WFH Global Forumon the Safety and Supply of Hemophilia Treatment Products

Montreal, Canada • January 21-22, 2002 3

Table of Contents

WFH Global Forum – Executive Summary...................................................................................... 5

Session 1: Variant CJD – The State of Affairs..................................................................................11Opening Address.................................................................................................................................................. 11Experimental Transmission of vCJD Through Blood Components.................................................................... 11The Risk of vCJD in Blood Products – Global Regulatory Response............................................................... 13World Health Organization Activities on vCJD.................................................................................................. 14Variant CJD – The State of Affairs from an Industry Perspective...................................................................... 15The State of Affairs – Treater Perspective.......................................................................................................... 16A Patient’s Perspective of vCJD.......................................................................................................................... 16Discussion............................................................................................................................................................ 17

Session 2: The Decision-making Process – A Question of Risk................................................ 19Is History Being Repeated? A Comparison of vCJD with HIV.......................................................................... 19Assessing the Risk of vCJD: A Decision-making Model................................................................................... 19Risk Assessment from a Hemophilia Organization’s Perspective...................................................................... 20A Regulator’s View of Risk and Risk Assessment (EMEA).............................................................................. 21Risk Assessment from a Regulator’s Perspective (FDA)................................................................................... 21Risk Assessment – Industry Perspective (PPTA)............................................................................................... 23Discussion........................................................................................................................................................... 23

Session 3: Current Supply Issues – Recombinant and Plasma Product Shortages.........25Industry Perspectives (PPTA)............................................................................................................................. 25Industry Perspectives (EPFA)............................................................................................................................ 27The Influence of the Shortage of Recombinant Products on Treatment............................................................ 27The Perspective of the Hemophilia Treater........................................................................................................ 28Patient Organization Perspective (U.S.)............................................................................................................. 29Patient Organization Perspective (Malaysia)..................................................................................................... 29Patient Organization Perspective (Brazil).......................................................................................................... 30Needs Assessment of Factor VIII Usage in China............................................................................................. 30

Session 4: Open Forum Discussion..................................................................................................... 33

Session 5: Communicating Risk - The Example of vCJD......................................................... 37The U.K. Experience – Treater Perspective...................................................................................................... 37The U.K. Experience – Patient Association Perspective.................................................................................. 37Discussion........................................................................................................................................................... 38

Session 6: Global Regulatory Assessment of Products................................................................ 41Review of Assessment Processes Worldwide.................................................................................................... 41Assessment of Products Not Licensed by the FDA and the EMEA.................................................................. 42The WFH Regulatory Guide.............................................................................................................................. 43Discussion.......................................................................................................................................................... 43

Session 7: Feedback and Next Steps.................................................................................................. 45

List of Participants.................................................................................................................................... 47



blood or have transmitted infectious pri-ons through any blood products. Despitethe mounting evidence that vCJD is nottransmissible through blood products,Mr. Waller stressed, the industry contin-ues to treat the theoretical risk as a realrisk.

Wolfgang Schramm (Ludwig-Maximilian University HemophiliaCentre) agreed, stating that the transmis-sion of vCJD via plasma seems unlikelysince the agent is almost completelyeliminated during the productionprocess. Although it is never possible tocreate complete safety, Prof. Schrammcontended that the blood supply is thesafest it has ever been. Still, from atreater’s perspective, it is critical to bal-ance safety measures with supply con-cerns, he said. Hemophilia is a life- andlimb-threatening disease that necessitatesthat real risks must be balanced, and thatincludes the risks attendant upon productshortages, he said.

This subject generated much discussionand debate. A number of participantscautioned against being overly optimisticregarding the evidence on vCJD trans-mission so far. It is too soon to say, con-clusively, that the results of real cases ofvCJD patients are reassuring, anotherparticipant said, while stressing that the-oretical studies have been much lessreassuring.

There was a marked change in opinionof patients on whether vCJD can betransmitted through blood products. Atthe start of the session, 22 percent ofrespondents agreed that vCJD could betransmitted through blood products, butat end of the session, 43 percent agreed.

More than 100 participants from aroundthe world gathered in Montreal for thesecond WFH Global Forum on theSafety and Supply of HemophiliaTreatment Products. The forum includedrepresentatives from major regulatorybodies, leading scientists, specialists, cli-nicians in the field, leaders from hemo-philia societies, and representatives ofcommercial and not-for-profit producersof blood products.

Discussion focused on the two criticalissues of variant Creutzfeldt-Jakob dis-ease (vCJD) and the recombinant prod-uct shortage. As outbreaks of bovinespongiform encephalopathy (BSE)spread in Europe and now in Japan, andnew cases of vCJD are being diagnosed,the bleeding disorders community isbecoming very concerned with thisthreat. Issues addressed at the forumincluded: can vCJD be transmitted byblood? What is the level of risk? Whatmeasures are being taken to minimizerisks? Has communication about vCJDbeen effective or alarmist?

The recent recombinant shortage, whichbegan in March 2001, has become theprimary concern for the community aspatients are forced to switch products,treatment regimes are altered, and sur-geries and other procedures are beingpostponed. Discussions focused on whatthe cause and effects of the shortagewere, and how shortages can be avoidedin the future.

Different points of view on variousissues were presented, including those ofindustry, treaters, regulators, andpatients. In his opening address, BrianO’Mahony, President of the WorldFederation of Hemophilia, said the goalof the meeting was not to change view-points, but to bring new perspectivesinto an open and constructive dialogueon the issues.

To encourage participation and giveeveryone a say in the discussion, eachparticipant had an electronic voting padto capture audience opinion on theissues. To determine the impact of thediscussion on people’s opinions, thesame questions were asked at the begin-ning and end of a session. On someissues, different groups of participants(patients, regulators, industry, etc…)were asked to vote separately, whichrevealed some interesting differences.

Transmissibility of vCJD

One of the most important concerns forthe hemophilia community is whethervCJD is transmissible by blood.Scientists, treaters, and other presentersshared the latest information with forumparticipants.

There is no epidemiological or experi-mental evidence of vCJD transmissionthrough blood transfusion or use of plas-ma-derived products, explained LarisaCervenakova (The American Red CrossHolland Laboratory). However, data shepresented on her experiments with miceinoculated with blood components fromvCJD-infected mice did show that thedisease was transmissible by bloodunder laboratory conditions in someinstances. Noting that these data werenot conclusive, Dr. Cervenakova told theaudience that she looked forward toadditional data, which she hoped wouldhelp answer the question of whether ornot blood from patients with vCJD isinfectious.

Charles Waller (Plasma ProteinTherapeutics Association, Europe) saidthere is no evidence that people withpre-clinical or clinical CJD, includingvCJD, carry infectious prions in their

WFH Global Forum – Executive Summary


Montreal, Canada • January 21-22, 20026

risk of vCJD. He noted that the peak ofBSE in Europe is predicted to occurbetween 2002 and 2005, and that thehighest risk of plasma donor infectivityis in the U.K., France, and possiblyJapan. In addition, he reported that cur-rent methods for producing factor VIIIare expected to clear three to six logs ofinfectivity and factor IX manufacturingmethods should clear seven logs.

Overall, participants did not perceivevCJD to be as serious a threat as HIV.By the end of the session, 88 percent ofthose in the audience voted that they didnot perceive vCJD to be as dangerous asHIV was in 1982.

Do you feel that vCJD posesthe same threat to the hemo-philia community as HIV didin 1982?

Beginning of session:

Yes: 7%No: 82%Don’t know: 10%

End of session:

Yes 5%No 88%Don’t know 7%

Judging the relative risk in the face ofnumerous unknowns is the difficult taskregulators face, said Manfred Haase(European Agency for the Evaluation ofMedicinal Products). Risk analysis is ascientific evaluation of the probability ofoccurrence and the magnitude and sever-ity of the effect. In areas of uncertainty,he noted, there should be a balancebetween the need for clinical data toevaluate risks and the avoidance ofdelays in making available efficaciousmedicinal products to patients in medicalneed.

Francine Décary (Hema-Québec) elabo-rated on the process of making decisions

Other issues addressed the need to learnmore about TSEs.

Ana Padilla (World Health Organization)described the WHO’s activities onvCJD, including a project for the devel-opment of international reference materi-als for the diagnosis and study of humanTSEs (both spCJD and vCJD).Considerable progress has been made inthe development of laboratory tests forthe detection of the pathological protein(PrPSc), she reported, but the predictivevalues of these assays in terms of TSEinfectivity have not been independentlyconfirmed.

During the open forum session, GlennPierce (National HemophiliaFoundation) noted that the link betweenprions and infectivity is unclear.Participants had wide-ranging opinionson whether prions caused vCJD. Onelikened doubting the link between prionsand vCJD to governments claiming thatthey don’t know what causes AIDS.Another suggested that although prionsare the likely culprit, there is still a pos-sibility that vCJD may be a virus.

Assessing and Minimizing Risk

Discussion about assessing and minimiz-ing risk focused on techniques for evalu-ating risk in times of uncertainty and thedifficulty, for regulators and others, ofpredicting future outcomes. “We areforced to live with the reality that wecannot make decisions that eliminate allrisk for all patients,” said Bruce Evatt(Centers for Disease Control andPrevention, and WFH Vice-PresidentDeveloping World).

Risk Assessment

Dr. Evatt set the stage by providing aninsightful comparison on risk assessmentcomparing CJD and vCJD with HIV atsimilar points in their respective crisistimelines. He also provided someencouraging working assumptions on the

“With regard to the risk oftransmission of vCJD viareplacement therapy, are youvery concerned, concerned ornot concerned.”


Very concerned: 11%Concerned: 62%Not concerned: 28%

End of session:


“In the light of evidence cur-rently available, do youbelieve that vCJD can betransmitted through the infu-sion of coagulation factorconcentrates?”


Non-patients:Yes: 13%No: 55%Don’t know: 33%

Patients:Yes: 22%No: 28%Don’t know: 50%

End of session:

Non-patients:Yes: 13%No: 55%Don’t know: 33%

Patients:Yes: 43%No: 29%Don’t know: 35%



During discussion, it was acknowledgedthat those countries that imported MBMfrom the U.K. are starting to see BSE intheir own cattle. It was agreed that thisis a risk and that entry of TSEs into thefood chain needs to be studied moreclosely.

Regulatory process

In reviewing the regulatory process, Dr.Farrugia noted that plasma products arevery heavily regulated and dominated bythe FDA in North America and theEMEA in Europe. He described the sec-tor as “disproportionately regulated”given the actual risks involved, but con-ceded that this was a response to publicpressure based on historical events.

In less-resourced countries, there is atendency to accept the assessments anddecisions of the FDA and EMEA; this isundesirable, Dr. Farrugia said, because itdoes not take into consideration impor-tant local issues and discourages thedevelopment of independent regulatoryauthorities. Regulation, however, playsonly one part in issues around bloodproducts; market forces are also veryimportant.

There was a general call from partici-pants for more harmonization.However, during his presentation, JanM. Bult (Plasma Protein TherapeuticsAssociation) said harmonization of stan-dards is a long way off, and called fordebate in this area to be based more onscience than politics. The introduction ofnew regulations has to be carefully bal-anced against the potential impact onsupply, Mr. Bult concluded.

One of the recommendations from thefirst global forum was that the WFH pre-pare a regulatory guide to provide assis-tance to product prescribers, purchasers,and regulators. The guide is underwayand will cover aspects of hemophiliatreatment products, licensing arrange-ments, and guidance on good practices,and will include a glossary of terms. It isscheduled to be released in July 2002.

regarding risk, using the example of theCanadian province of Quebec as a casestudy. The recommendation on the pre-cautionary principle of the Commissionof Inquiry on the Blood System inCanada was the motor for decision-mak-ing. The recommendation calls for theprinciple of safety to transcend otherprinciples and it also states, “The bal-ancing of the risks and benefits of takingaction should be dependent not only onthe likelihood of the risk materializingbut also on the severity of the effect ifthe risk does materialize, on the numberof persons who could be affected, and onthe ease of implementing protective orpreventive measures. The more severethe potential effect, the lower the thresh-old should be for taking action.”

When asked to weigh the relative risk ofvCJD versus shortages of factor concen-trates, 95 percent of participants, and91 percent of patient group representa-tives, felt that shortages were a greaterrisk to people with hemophilia.

“Based upon current informa-tion, which do you think is agreater risk to people withhemophilia?”

All participants:vCJD 5%Shortages of factor

concentrates 95%

Patient groups only:vCJD 9%Shortages of factor

concentrates 91%

Minimizing Risk

Deferring blood donors who are at riskof being infected with vCJD has beenthe primary approach for minimizing therisk of vCJD in the blood supply. Thiswas an issue that received much atten-tion, given the U.S. Food and DrugAdministration’s recently revised guid-ance. However, speakers and partici-

pants addressed a variety of other issues,including steps in the manufacturingprocess of blood derivatives that removeTSE agents.

Dorothy Scott (U.S. Food and DrugAdministration) discussed vCJD risks indonors, which were taken into accountwhen the FDA developed new donordeferral guidelines. In predicting resultsof various deferral actions, differentmeasures have different effects uponsupply, but equivalent safety outcomes,she said. There was particular concernabout the effect on plasma derivativesupplies of a ban on donors who lived inEurope for five years or more. Anexception to the pan-European donordeferral was made for donors of sourceplasma for plasma derivatives, sheexplained, because manufacturing ofthese products includes steps that havebeen shown experimentally to removeTSE agents.

In his presentation, Albert Farrugia(Australian Commonwealth TherapeuticGoods Administration and member ofthe WFH Task Force on TSEs) said thatthe FDA’s policy has an enormousimpact on regulators worldwide. He saidit was reassuring that the FDA has madea distinction between fresh and fraction-ated products.

He also warned against limiting donordeferrals to Europe, pointing to thealarming arrival of BSE in Japan lastyear. Dr. Farrugia said it might be neces-sary to extend donor deferrals to peoplefrom other geographic regions. He sug-gested the most important question is notwhere there is BSE, but where it may be.

However, he highlighted the difficulty oflimiting the unknown risk of vCJDthrough donor deferral, which leads toever-increasing levels of product loss.He illustrated this point using the exam-ple of distribution of infected meat andbone meal (MBM) from the U.K. intoAsia and other countries, which couldintroduce BSE in those countries.



that the limited number of recombinantproduct suppliers creates supply vulnera-bility, as does the dependency on thesupply of starting material. Marketmechanisms are not sufficient to ensureadequate product supply, and there is areal need for strategic provisions toreduce vulnerability and prevent short-ages, he stressed.

H. Marijkeala van den Berg (VanCreveld Clinic-National HemophiliaCenter) provided a treater’s perspectiveon supply issues. Home treatment, pro-phylaxis, and longer life expectanciesfor people with hemophilia, coupledwith safety concerns, have all con-tributed to increased demand for recom-binant products, she said. She stressedthe need to determine more exact infor-mation on dosage as well as to deter-mine the cost-effectiveness and broaderimplications of specific therapeuticapproaches.

The supply problems experienced in thedeveloped world in the last year wereput into perspective by Prof. Hu Ching-Li (Shanghai Second MedicalUniversity), who spoke on supply andtreatment issues in China. Based on theestimated number of people with hemo-philia requiring treatment, he said thatChina needs 2,775 million InternationalUnits (IU) of factor VIII concentratesannually. The number of units availableis 15 million.

Providing a patient group perspective,Mark Skinner (National HemophiliaFoundation) said the situation caused bylast year’s shortages was a “soberingstep backwards” for patients in the U.S.He cautioned against neglecting supplyissues in future. Mr. Skinner recom-mended continuing to enhance the dia-logue between regulators and manufac-turers, and he warned that there is a realpossibility of future shortages since theUnited States is still largely dependenton a single supplier for recombinants.

During the open forum session, facilita-tor Ashok Verma (HemophiliaFederation India) noted that worldwide

At the end of the session, more than 90percent of participants agreed that peo-ple with hemophilia who received con-taminated clotting factor concentrateshould be informed.

“Given the current state ofknowledge, do you think aperson with hemophilia whohas received a factor concen-trate manufactured with plas-ma from a donor later diag-nosed with vCJD should beinformed of the fact?”

Yes 93%No 7%

Supply Issues

The causes, effects, and long-term out-comes surrounding the recent productshortage were the main issues discussed.Participants also reported on the supplysituation around the world and sharedpotential remedies for future supplycrises.

By July 2001, Dr. Evatt reported, theshortages had grown so acute that manybegan to fear patients might die in emer-gency situations. However, inventoriesimproved by November and Dr. Evattprojected that supplies would continue torise through 2002. The situation, he con-cluded, underscored the need for open,frank discussions involving all con-cerned parties.

Mr. Bult addressed some of the difficul-ties of trying to predict shortages. ThePPTA could only make predictions basedon publicly available data, he said.Moreover, some things are just not pos-sible to predict. Mr. Bult noted that man-ufacturing is only one stage in theprocess, and stressed the need to exam-ine collection and product distributionissues as well.

Theo Evers (European PlasmaFractionators Association) contended

Communicating Risk

The issue of how to communicate riskwas addressed from the point of view ofpatient organizations and treaters. Thequestions under discussion were how,what, and when to inform patients aboutrisk. It was almost unanimously agreedthat patients have a right to know if theyhave been exposed to contaminatedblood products.

There continues to be wariness amongpatients about information coming fromgovernment and regulators, notedGordon Clarke (European HaemophiliaConsortium, a regional office of theWorld Federation of Hemophilia), whopresented the results of a survey that hehad conducted of national hemophiliaorganizations in Europe. He stressed thatpeople with hemophilia want more directinformation and more face-to-faceopportunities to ask their own questions.

David Page (Canadian HemophiliaSociety and WFH Vice-President NMOsand Youth) raised the question of whatrole a patient organization has in termsof policy decisions and assessing risk.He called on patient organizations toensure consultation and to communicatewith members about safety and supplyissues. He called on blood authorities toopen up to those who are most affectedby policy decisions.

Paul Giangrande (Oxford HaemophiliaCentre and WFH Vice-PresidentMedical) and Simon Taylor (U.K.Haemophilia Society) gave two perspec-tives – the treaters’ and the patientgroup’s – on the issue of informingpatients if they are exposed to vCJD-contaminated blood products. Theyrecounted an incident last year involvinghemophilia treatment products in theU.K. containing plasma from a donorwho developed vCJD, and how the twogroups dealt with informing and reassur-ing patients. Dr. Giangrande noted thatfuture incidents such as these areinevitable, and the community must beprepared to deal with them.



shortages caused by prophylaxis are cre-ated in the northern hemisphere, he said.Such shortages can be much more dan-gerous to the developing world althoughthey originate from the developed world.

Participants discussed whether or notthe recent supply crisis would lead tonew thinking about modifying recom-mended dosages and the consensusseemed to be that it would not. Severalparticipants said the shortage was anemergency situation that caused artificialreductions with potential detriment andlittle or no benefit.

Next steps

There was overwhelming agreementamong participants that another globalforum should be organized by the WFHto maintain dialogue on key issues forthe global hemophilia community. Thenext forum is proposed for 2003.

The WFH is grateful to its patron, Jan Willem André de la Porte, who provided funding for the

WFH Global Forum on the Safety and Supply of Hemophilia Treatment Products.



Previous studies of TSE infectivity inthe blood of experimental mice wereconducted using the Fukuoka-1 strain ofhuman TSE, which originated from apatient affected with genetic form ofTSE, called Gerstmann-Sträussler-Scheinker disease, Dr. Cervenakovaexplained, while her ongoing experi-ments used a strain of mouse-adaptedvCJD. Evidence from the Fukuoka-1strain experiments would be cited forcomparison purposes, she said.

The experiment was designed by usingbrain of a mouse euthanized at the clini-cal stage of the disease (courtesy of Dr.Moira Bruce, Institute for AnimalHealth, Edinburgh, Scotland, UnitedKingdom) that had been previously inoc-ulated intracerebrally and intraperi-toneally with a 10% homogenate pre-pared from brain tissue of a deceasedindividual afflicted with vCJD. A newgroup of animals was inoculated intrac-erebrally with 1% brain homogenatefrom a vCJD-infected mouse. After 154days the first animal from that groupdied from the disease and others showedsigns of the disease. All mice were euth-anized after 157 days following inocula-tion and their blood was collected andseparated into components. Brain tissuewas harvested and assayed for the pres-ence of abnormal prion protein usingimmunoblotting assay.

It was interesting to note that the incuba-tion period shortened upon secondarytransmission of vCJD, said Dr.Cervenakova, just as it had in earlierexperiments with other strains of TSEs,including BSE strain. Experimental dataalso indicates that the incubation periodfor Fukuoka-1 is much shorter than theincubation period for vCJD, regardlessof whether Swiss or RIII mice are used.

Dr. Cervenakova further noted that thecharacteristic pattern of PrP27-30 (abnor-

Opening Address

Dr. Peter Jones, WFH ExecutiveCommittee member and chair of theforum, welcomed participants andexpressed his hope that this forum wouldbe as productive and informative as thefirst WFH Global Forum on the Safetyand Supply of Hemophilia TreatmentProducts.

Brian O’Mahony, President of the WorldFederation of Hemophilia, noted that theforum was a unique opportunity to lookat sensitive and contentious issues, withopen and constructive dialogue. Heemphasized that the meeting’s purposewas not to change views but to bringnew perspectives and promote discus-sion.

Facilitator Simon Taylor of the U.K.Haemophilia Society outlined the proce-dure for group discussions. He explainedthat the WFH would publish proceedingsof this forum, and noted that no com-ments other than the speakers’ formalpresentations would be attributed. Heencouraged participants to be open andfrank. Participants would have theopportunity to express opinions on aseries of questions at various timesthroughout the forum using electronicvoting system, he added.

To start off the forum, he asked the fol-lowing questions:

With regard to the risk oftransmission of vCJD viareplacement therapy, are you:


In the light of evidence cur-rently available, do youbelieve that vCJD can betransmitted through the infu-sion of coagulation factorconcentrates?

Non-patients only:Yes: 13%No: 55%Don’t know: 33%

Patients only:Yes: 22%No: 28%Don’t know: 50%

Experimental Transmissionof vCJD Through BloodComponents

Larisa Cervenakova, The American Red Cross HollandLaboratory

Dr. Cervenakova presented the latestresults of the Holland Laboratory experi-ments on transmission of vCJD. Shebegan by stressing that there is no epi-demiological or experimental evidenceof vCJD transmission through bloodtransfusion or use of plasma-derivedproducts. Moreover, Dr. Cervenakovasaid, the blood of animals with the natu-ral transmissible spongiformencephalopathies (TSEs) – scrapie ofsheep and bovine spongiformencephalopathy of cattle – has neverbeen demonstrated to be infectious wheninoculated into experimental animals,and the blood of experimentally infectedlaboratory animals contains significantlylower levels (105 times) of infectivitycompared to the brain.

Session 1:Variant CJD – The State of Affairs



from sporadic CJD patients developedthe disease. Low efficiency transmissionwas achieved in experimental studiesusing rodents: one of 21 mice transfusedwith blood from Fukuoka-1-infectedmice developed the disease; three of 47hamsters transfused with blood from ani-mals infected with high-dose 263Kscrapie strain developed the disease,while there was no disease transmissionby transfusion of blood collected fromhamsters infected with low-dose of theagent. There was a report on transmis-sion of the disease by transfusion ofblood from a sheep experimentally (perorally) infected with bovine spongiformencephalopathy. Dr. Cervenakova report-ed that a number of mice were trans-fused with blood from vCJD-infectedmice at the Holland Laboratory, but nodata were available yet.

Dr. Cervenakova concluded that the datacollected in the current study usingvCJD agent are consistent with previous-ly collected data using Fukuoka-1 andBSE agent. The infectivity levels inblood components of mice infected withvCJD do not appear to be different fromthat for the Fukuoka-1 strain. She alsonoted that the level of infectivity inbuffy coat is higher than in plasma at theclinical stage of the disease.

buffy coat of vCJD mice is lower than inFukuoka-1-infected mice.

Analysis of combined data on bloodtransfusion studies from various labora-tories was also presented by Dr.Cervenakova. In a historical study con-ducted at LCNSS, NIH (Bethesda,Maryland, U.S.A.) none of three chim-panzees transfused with units of blood

mal, proteinase K-cleaved form of prionprotein) from the brain of infected miceis specific for Fukuoka-1 and vCJDstrain, and remains unchanged in Swissand RIII mice.

Whole blood was divided into red bloodcells, buffy coat, platelet-rich plasma,platelet concentrate, and platelet-poorplasma. All of these components wereinoculated intracerebrally and intra-venously, with the exception of plateletconcentrate, which was only inoculatedintracerebrally.

In mice inoculated with buffy coat fromvCJD-infected mice at the clinical stageof the disease, Dr. Cervenakovaobserved, infection can occur at differenttimes after inoculation. In animals inoc-ulated intracerebrally, three of 17 micedeveloped the disease, while two of sixanimals inoculated intravenously devel-oped the disease. Low levels of infectiv-ity have been also detected in platelet-rich and platelet-poor plasma of clinical-ly ill vCJD-infected mice using bothintracerebral and intravenous route ofinoculation.

Dr. Cervenakova compared data of thisexperiment with previous experiments,and found that the level of infectivity in



to other countries. There has been a highdensity of meat and bone meal penetra-tion in Asia, Dr. Farrugia noted, whichcreates a potential for recycling of BSE-infected material. As a result, he reiterat-ed, it may be necessary to extend donordeferrals to people from other geograph-ic regions – a possibility that the FDAhad already conceded, he added. Thishighlighted the difficulty of limiting theunknown risk of vCJD through donordeferral, which leads to ever increasinglevels of product loss.

Dr. Farrugia also pointed out the lack ofharmonization among regulatory authori-ties about what constitutes a “European”country. Political geography is having aneffect on health policy, he said.

He said it is reassuring that the FDA hasmade a distinction between fresh andfractionated products. There is strongevidence that plasma fractionation elimi-nates high levels of TSE infectivity, heobserved.

Dr. Farrugia presented a summary of thevarious measures for donor deferral,which are in place in various Europeancountries. He noted that this informationwas available on the WFH web site.

Dr. Cervenakova looked forward toadditional data, particularly from ongo-ing mice and primate studies, which shehoped would help answer the question ofwhether or not blood from patients withvCJD is infectious.

The Risk of vCJD in BloodProducts – GlobalRegulatory Response

Albert Farrugia, Australian Commonwealth TherapeuticGoods Administration and WorldFederation of Hemophilia

The main influence on the global regula-tory response to vCJD, Dr. Farrugia con-tended, is the U.S. Food and DrugAdministration’s decisions and thereforeit is necessary to examine the recentlypublished Guidance for Industry.

According to the FDA Guidance:“…until suitable donor screening testsare available, the FDA is recommendinginterim preventive measures that wedeem to be prudent based on the avail-able scientific data and the evolving stateof knowledge regarding these diseases.”Dr. Farrugia described this as a “revolu-tionary” statement for a regulatoryauthority. He noted that the FDA appearsto be saying that they may reintroducethe excluded donors once reliablescreening testing is available. This, hemaintained, is a modification of the stan-dard approach of regulators, which is tohave a tripod of measures composed ofselection, screening, and inactivation ofthe relevant pathogen. This would resultin a revision of current principles whichmay well be desirable.

The Guidance, he continued, also con-tends that the vCJD epidemic in theUnited Kingdom continues to increase.The most recent evidence, he noted, sug-gests that the vCJD epidemic is peakingand creates room for hopeful optimismthat the worst of the crisis has passed.

Dr. Farrugia also presented evidence of

the rates of BSE in Europe, contendingthat the BSE epidemic is not homoge-neous, and varies from region to region.He noted that the rates of BSE inSwitzerland had appeared to be falling in1998, when the Swiss began to testapparently healthy cattle; that resulted ina large jump in the number of cases andcreated widespread public concern.However, he added, the rates appear tobe falling again.

Dr. Farrugia presented a copy of anAmerican Red Cross news release fromJanuary 18, 2001. He maintained that theAmerican Red Cross’s unilateral declara-tion of the need for further tightening ofthe ban on blood donors who had visitedthe U.K., France, and Western Europeforced the FDA to revise its position.That position was based on the preva-lence of BSE in those particular areas.However, he insisted, the most salientquestion is not where there is BSE, butwhere it may be. Dr. Farrugia pointedout the alarming arrival of BSE in Japanlast year.

It is inconsistent, he said, to excludeJapan from donor deferrals. He present-ed data on the level of exports of meatand bone meal from the European Union



Dr. Padilla explained that once the mate-rials have been examined using a rangeof procedures, it will be possible toestablish a correlation between in vitroand in vivo experiments (that is, thesame reference material can be used).The material can also be used for cali-bration, by distributing the referencematerial to various laboratories conduct-ing experiments.

A WHO collaborative study has alsobeen undertaken to define a harmonizedPrPSc detection protocol, Dr. Padilla stated.

The working group is also studyinghuman TSE blood-derived materials, inorder to facilitate the study of diagnosticmethods and validation processes. Dr.Padilla observed that the development ofblood reference material would be verydifficult, because of the absence of thedetection of infectivity of PrPSc in humanblood. Rodent-adapted TSE strains pro-vide another approach, but some diffi-culty remains as there is disagreementon the appropriate spike preparationused in various protocols.

The group has already initiated a harmo-nized protocol for the collection of bloodfrom humans with CJD for use in theinvestigation of blood-based diagnostictests, Dr. Padilla said. Consultations onthe protocol are in progress.

Dr. Padilla summarized a number ofother activities in which the WHO iscurrently involved, and invited partici-pants to access more complete informa-tion at the WHO web site:http://www.who.int/biologicals.

Dr. Padilla outlined the specific terms ofreference for the working group:

• the selection and characterizationof candidate materials which couldserve for the preparation of interna-tional reference materials;

• the development of protocols forcalibration of those materials forWHO collaborative studies;

• the harmonization of proceduresfor the classification and nomencla-ture of PrPSc typing in human cases;

• and the examination of issues con-cerning the appropriate use of pro-posed reference materials.

Considerable progress has been made inthe development of laboratory tests forthe detection of the pathological PrPprotein (PrPSc), Dr. Padilla said.However, she added that the predictivevalues of these assays in terms of TSEinfectivity have not been independentlyconfirmed. Therefore, a correlation withbioassays from animal models is stillrequired. As a result of these factors, thegroup is currently considering severaldifferent types of reference materials.They include human TSE brain-derivedmaterials (calibrated in a WHO collabo-rative study), rodent-adapted strains ofTSE agents, human TSE blood-derivedreference materials, and spleen-derivedreference materials.

To date, the group has developed humanbrain homogenates that were preparedfrom samples taken from four brainssupplied by the CJD surveillance unit inEdinburgh. One was from a neurologi-cally normal subject, one from a vCJDpatient and two from sporadic CJDpatients. The homogenate has beendivided into 2,000 vials and will be usedin in vitro and in vivo assays, Dr. Padillasaid.

Preliminary data indicate that the vCJDmaterial is suitable for both in vivo andin vitro assays. However, both spCJDsamples presented the unexpected coex-istence of two different glycotypes (oneType 1, one Type 2).

Among the ongoing issues that regulato-ry authorities are still grappling with isthe spread of universal leukocyte pro-duction of all collected blood, Dr.Farrugia said. This is driven by the ideathat removing white blood cells willreduce the levels of infectivity, heexplained. However, he contended thatthe evidence suggests that is not thecase. Plasma processing creates cross-contamination issues because the bloodproduct industry is global, he noted,which creates enormous implications forproduct supply.

Dr. Farrugia concluded by remindingparticipants that regulators react toevents; they don’t shape them. He alsorestated the enormous impact that FDApolicy has on all regulators worldwide.

World Health OrganizationActivities on vCJD

Ana Padilla, Health Technology and PharmaceuticalsCluster, World Health Organization

Dr. Padilla described the World HealthOrganization (WHO) project for thedevelopment of international referencematerials for the diagnosis and study ofhuman TSEs (both spCJD and vCJD). Itis a complex and difficult project, initiat-ed in 1999 with the cooperation of vari-ous international partners and researchinstitutes, she stated.

Dr. Padilla explained that she worked ina program dealing with quality assuranceof biological products. The main interestwas how to facilitate the development ofdetection tests for TSEs; this amplifiedthe need for global harmonization inevaluating process validation data, andthe specific need for reference reagentsand reference panels. In recognition ofthose needs, the WHO formed a workinggroup on international reference materi-als for the diagnosis and study of TSEs.The objective of that group is to preparereference materials that will advance thedevelopment of diagnostic tests for TSEs.



sary to strike a balance between thecompeting demands of safety and sup-ply, he concluded.

The State of Affairs –Treater Perspective

Wolfgang Schramm, Ludwig-Maximilian UniversityHemophilia Centre

Treaters want to help their patients whileavoiding any potential problems forthem, stated Prof. Schramm. He stressedthe importance of taking responsibilityfor all hemophilia patients – not just the20 percent who are well treated, but alsothe 80 percent throughout the world whoreceive poor treatment.

Prof. Schramm noted that there are cur-rently more than 100 cases of vCJD inthe U.K., three in France, and one inIreland. Extrapolations using the currentmodel, he contended, suggest that therecould be hundreds of new cases inFrance and Germany in the near futurethrough primary infection via the foodchain. More alarmingly, it is still notknown how and if secondary infectionsfrom human to human may occur, Prof.Schramm added. Data from the GermanHemophilia Registry, which has beentracking patients since 1982, has still notseen any co-occurrence of hemophiliaand vCJD, he reported.

Prof. Schramm described the strategythat has been adopted by the Germanauthorities regarding vCJD. The trans-mission of vCJD via plasma seemsunlikely, since the agent is almost com-pletely eliminated during the productionprocess. Even if the vCJD agent is trans-missible via blood transfusion, the riskwould be eliminated once a reliablescreening test is developed, he said.

From a treater’s perspective, it is criticalto balance safety measures with supplyconcerns, Prof. Schramm said. There arevarious options to reduce the risk ofvCJD transmission through transfusions.These include: the use of the safest pos-

Variant CJD – The State ofAffairs from an IndustryPerspective

Charles Waller, Plasma Protein TherapeuticsAssociation (Europe)

Mr. Waller began by stressing that indus-try takes all potential risk very seriously.Although the risk of vCJD is theoretical,it is being treated as a real threat andtaken very seriously, he stated.

There is no evidence that people withpre-clinical or clinical CJD, includingvCJD, carry infectious prions in theirblood or have transmitted infectious pri-ons through any blood products, Mr.Waller emphasized. There are numerousstudies with classical CJD and variousstudies underway with vCJD, and nonehas indicated infectivity through bloodproducts, he said. Mr. Waller cited tworecent articles in the Lancet, reportingthat researchers could not detect anyinfectivity in the blood of vCJDpatients.1,2 There is increasing circum-stantial evidence that is encouraging, headded, while reiterating that industrycontinues to take all possible precau-tions.

The U.K. provides a microcosm of theoverall issue, Mr. Waller said. Despitethe use of U.K. plasma and many mil-lions of transfusions, there is still no evi-dence of any vCJD transmission. He

conceded that several patients who diedof vCJD had received transfusions, butnone of their infections was traced backto their donors. Moreover, there havebeen no cases of CJD or vCJD detectedamong recipients of blood or plasmafrom donors who were, subsequently,known to have vCJD. Mr. Wallerstressed that to date, there has been noevidence in the U.K., where 99 percentof all cases of BSE and 96 percent of allvCJD have been reported, that vCJD hasbeen transmitted through blood or bloodproducts.

Mr. Waller noted that eight vCJDpatients had received transfusions, butnone had been traced back to a donoridentified with CJD. Fourteen patientswith vCJD donated blood and eightvCJD patients had their donations tracedto 22 recipients, none of whom devel-oped vCJD, he added. There have alsobeen eight confirmed donations fromvCJD patients that were pooled for frac-tionation; however, Mr. Waller notedthat none of the thousands of productrecipients has been identified with vCJDto date.

Despite the mounting evidence thatvCJD is not transmissible through bloodproducts, Mr. Waller reiterated, theindustry continues to treat the theoreticalrisk as a real risk. The industry is takingnumerous steps to ensure the safety andsupply of blood products. These stepsinclude the sponsorship of relevantresearch and the sharing of data, whichMr. Waller described as an importantand positive development.

Beyond research, Mr. Waller said, theindustry is attempting to communicatethe most recent, accurate information aswidely and comprehensively as possible,using workshops, direct mail, publica-tions, and its multilingual web site(www.plasmatherapeutics.org).Industry’s approach is to involve con-sumers and encourage the free flow ofinformation to create a good understand-ing of the issues and challengesinvolved, he said. Various precautionaryactions are being taken, but it is neces-

1, M.E. Bruce, I. McConnell, R.G. Will,J.W. Ironside (2001) Detection of vari-ant Creutzfeldt-Jakob disease infectivi-ty in extraneural tissues Lancet358:208-209

2 J.D.F.Wadsworth, S. Joiner, A.F. Hill,T.A. Campbell, M. Desbruslais, P.J.Luthert, J. Collinge (2001) Tissue dis-tribution of protease resistant prionprotein in variant Creutzfeldt-Jakobdisease using a highly sensitiveimmunoblotting assay Lancet 358:171-80



4. Are there other views youwould like to hear?

WFH/ EHC 5Scientists 7Doctors 2Regulatory bodies 7Government 7Other (pharmaceuticals, othercountries) 2

5. What questions about vCJD aremost frequently asked by yourmembers?

• We get almost no reaction on thismatter, probably due to almost100 percent use of recombinantproducts.

• Are government, scientists, anddoctors telling the truth?

• Why can’t we all just have recom-binant product?

• Is the product used in our countrysafe?

• Can we get certain assurance thatproduct is safe to use?

• Is there any difference in safetybetween plasma and recombinantproducts?

• Are blood donors tested forvCJD?

• How dangerous is infection fromblood products?

• Will vCJD be a problem like HIVin the future?

• Are there cases of vCJD in ourcountry?

• What are the signs of vCJD?

6. What steps has your nationalhemophilia organization taken todistribute information to members:

Seminars/expert speakers 2Newsletter articles 8Explanatory letter 4Agenda at members’ meeting 6Web site articles 7Other (brochure, etc.) 1

A Patient’s Perspective of vCJD

Gordon Clarke, European Haemophilia Consortium

Mr. Clarke presented the results of a sur-vey that he had conducted of nationalhemophilia organizations. Although thesurvey was short and straightforward,only 12 member organizations respond-ed, a response rate of only 29 percent, hecommented.

There are several possible explanationsfor the low response rates, Mr. Clarkeobserved. A number of countries viewthe theoretical risk of vCJD as lessimportant than how to access treatment“in real time.” At the other extreme,there are a growing number of countriesthat have moved to a nearly 100 percentrecombinant supply, so they’re less con-cerned about blood-borne infections.Finally, many organizations just findthemselves with too much to do and toofew resources, he said.

Mr. Clarke presented a summary of theresponses to his survey.

1. Do you consider your nationalmember organization to be:

Very well informed? 2Adequately informed? 9Poorly informed? 1

2. From which sources have youreceived information?

Government 5Hemophilia doctor 9Other doctor 2WFH/ EHC 12Other (Internet, media, BPL) 5

3. Has the information been:

Timely? 8Informative? 12Comprehensive? 6Understandable? 9

sible blood products available (optimaluse); the development of reliable diag-nostic tests to screen blood donations forvCJD infection; the exclusions of somepersons from the donor pool; and leuko-cyte depletion in the production process-es of erythrocyte and thrombocyte prod-ucts.

Concurrently, there are options that canensure the provision of a sufficient long-term supply of blood and blood prod-ucts, Prof. Schramm explained. Theseinclude: the critically indicated applica-tion of blood product (optimal use); pro-moting advertising for the recruitment ofdonors; motivation campaigns for donorrecruitment; and the revision of exclu-sion criteria.

There is still no documented evidence ofany person with hemophilia having clas-sical or variant CJD, Prof. Schramm reit-erated, despite many studies from theU.K., U.S., and other countries.Although it is never possible to createcomplete safety, Prof. Schramm con-tended that the blood supply is the safestit has ever been. Hemophilia is a life andlimb-threatening disease which necessi-tates that real risks must be balanced,and that includes the risks attendantupon product shortages, he said.

Prof. Schramm urged participants toconsider the degree of safety that is opti-mum, particularly in developing coun-tries where supply is a serious issue andwhere it is often very difficult to collectsufficient donations to produce plasma-derived products.

Traditionally, he concluded, we measurecost-benefit and cost-utility in economicterms. It would be more meaningful ifhuman issues such as quality of lifebecame part of those equations, he said.



In the light of evidence cur-rently available, do youbelieve that vCJD can betransmitted through the infu-sion of coagulation factorconcentrates?

Non-patients responded:Yes: 12%No: 53%Don’t know: 35%

Patients responded:Yes: 43%No: 29%Don’t know: 35%

Clearly, the message from patient organ-izations is to “keep the informationflowing,” Mr. Clarke said, and toimprove the information exchangebetween countries. There continues to bewariness among patients about informa-tion coming from government and regu-lators, he noted. He stressed that patientswant more direct information and moreface-to-face opportunities to ask theirown questions. Moreover, they want theinformation to be useful and understand-able, and they want their national hemo-philia organizations to do more to bringanswers to their members, he stated.

Discussion

Simon Taylor summarized his impres-sions of the presentations. He objectedto the use of the term “theoretical risk.”To describe risks as theoretical, he con-tended, is to attempt to dodge the realissue. There is a risk – the matter for dis-cussion is how big the risk is and whatshould be done about it, he said.

Mr. Taylor invited questions or com-ments from the floor.

One patient participant suggested thatpatients would feel more comfortable ifeach vial of treatment products or pack-aging listed the source of the plasma.

A regulator in the audience noted thatplasma source is required informationfor every regulatory authority. However,others remarked that most patients haveno access to regulatory data. Severalparticipants expressed support for pro-viding source information on every bot-tle.

A participant from a developing countrysaid he was angry that U.K. meat andbone meal had been exported to so manycountries, including Asia. He asked Dr.Farrugia if donor deferral policies shouldtake into account people who have con-sumed these products. Dr. Farrugiareplied that it should be a consideration.However, he noted that in all cases theexporters claim that the meat and bone

meal was not used to feed cattle or live-stock. He also noted that if the processwere carried to its logical conclusion, allof those who may have consumed meator bone meal at risk of BSE contamina-tion would need to be excluded fromdonations, which means excluding near-ly everyone.

Another participant expressed her sur-prise that people are so confident whenthey declare that there has been no evi-dence of vCJD transmission so far. Shestressed that the time frame for researchhas been so short, that it is difficult tocite any reliable epidemiological evi-dence with confidence. She also ques-tioned the efficacy of using spikingmaterial for testing, suggesting that notenough is known about the actions ofinfective prions in the blood.

Other participants echoed her concerns.One noted that it is too soon to say, con-clusively, that the results of real cases ofvCJD patients are reassuring, whilestressing that theoretical studies havebeen much less reassuring. Anotheraudience member stressed that it isimportant not to become complacent.Remember the experience of hepatitis C,which remained dormant for years, heurged.

Mr. Taylor asked participants to recon-sider the questions they answered at thebeginning of the session, to see if thepresentations had changed their percep-tions in any way.

With regard to the risk oftransmission of vCJD viareplacement therapy, are you:

Very concerned? 13%Concerned? 64%Not concerned? 22%



the titer of infectious agent in a donor,and potential for manufacturing process-es to remove the agent are needed to fur-ther evaluate the risk of vCJD infection.

Dr. Evatt next discussed assumptionsthat scientists are following in their workwith vCJD. It is predicted that the peakof BSE in Europe will occur between2002 and 2005. The highest risk of plas-ma donor infectivity is in the U.K. andFrance, and possibly Japan. Currentmethods for producing factor VIII areexpected to clear three to six logs ofinfectivity, and methods for manufactur-ing factor IX should clear seven logs,greatly increasing safety. To date in theU.K., eight donors with vCJD weretraced to 22 recipients of blood products.None of the 22 has developed CJD.

In the developed world, concern isfocused on product safety, while avail-ability remains the number one issue inthe developing world. “We are forced tolive with the reality that we cannot makedecisions on donor exclusions whicheliminate all risk for all patients,” Dr.Evatt concluded.

Assessing the Risk ofvCJD: A Decision-makingModel

Francine Décary, Hema-Québec

Dr. Décary used the example of Québec,Canada, as a decision-making model forassessing the risk of vCJD. On October15, 1998, a report from the BayerAdvisory Council on Bioethics on CJDwas made public. Recommendation 20stated, “That persons who at any timesince 1980, have resided in a geographicarea with a significant incidence of BSEor nvCJD not be permitted to contribute

Before introducing the speakers for thesecond session, Simon Taylor gave abreakdown of the participants at theforum: approximately 30 industry repre-sentatives, 20 medical practitioners, 20patient groups, and 10 regulators.

Participants voted on the following ques-tions.

Do you feel that CJD posesthe same threat to the hemo-philia community as HIV didin 1982?




Is History Being Repeated?A Comparison of vCJD with HIV

Bruce Evatt, Centers for Disease Control andPrevention and World Federation ofHemophilia

Dr. Evatt compared CJD and vCJD withHIV at similar points in their respectivecrisis timelines – HIV in 1982, CJD in1998, and vCJD in 2001. He began bycontrasting CJD with HIV. Dr. Evattnoted that HIV was a new disease in1982, whereas CJD was an old one in

1998. At the time of each crisis, the dis-ease was caused by an unknown agent;but the CJD numbers were stable, whilethe HIV numbers were increasing. HIVhad an unknown incubation period, waspresent in people with hemophilia, andwas known to be transmitted in blood.CJD had a known incubation period, ithad not been detected in people withhemophilia, and there had been noknown blood transmission. Knowing theincubation period is important to esti-mating the extent of the epidemic.Finally, HIV lacked animal models,while CJD does not. As more data accu-mulates, there is growing confidencethat CJD is not being transmittedthrough the blood supply.

Dr. Evatt then compared vCJD withHIV, as well as with CJD, according tothe same characteristics. During the cri-sis times, both vCJD and HIV were newdiseases caused by an unknown agent,with increasing numbers of infectedpatients. Both diseases had unknownincubation periods. Despite the absenceof human blood transfusion-transmissioncases, vCJD – unlike CJD – appears tohave a transfusion-transmission risk inanimals. In addition, the vCJD agent isfound in many more tissues of infectedpatients than is the CJD agent, includingsuch tissues as lymphoid tissues, whichcontain blood cells. This presence of thevCJD agent is of particular concern inrelation to the potential for blood infec-tivity, but further study is needed on pri-ons in lymphoid tissue. Finally, the incu-bation period of vCJD is shorter inexperimental animals than that of CJD,suggesting a more virulent organismthan CJD.

The result of the comparison betweenvCJD and HIV is not as encouraging asthat between CJD and HIV. Thus theestimation of the relative number ofdonors in the plasma pool, estimation of

Session 2:The Decision-making Process – A Question of Risk



• identifying issues that are impor-tant to users of blood and bloodproducts;

• consulting with those who have themost to gain or to lose as a resultany eventual decision;

• contributing to the analysis andadoption of policies that are consis-tent with the priorities of the popu-lation; and

• communicating with patients andthe public in ways that they canunderstand.

Who does a hemophilia organizationrepresent? The first constituency is itsmembers, but Mr. Page also questionedthe organization’s responsibility to otherdisease groups and the public in general.“Can a hemophilia organization demandaction to minimize risk to its own mem-bers, knowing that this could increaserisk to others?” He concluded that ahemophilia organization must considerthe effects of its actions on broader poli-cy issues while not losing sight of itsprimary responsibilities. It is worthwhileto build coalitions with other blood-usergroups to share knowledge and skills.

He highlighted the importance of build-ing up its expertise and credibility in theblood system. Hemophilia organizations

and benefits of taking action should bedependent not only on the likelihood ofthe risk materializing but also on theseverity of the effect if the risk doesmaterialize, on the number of personswho could be affected, and on the easeof implementing protective or preventivemeasures. The more severe the potentialeffect, the lower the threshold should befor taking action.”

She concluded: “Taking into accountthat the vCJD challenge was presentedto the new operators of the blood supplyin Canada just two weeks after theirstartup, it is important to recognize thecontribution of Justice Krever’s recom-mendation 2(e), which has served as atemplate to make decisions in the con-text of uncertainty.”

Risk Assessment from aHemophilia Organization’sPerspective

David Page, Canadian Hemophilia Society, andWorld Federation of Hemophilia

Mr. Page asserted that hemophilia organ-izations have a unique role to play at allstages of the risk assessment process by:

blood or plasma until the hypotheticalrisk of accepting donations from suchpersons can be evaluated.”

Canada’s blood suppliers, HealthCanada, and other stakeholders met toevaluate the situation. They made threeobservations: there was no current scien-tific evidence that vCJD could be trans-mitted by blood; deferring donors whohad resided in the U.K. could create riskto Canada’s blood supply; and the travelhabits of Canadians were unknown. Itwas decided that a large deferral wouldbe problematic, but a rapid loss of threeto five percent of donations could bewithstood. A survey of donors found thatdonors in Québec were less likely tohave travelled to the U.K. than donors inthe rest of Canada. Hema-Québec, theblood supplier for the province, feltcomfortable that excluding these donorswould not threaten the blood supply, Dr.Décary said.

In April 1999, it was decided to defer alldonors who had spent a month or morein the U.K. since 1980. This would leadto a three percent loss in donations,which was judged an acceptable risk tothe blood supply because it would bringa risk reduction of 70 to 85 percent. Itwas also decided to exclude from frac-tionation the plasma of any donor whohad spent time in the U.K. since 1980.This would lead to a five percent reduc-tion in plasma supply and a risk reduc-tion of 100 percent for Hema-Québecplasma. In October 2000, the sameapproach was used for donors who hadspent six months in France in the sameperiod.

Dr. Décary described the governanceframework for making such decisions,including risk management policy anddecision-making policy implementation.The recommendation on the precaution-ary principle of the Commission ofInquiry on the Blood System in Canada,presided by Justice Krever, was themotor for decision-making. The recom-mendation calls for the principle of safe-ty to transcend other principles and italso states, “The balancing of the risks



investigating risk for different patientgroups, he stated.

In Europe, sites where products are man-ufactured have to hold a marketingauthorization and have a satisfactoryrecent inspection showing compliancewith good manufacturing practice(GMP). The Committee for ProprietaryMedicinal Products (CPMP) may requestgood clinical practice (GCP), good labo-ratory practice (GLP), and pharmacovig-ilance inspections. At the time of granti-ng a marketing authorization, there is asubstantial body of data on the product’squality, safety, and efficacy. The size andvalidity of the database is crucial, saidDr. Haase, while noting that the qualityof inspections in Europe is improving.

There should be a balance between theneed for clinical data to evaluate risksprior to marketing authorization and theavoidance of delays in making availableefficacious medicinal products topatients in medical need. Clinical trialsgive more substantial assurance on effi-cacy compared to safety, as a very largenumber of subjects are required to ruleout rare adverse reactions.

During clinical trials, populations aredefined by strict inclusion and exclusioncriteria. Larger and less-well-definedpopulations are likely to be exposed toproducts with time. The larger exposurewill lead to adverse reactions and inter-actions.

Risk Assessment from aRegulator’s Perspective(FDA)

Dorothy Scott, FDA Center for Biologics Evaluationand Research

A major challenge of risk assessment isweighing the risk of disease transmissionby products versus the risk of limitedsupply, especially in a worldwide con-text, stated Dr. Scott. Another pitfall is

must make blood safety and supplyissues a top priority internally, Mr. Pagesaid. He recommended cultivating a coregroup trained and informed on the issue,and ready to work with other stakehold-ers.

Maintaining credibility is difficult, espe-cially with one’s own members, henoted. Because of HIV and hepatitis C,many people with hemophilia nowbelieve that no matter how remote thethreat, it will become a reality. Mr. Pagediscussed the case of a Utah donor diag-nosed with CJD in 1998. Some productsusing his plasma were sent to Canada.Health Canada originally quarantined allimplicated blood products, then releasedthe products on Christmas Eve, with thesupport of the Canadian HemophiliaSociety (CHS), based on its assessmentthat the risk of classical CJD was mini-mal. However, medical and scientificopinions on the actual level of risk weresplit and many patients reacted in panic.The CHS was accused of caving in tothe pharmaceutical industry. The CHSspent six months trying to put the riskinto perspective, Mr. Page said.

The CHS actions were based on scientif-ic risk analysis as well as a set of values:transparency, autonomy of the person,and greatest benefit, least risk. “Thechallenge is to focus on the real risk.Hepatitis B led us to underestimate HIV.HIV blinded us to hepatitis C. NowvCJD is absorbing us, while 75 percentof people with hemophilia in the worldgo without treatment,” he said.Moreover, “many of those that doreceive care are treated with cryoprecipi-tate that is not even virally inactivated.”Mr. Page concluded by calling on theblood authorities around the world toopen up to those who have the most tolose from any policy decision.

A Regulator’s View of Riskand Risk Assessment(EMEA)

Manfred Haase, Paul Ehrlich Institut and the EuropeanAgency for the Evaluation of MedicinalProducts (EMEA)

The principal purpose in the regulationof medicinal products is to make avail-able safe and effective products, of goodquality, which provide benefits that out-weigh their risks, stated Dr. Haase. Thisis easier said than done, because it is dif-ficult for licensing authorities to makesuch a judgement.

Dr. Haase discussed risk analysis as itapplies to determining the level ofacceptable viral risk. Risk analysis is ascientific evaluation of the probability ofoccurrence and the magnitude and sever-ity of the effect. In areas of uncertainty,such as emerging threats, risk analysis isa difficult but necessary exercise. Whereuncertainty exists, a precautionaryapproach should be taken. Precautionsmust be proportional to the degree ofuncertainty and take into account theexpected benefits of the product. This iscomplicated, and a science-basedapproach is warranted, said Dr. Haase.

Benefit-risk assessment for individualmedicinal products takes into accountgeneral public health issues and individ-ual patients. Immunocompromised indi-viduals and children should get particu-lar attention. In the evaluation of prod-ucts, the objective of the quality data isto demonstrate that a product of goodand consistent quality is produced, andthat potential safety issues arising frommanufacture are avoided or minimized.

Safety information will be derived byextrapolation from non-clinical data andfrom the overall experience with the useof a new medicine. Evidence of efficacyis provided by clinical studies. Ensuringsafety in special populations means



the tendency to interpret results of riskassessments as facts. Risk assessmentsshould estimate the worst case, butshould also provide outcomes for arange of assumptions. Assessing thecost of taking precautions to reduce risk,e.g. “collateral damage,” is also a chal-lenge.

Dr. Scott discussed vCJD risks indonors. It is entirely unknown whetherhuman blood is capable of vCJD trans-mission at a low frequency. Estimatesof how many people may be at risk ofhaving vCJD may not be precise, due tolack of information about the vCJD epi-demic. Some unknowns include incu-bation time, and distribution of vCJD inthe population. The highest numbers ofcases are in the U.K. and France, and arerelated to beef consumption. Food chaincontrols are important in preventinghumans from contracting vCJD, she stat-ed. The role of secondary exposurethrough the blood supply is unknown atthis time.

She then reviewed the FDA’s risk assess-ment process leading up to the newdonor deferral guidelines. The precau-tionary principle has no status in U.S.law, Dr. Scott said, but it is especiallyapplicable where adverse effects mayemerge long after exposure, and whenrisks that are carried forward into thefuture cannot be eliminated or reducedexcept at the time of exposure.

In predicting results of various deferralactions, it was found that different meas-ures had different effects upon supply,but equivalent safety outcomes. Theevaluation of donor deferral scenarioshelps regulators to optimize safety meas-ures, while minimizing the chance thatdangerously low supplies will occur. Inaddition to new donor deferral guide-lines, the U.S. encouraged a nationaldonor recruitment campaign and institut-ed a system to monitor adequacy of theblood supply.

There was particular concern about theeffect on plasma derivative supplies of aban on donors who lived in Europe for



Regulatory requirements and voluntaryindustry initiatives together ensure thattoday’s plasma protein therapies haveachieved the highest margin of safetyever. Risk of transmission is negligiblefor enveloped and non-enveloped virus-es, and remains theoretical for vCJD.The introduction of new regulations hasto be carefully balanced against thepotential impact on supply, Mr. Bultconcluded.

Discussion

Simon Taylor initiated the discussion,which focused on the trade-off betweenmeasures that are intended to increasesafety, and their impact on supply.

A clarification was requested on the caseof the Utah donor. David Page said albu-min from the donor was used in thepreparation of recombinant factor VIII.There was also clarification on the con-cept of holding donations before usingthem.

It was noted that the donation rate inCanada and Quebec is not high in com-parison to other countries. The bloodsuppliers in Canada are looking at howto do a better job of recruiting.Recruitment of donors is a “soft science”

tific and regulatory communities to sup-port improved validation. In the years tocome, new standards for NAT will come,providing standardized technology andlanguage.

Quality control and quality assurance areextremely important. PPTA membershave used a third-party review to ensurethat the correct systems are in place, andthis adds another layer of protection.Manufacturers are responsible for activepharmacovigilance, traceability of prod-ucts, batch recall standards operatingprocedures, and patient notification. Anexample is the Patient NotificationSystem as it currently exists in the U.S.

International harmonization of regulato-ry requirements is a long way off, Mr.Bult said. He called for the debates inthis area to be more on science than pol-itics. He cited the decision in Japan todefer any donor who had lived in acountry with significant BSE, or onecase of vCJD, or an increase in TSE.This decision was made before BSE wasfound in Japan. He wondered whetherthe implemented policy will impact thecollection practices in Japan. Othercountries potentially face a similarconundrum, as the extent of the spreadof BSE becomes clear.

five years or more. Furthermore, plas-ma derivative manufacturing includessteps that have been shown experimen-tally to remove TSE agents. Based uponthese factors, an exception was made tothe pan-European donor deferral fordonors of source plasma for plasmaderivatives.

Risk Assessment – IndustryPerspective (PPTA)

Jan M. Bult, Plasma Protein TherapeuticsAssociation

For industry, dedicated donors are cen-tral to risk assessment and the decision-making process, Mr. Bult said.Initiatives by the Plasma ProteinTherapeutics Association (PPTA) andindustry to include appropriate donorgroups have included public education,working in a robust regulatory environ-ment, good centre location, the use ofwell-crafted questionnaires, employmentof experienced professionals, state-of-the-art testing technology and deferral ofdonors who spent time in certain geo-graphic locations.

Mr. Bult questioned practices that he hasseen with mobile public sector collectionunits operating at campsites in Francewhere donors had to wait in the heat fora long time. PPTA initiatives include adonor motivation campaign, and usingplasma from North America and Europefor fractionation. The use of an “invento-ry hold period” means that donations canbe traced and rejected up to 60 daysafter collection as the result of post-donation information.

Mr. Bult then discussed nucleic amplifi-cation technology (NAT). The advan-tages of NAT are reduction of the virus-related window by early detection ofhighly viremic donations. Methods forthe inactivation and removal ofpathogens have to be effective, validat-ed, and robust, Mr. Bult stated. PPTAhas collaborated with others in the scien-



Are current risk assessmentmodels used in making deci-sions on vCJD more scientif-ic, more political, or bal-anced?

Regulators only:More scientific? 20%More political? 40%Balanced? 40%

Should current restrictions ondonors for vCJD be:

Strengthened? 14%Reduced? 27%Remain the same? 59%

but an essential part of the industry.

The concept of a plasma master file hasnot yet been accepted worldwide. On theissue of whether there is disharmonybetween deferral criteria, it was suggest-ed that there is no disharmony on mini-mum standards, although some nationsmake a choice to exceed those standards.There was more discussion on balancingrisk and the different views of scientistsand patients.

Participants cast opinions on severalquestions.


Yes 5%No 88%Don’t know 7%


All forum participants:More scientific? 17%More political? 33%Balanced? 50%


Producers only:More scientific? 13%More political? 31%Balanced? 56%



Industry Perspectives(PPTA)

Jan M. Bult, Plasma Protein TherapeuticsAssociation

Mr. Bult began by revisiting a number ofindustry responses to global productshortages that he had raised at the lastWFH Global Forum, in April 2000. Atthat time, he suggested the possibility ofharmonization, the continued use of“plasmatics,” improved margins of safe-ty, increased use of recombinant prod-ucts, more continuity in supply, andincreased use of prophylaxis. Whilesome of those predictions came true, henoted, some of them were incorrect –particularly the predicted supply conti-nuity and increased use of recombinantproducts.

No one is happy about the shortages ofthe last year, Mr. Bult stated. One of theindustry’s first responses was to ensurethat the products that were availablewere delivered as quickly as possible toconsumers. In addition, the industryincreased production capacity, increasedfractionation of plasma-derived prod-ucts, and held multiple meetings withconsumers and government agencies.The rate of data collection was increasedto twice per month, and as much infor-mation as possible was shared publiclythrough various publications and thePlasma Protein Therapeutics Association(PPTA) web site.

Mr. Bult provided detailed informationon the evolution of the supply fluctua-tion in 2001. The shortages became evi-dent in North America in April 2001; the

Session 3:Current Supply Issues – Recombinant and Plasma Product Shortages



production of plasma-derived factor VIIIwas increased to address it. Throughoutthe period, consumers were providedwith information as quickly as possible.The situation in Europe mirrored that inNorth America, with distribution of plas-ma-derived factor VIII increasing, whilerecombinant product decreased. In fact,the overall consumption of recombinantproducts was higher than plasma-derivedproducts in Europe during 2001.

The supply shortages did lead to someconsumer benefits, particularly moretimely information that contained moreaccurate real numbers, Mr. Bult said.

He addressed some of the difficulties oftrying to predict shortages. The PPTAcould only make predictions based onpublicly available data. Moreover, headmitted, some things are just not possi-ble to predict. He also noted that manu-facturing is only one stage in theprocess, and stressed the need to exam-ine collection and product distributionissues as well.

Patient groups and government organiza-tions want the industry to take certainmeasures to guarantee supply, said Mr.Bult. However, he maintained, anti-trustlaws make it illegal to facilitate informa-tion exchange because U.S. law doesn’tallow manipulation of the market, price-fixing, or production and output agree-ments.

On behalf of the industry, Mr. Bultpledged to continue to provide as muchinformation as possible and to keepimproving product quality. He concludedby stressing that industry had come torealize that, for patients and treaters, it ismore helpful to provide bad news thanno news at all.



Union to recognize the need for strategicprovision of products, and to provideappropriate frameworks within which allparties can collaborate to accomplishthat goal.

The Influence of theShortage of RecombinantProducts on Treatment

Bruce Evatt, Centers for Disease Control andPrevention and World Federation ofHemophilia

Dr. Evatt outlined some of the causes ofblood product shortages in the UnitedStates in 2001. One cause was theincreased use of primary prophylaxis.Other causes included temporarilyreduced global access to recombinant(resulting in increased use of plasma-derived factor VIII), the increased use ofsecondary prophylaxis in older children,and more elective surgeries.

One reason for the increased use of pri-mary prophylaxis was a greater numberof patients on long-term prophylaxis.The impact of this greater number hasbeen startling. More than three-quartersof people with hemophilia use bloodproducts; half of these patients use on-demand therapy and account for one-third of the use of factor VIII in theUnited States.

Industry Perspectives(EPFA)

Theo Evers, European Plasma FractionationAssociation

The European Plasma FractionationAssociation (EPFA) is the internationalassociation of not-for-profit manufactur-ers of plasma products. Its aim is toensure continuity of supply of safe andhigh-quality products, and promote vol-untary non-remunerated donations andcommunity self-sufficiency. It is com-mitted to the sharing of information andtransparency, Mr. Evers said.

The EPFA works in collaboration withthe European Blood Alliance, and itsmembership comes primarily from thepublic health sector. The primary goal ofthe EPFA members continues to be pro-viding products in EPFA member coun-tries, using starting material collectedregionally or nationally from voluntarynon-remunerated donors, he said. Inaddition, many members are currentlyexporting surplus products.

During the current supply crisis, EPFAmembers managed to provide a continu-ous supply of plasma-based products.There are currently major concernsabout supply of plasma and plasmaproducts in Europe, as there are in mostparts of the world. Despite EuropeanDirective 89/381 in which regulatorsencouraged self-sufficiency, few initia-tives have been taken to increase thesupply of blood and plasma from volun-tary unpaid donors.

The European Union Blood Directive islegislation regarding the quality andsafety of blood and blood product col-lection, testing, processing, and distribu-tion. As a result of recent shortages, sup-ply issues have become part of thedebate around the directive, Mr. Eversexplained.

At the beginning of the recombinantsupply shortage, there was uncertaintyabout the probable duration of the short-age. The initial responses focused onmodifying treatment regimes. Althoughthere was early reluctance to switch toplasma-based treatments, the length andseverity of the shortage led to broad con-sultations with patients, treaters, govern-ment, and industry, and subsequently ledto increased demand for plasma prod-ucts.

In response, there was an increase inoutput by EPFA members of as much as15 percent, although the ability toincrease production varied depending onthe country or member organization.EPFA members succeeded in providingsufficient product to meet immediatedemands, Mr. Evers noted.

The different measures taken in differentmarkets to overcome the shortages hadconsequences in other markets. Mr.Evers contended that the limited numberof recombinant product suppliers createssupply vulnerability, as does the depend-ency on the supply of starting material.Market mechanisms are not sufficient toensure adequate product supply, andthere is a real need for strategic provi-sions to reduce vulnerability and preventshortages, he stressed.

Some countries have succeeded inincreasing or achieving self-sufficiencyin product and plasma supply. It is possi-ble and advisable, Mr. Evers concluded,for regional authorities like the European



tor VIII, while half delayed or reducedprophylaxis. Guidelines issued by theNational Hemophilia Foundation’sMedical and Scientific Advisory Council(MASAC), which outlined recommend-ed conservation strategies, assisted inreducing patient demand for clotting fac-tor by 20 to 40 percent.

By July 2001, the shortages had grownso acute that many began to fear patientsmight die in emergency situations. Tocontend with this possibility, a workshopwas held by the Centers for DiseaseControl and Prevention to try to organizean emergency system for delivering clot-ting factor to deal with life-threateningemergencies.

Dr. Evatt commended the industry for itsdiligent work in overcoming difficultiesin manufacture and distribution.Inventories had improved by November,although plasma-derived factor VIIIremains in short supply. Dr. Evatt pro-jected that supplies would continue torise through 2002 and noted that evenduring the extreme shortages, there wereno reports of any patients remainingcompletely untreated. The situation wasmultifaceted, he concluded, and under-scored the need for open, frank discus-sions involving all concerned parties.

The Perspective of theHemophilia Treater

H. Marijkeala van den Berg, Van Creveld Clinic-National HemophiliaCenter

Dr. van den Berg began by noting thatclotting factor concentrates havechanged the lives of people with hemo-philia dramatically and that with a suffi-cient supply of therapeutic products,their life expectancy has become normal.Near the beginning of the developmentof cryoprecipitate, there was a closerelationship between patient, doctors,donors, and the local blood bank. Thisrelationship, however, disappeared withthe development of concentrates and the

30 percent. Countries with internal sup-plies also saw shortages, from 10 to 20percent.

In discussing the shortages, Dr. Evattpresented the findings of a survey con-ducted among hemophilia treatment cen-tres (HTCs) in the United States. Thenumber reporting difficulty in obtainingrecombinant factor VIII peaked in mid-2001. Between 60 and 80 percent ofHTCs responded to the shortage byswitching patients to plasma-derived fac-

The other reason for the increased use ofclotting factors involves high doses. Asmall number of patients (fewer thanthree percent) are on extremely highdoses of immune-tolerance therapy.

Also during 2001, a number of manufac-turing and production problems made itdifficult to obtain certain types of clot-ting factors in the United States. Theeffects were felt worldwide, with coun-tries that depend entirely on externalsupplies experiencing shortages of up to



Mr. Skinner recommended continuing toenhance the dialogue between regulatorsand manufacturers. He warned that thereis a real possibility of future shortagessince the United States is still largelydependent on a single supplier forrecombinants.

He recommended an increased commit-ment to accelerated licensing of newfractionation plants in times of crisis,and a variety of data collection devicesat all levels (including the consumer).An emergency distribution system needsto be put in place, which will guaranteeprompt access to clotting factors in criti-cal situations.

He concluded by expressing his concernthat payers might respond to this periodof “sub-optimal” care by refusing toinsure the previous levels of therapy.

Patient OrganizationPerspective (Malaysia)

Norhanim Asidin, Hemophilia Society of Malaysia

Malaysia did not experience the sameproduct shortages described in othercountries, said Dr. Asidin. Since 1975,there has been a centralized NationalService Centre in Kuala Lumpur, whichhouses the central registry for hemophil-ia and congenital bleeding disorders.The centre is also a WFH-accreditedInternational Hemophilia TrainingCentre.

Malaysia’s goal is to establish a pool ofnon-remunerated voluntary donors, safefrom transfusion-transmitted diseases,and to ensure the highest quality andsafety in screening and testing proce-dures. The plasma collected from thesedonors is made into contract-fractionatedproducts, mainly factor IX, in whichMalaysia is self-sufficient. Production offactor VIII, albumin, and immunoglobu-lin still only meets about 20 percent ofdemand, requiring importation of prod-ucts to make up the difference.

situation further changed in the 1980swhen regulators like the FDA andEMEA came into place and developedsafety guidelines.

The patient used to be at the centre ofthe process and all the people and insti-tutions involved in her/his care werelocated nearby. The current scenarioplaces industry at one end of the processwith donors in the middle and patients,doctors, caregivers, and the WFH at theother extreme. Safety was the main fac-tor in increasing the distance betweenpatients and producers, she said.

The rapid development of safer, ultra-pure recombinant products and thestricter regulation of blood productshave been major factors in increasingcost, Dr. van den Berg explained. Hometreatment, prophylaxis and longer lifeexpectancies for people with hemophilia,coupled with safety concerns, have allcontributed to increased demand forrecombinant products, she said. This isparticularly true in the developed world.

At the same time, increased distancesbetween supply and patient made nation-al overview more difficult. Given that 55percent of the European patient commu-nity is on recombinant product therapy,the shortages were a big issue, especiallyin countries where there was a lack ofplasma-derived clotting factors. Choicesmade in Europe depended on local situa-tions, she stated.

Since recombinant product is the treat-ment of choice, it is traditionally used totreat children whenever possible.Consequently, children were the first tobe affected by the shortages. The prob-lem was compounded because smallvials were often unavailable, resulting inwaste.

The shortages led to the suspension ofimmune tolerance treatment and the can-cellation of orthopedic surgeries.Furthermore, the shift in demand forplasma-derived products created severeshortages in the developing world. Dr.van den Berg warned that the reschedul-

ing of cancelled orthopedic and electivesurgeries could create new shortages inthe future.

She concluded by asking participants tocarefully consider the implications of anindustry-driven environment and the cor-relation between extremely high safetystandards, high price, and lower avail-ability. She stressed the need to deter-mine more exact information on dosage as well as to determine the cost-effectiveness and broader implications ofspecific therapeutic approaches.

Patient OrganizationPerspective (U.S.)

Mark Skinner, National Hemophilia Foundation

Last year’s shortages caused a total shiftin the treatment “mantra” in the UnitedStates, said Mr. Skinner. The principlesof treat when in doubt, be independentof our treaters, and treat early, werethrown out the window, he said. Patientsfound themselves tethered to their physi-cians for the day-to-day management oftheir conditions, he said. The situation,normal for patients in much of the restof the world, was a “sobering step back-wards” for patients in the U.S.

There has been such a focus on ensuringthe safety of products for so long, thatsupply monitoring issues were neglect-ed, Mr. Skinner said. Patients want tounderstand what happened, how, andwhy. While there is no benefit in appor-tioning blame, it is necessary to under-stand the situation to prevent it fromrecurring.

Information sharing is still very limitedand tends to be retrospective. A valuablelesson could be learned by analysingwhat happened at Berkeley with Bayer.There is no doubt that Bayer’s problemswere the largest precipitating cause ofthe crisis. Many opportunities to addressthe shortages were lost because peopledid not have the necessary informationin time.



Needs Assessment ofFactor VIII Usage in China

Hu Ching-Li, Shanghai Second Medical University

Dr. Hu stated that he sees the issue ofshortages from a different perspectivethan the other presenters. China has ahuge territory (9.6 million square kilo-metres) with nearly a quarter of theworld’s population. He contrasted thepopulation of the city of Shanghai (13million) to Switzerland (6 million) in aneffort to illustrate the challenge that“sheer magnitude” creates.

The population and territory of Chinaare so large that it has not been possibleto carry out an accurate survey of peoplewith hemophilia. There are no officialdata related to the number of hemophiliacases in China. A survey in Anhuiprovince estimated that the prevalence ofhemophilia A was five per 100,000 pop-ulation. However, Dr. Hu cautioned thatthis figure could be inaccurate. If theWHO-estimated world incidence of onecase per 10,000 population applies, theexpected number of hemophilia patientsshould be 127,000, and the number ofsevere and moderate cases should be79,300. Yet, there are only 5,000 regis-tered cases. This indicates the extent towhich hemophilia is undiagnosed anduntreated in China, he said. The largegap also points to China’s critical needfor help from international organizationslike the WFH.

If the need for factor VIII is estimatedaccording to the WHO recommendationfor dosage levels and the estimated num-ber of people with moderate and severehemophilia A, 2,775 million units of fac-tor VIII would be needed annually.However, there is no way that Chinacould afford that level of treatment, sopractitioners make do with lowerdosages. In fact, the whole country con-sumes only 15 million units per year.

When recombinant products were devel-oped, the expectation was that theywould be free of contamination and therisk of inhibitors with unlimited produc-tion capacity. In reality, the supply canaffect safety and there are limitations toproduction capacity.

Three-quarters of people with hemophil-ia worldwide suffer from inadequatetreatment, suffering pain, isolation, andpremature death. Most of those patientsare in the developing world.

During the recent supply crisis, theshortage of recombinant products indeveloped countries led to increased useof plasma-derived products and resultedin dire consequences in developingcountries. Acute as shortages were inplaces like the U.S. and Europe, theypaled in comparison to those felt inmuch of the rest of the world, shestressed.

Brazil’s geography and demographicscreate particular challenges; 75 percentof the population live in rural areas andthere is very low population density innorthern areas. The Brazilian Ministry ofHealth has created a hemophilia sub-committee to oversee the treatment ofover 7,000 registered patients in 27states. The government’s priorities arenormalization, product purchase, distri-bution, and consumption administration.The regional hemocentres are a “bloodnetwork” that covers the entire country;however, some regions (such as theAmazon) are still poorly serviced.

The objectives of the BrazilianFederation of Hemophilia are to ensurepatient safety and adequate supply. Theorganization provides an interfacebetween patients, physicians, govern-ment, and industry. The critical goal forBrazil and the rest of the developingworld is to provide quality products insufficient quantity, she concluded.

Most cases are treated on demand. Thereis very little prophylaxis. Factor VII isonly used to treat certain cases withinhibitors. All treatment at the NationalService Centre is free, supported by thegovernment.

Since 1985, there has been a shift fromusing cryoprecipitate and plasma to atotal dependence on factor concentrates.That shift has raised real concerns whenthere is a world shortage of clotting fac-tors. The country has experienced short-ages of two products, generally importedfrom the U.S. To counter this, Malaysiahas increased production of factor con-centrates, which are manufacturedthrough a contract fractionation pro-gram, and is attempting to increase thecollection of blood and plasma inprovinces outside of Kuala Lumpur. Allcollection is administered by a centralauthority.

Although no shortages have been experi-enced to this point, there continues to begreat fear about the security of futuresupply, she concluded.

Patient OrganizationPerspective (Brazil)

Maria Foshi Nivia, Unidade de Hemofilia-HospitalBrigadeiro

Dr. Nivia explained that she was makingthe presentation on behalf of BrazilianFederation of Hemophilia PresidentMaria Cecilia Magalhaes Pinto, who wasunable to attend. Hemophilia is a diffi-cult disease to manage, compounded bythe need to deal with complications fromtreatment as well as the disease. Safetyand supply of treatment products areuniversal issues.

In developing countries, the challengesof securing adequate supplies are moreimportant than guaranteeing “absolute”safety. It is important not to forget pastexperiences with contamination, Dr.Nivia said, but “real safety is the guaran-tee of supply with no further threats.”



There is no prophylaxis in China, hesaid. The price of factor VIII treatmentis only US$0.15 per unit, but it is stillbeyond the reach of most patients. Thefacility in Shanghai has the capacity totriple its production, but hasn’t botheredbecause so few can afford treatment.Similarly, the recommended frequencyof prophylaxis treatment in China is onlyonce per week (the WHO recommendsthree treatments per week), but it is stilltoo expensive for most.

Recently, there has been alarming newsabout HIV in China, with 28,000 report-ed cases and estimates of as high as600,000 cases. This is creating concernsabout the safety of transfusions, hereported. It is reassuring that there havebeen only 10 known cases of CJD andnone of vCJD in China. However, thepresence of BSE in Japan is disturbingsince it is so close to China, and is giv-ing rise to new concerns about vCJD andother communicable diseases. The lackof a good regulatory body combineswith these other issues to create a com-pletely different perspective in China,which Dr. Hu urged participants to con-sider.



There was some discussion of the politi-cal and social issues connected to donordeferrals and beef in Europe. It wasnoted that decisions on safety of bloodand meat supplies are intimately linkedwith political gamesmanship. There arealso emotional factors associated withboth blood and food that make theseissues complex.

Given the tons of meat and bone meal(MBM) shipped from the U.K. through-out the world, a participant asked, doesvCJD now exist in countries which haveyet to report it? It was acknowledgedthat those countries that imported MBMfrom the U.K. are starting to see BSE intheir own cattle. Other factors play arole, such as how meat is processed, andthe genetic makeup of the population. Itwas agreed that this is a risk and thatentry of TSEs into the food chain needsto be studied more closely. To date, clin-ical vCJD has only been detected in theU.K. and France. It seems that vCJD is adisease of consumption of British beefproducts.

Noting the appearance of BSE in othercountries, a participant asked why theFDA does not defer donors who spenttime in those countries. The FDA islooking at the possibility of deferrals forJapan and other countries, replied anoth-er participant. This issue is made morecomplex because there is poor data onhow contaminated MBM was used; forexample, which countries were merelytransit points, and which nations wereend-users. Food chain control is obvi-ously essential. Recycling of the epi-demic can be prevented by not usingMBM to feed cattle.

There was discussion on whether coun-tries like the U.S., which are thus farfree of BSE, should adopt the higheststandards to protect themselves. Such adecision could involve a costly trade-off

The purpose of the open forum discus-sion period was to provide participantswith the opportunity to discuss anythingrelated to the safety and supply of hemo-philia treatment products, said SimonTaylor. Glenn Pierce, of the NationalHemophilia Foundation in the U.S.A.,and Ashok Verma, of HemophiliaFederation (India) and WFH ExecutiveCommittee member, facilitated the ses-sion.

Dr. Pierce asked the forum to vote onthe following question:

Do prions cause vCJD?

Yes 87%No 13%

The results were interesting, Dr. Piercesaid, adding that we only think weunderstand vCJD. If vCJD is not a con-cern, he said, what will come next andhow will it behave? We don’t knowwhere the next CJD-like agent will comefrom, he concluded.

In response, a participant suggested thatthere is excellent evidence linking prionsto infectivity. There is as yet, no methodsensitive enough to test for prions inblood or plasma. Perhaps in the future, athreshold will be determined, and unsafeproducts will be identified with morecertainty.

Dr. Pierce asked if the solution is to befound in having stricter deferrals, orfinding new ways to inactivate and elim-inate the virus. A participant suggestedthat even if measures could be used toallow lifting of deferrals, this might nothappen. For example, the screening forhepatitis C is quite good but intravenousdrug users are still deferred.

Another participant likened doubting thelink between prions and vCJD to gov-ernments claiming that they don’t knowwhat causes AIDS. There may not beproof but there is enough evidence tomake responsible decisions possible, theparticipant said.

It was noted that prions can be clearedby partitioning. Another participant sug-gested that although prions are the likelyculprit, there is still a possibility thatvCJD may be a virus.

Another audience member argued that itis a mistake to trust any one mechanismfor ensuring blood safety. Removing anycomponents of the process could openthe back door for agents to adapt andcome back, he warned.

A scientist suggested it is important tocorrelate removal of prion proteins(PrPs) with bioassays. This will providereassurance of the efficacy of processesto remove infectious agents, and willnecessitate the use of surrogate or actualviral agents.

Brian O’Mahony noted the extremelyvaried list of donor deferral systems. Hesaid the FDA and EMEA are world lead-ers in developing deferral guidelines bal-ancing safety and supply. He urged thatharmonized minimum standards bedeveloped. He also said that local deci-sions have to be made on how manydonors would be lost to each deferral.For example, Ireland can safely deferJapanese donors but the deferral of any-one who had lived in the U.K. would bedisastrous because of the loss of donors.

Many participants agreed with a call forregulators and stakeholders to come upwith some harmonized standards. It wasnoted that the WHO is looking at con-vening a consultation to look at harmo-nization sometime later this year.

Session 4:Open Forum Discussion



It was noted that the price charged bythe manufacturer is different from theprice paid by or for the patient. Whilehaving this data is helpful, it does nottell the whole story.

A participant pointed out that bloodproducts are regulated differently fromother pharmaceutical products. It wassuggested that any increase in standardsrequires higher investment by manufac-turers. There are also practical issuesassociated with risk assessment. It waspossible to ban fractionation of U.K.plasma but not possible to ban the use ofcellular blood components. Another par-ticipant disagreed with claims that moretesting would require higher investment,pointing out that hemophilia productsare profitable; they drive growth forcompanies and have high margins.

Cutting out the middlemen was proposedas one way to control prices. However,even reducing prices will not make a dif-ference for most people with hemophiliasince they rely on their governments topay for treatment. No matter how low-priced products become, they will stillbe unaffordable to a large proportion ofpeople with hemophilia.

It was suggested that the crisis in NorthAmerica last year was caused by regula-tory policy being driven by politicianswho demanded certain restrictions, notthe FDA. It was also noted that industry,in seeking a competitive edge, maymake unfounded claims about the rela-tive safety of a product. This was seen in1996 with the introduction of NAT.

A participant called for transparency inthe development of guidelines.

Worldwide shortages caused by prophy-laxis are created in the northern hemi-sphere, he said. Such shortages can bemuch more dangerous to the developingworld although they originate from thedeveloped world.

Simon Taylor said the statistics theforum had heard on the problem inChina were humbling.

A participant asked if the recent supplycrisis had led to new thinking aboutmodifying recommended dosages forless wasteful use of products. Severalparticipants said the shortage was anemergency situation that caused artificialreductions with potential detriment andlittle or no benefit. Concern was alsoexpressed about a secondary shortageoccurring when supplies are back up andprocedures that have been postponed arerescheduled. The challenge is phasingback into normal practice without creat-ing a second crisis, a participant said.

It was suggested that some patientgroups in the developed world misusefactors VIII and IX. Little is knownabout adequate dosages. The issue ofvial size still needs to be studied. Thedeveloped world has work to do onrationalizing the use of concentrates, oneparticipant stressed.

A participant cautioned that any move toreduce dosage could have a negativeeffect in developing countries. Anotheraudience member noted that usage inEurope varies from 1.5 units per capitain Greece to 7.6 units in Sweden. Nodeveloping country even comes close;many are between 0.01 and 0.4 units percapita.

There was a suggestion that the WFHdevelop a database reflecting pricesworldwide. It was suggested that thiswould pressure producers to harmonizetheir prices. It was noted that the shift tothe euro has meant greater price trans-parency in Europe. WFH ExecutiveDirector Line Robillard said that theWFH has started collecting global pric-ing data. Efforts to gather and dissemi-nate this information will continue.

in terms of supply for safety. In reality, aparticipant suggested, the U.S. has amore conservative approach thanEurope.

Participants discussed how the U.S.might respond when the first BSE-infected cow appears. It is not inevitablethat one cow would lead to deferral of250 million donors, a participant assert-ed. There are other issues that wouldneed to be looked at.

A participant asked which held thegreater risk – a vial of factor VIII madefrom pooled plasma in Europe, purifiedand viral inactivated, or eating friedsausages from pooled European meatproducts three times a week.

One response to this question was thatpeople are known to have contracted thedisease from eating meat, while there isno known case of transmission throughblood products. In the U.K., hemophiliapatients have taken products known tobe contaminated with vCJD withoutdeveloping the disease. Therefore, eatingthe meat has a higher risk associated.Most scientists seemed to agree that tak-ing the concentrate would be less of arisk than eating the sausages.

A participant asked about the theoreticalrisk of contracting CJD through bloodproducts, and the possible risks ofrecombinant products. It was noted thatthere has been a drive to eliminate albu-min from recombinants but questions ofstability have now arisen. Recombinantsand other alternatives are not risk-free.There is a lack of clinical experience inthis emerging area.

Another participant observed that med-ications are approved even when death isa rare side effect. Attempts to have zero-risk in blood products are based on adouble standard, she said.

Mr. Verma shifted the discussion fromsafety to supply and gave a developingworld viewpoint. Actions in the devel-oped world are not always rational froma global perspective, he stated.



Participants voted on the following ques-tions:

Based upon current informa-tion, which do you think is agreater risk to people withhemophilia?

vCJD 5%Shortages of factor

concentrates 95%

Based upon current informa-tion, which do you think is agreater risk to people withhemophilia?

Patient groups only:vCJD 9%Shortages of factor

concentrates 91%



down and made available. Doctors in theU.K. responded quickly to try to providea coordinated response and engaged inpositive dialogue with the U.K.Haemophilia Society.

On the negative side was media atten-tion, which was generally unhelpful andunwelcome. It was not possible toachieve unanimous agreement on aresponse amongst physicians. News wasimparted to patients in an impersonalfashion: typically, by letter. Unaffectedpatients were only reassured after sometime, causing unnecessary worry. It wasvirtually impossible to trace recipients ofother products such as albumin andimmunoglobulin.

Dr. Giangrande said that most patientshandled the crisis well but he is aware oftwo patients who have had lasting psy-chological problems because of the inci-dent. There has been increased pressureto switch to recombinant products. Somescheduled surgical procedures were can-celled because, despite the lack of evi-dence, recipients of the batches wererather arbitrarily viewed as being highrisk.

Dr. Giangrande concluded with thewarning that it is not a question of whatif this sort of incident will happen again,but when.

The U.K. Experience –Patient AssociationPerspective

Simon Taylor, U.K. Haemophilia Society

Mr. Taylor then discussed the same casefrom the point of view of the patientorganization. Hemophilia treaters gener-

The U.K. Experience –Treater Perspective

Paul Giangrande, Oxford Haemophilia Centre and WorldFederation of Hemophilia

Dr. Giangrande spoke about the treaters’experience of communicating risk, illus-trated by a U.K. incident last yearinvolving hemophilia treatment productscontaining plasma from a donor whodeveloped vCJD. He explained that heand Simon Taylor would discuss twodifferent perspectives on the incident:that of treaters and that of the patientgroup.

On December 14, 2000, notification wasreceived that plasma from a donor diag-nosed with vCJD had been supplied toBio Products Laboratory (BPL) in 1996and 1997. The plasma had been fraction-ated into several batches of differentproducts including albumin, immuno-globulin, and factor VIII and IX concen-trates. By the time the notification wasreceived, all products were past theirexpiry date and presumed to have beenused in clinical practice.

Dr. Giangrande noted that a similarproblem had occurred with factor VIII in1997. At that time, the advice from theNational Blood Authority to doctors wasnot to inform patients. The NBA stated,“the general view is that patients will notbenefit from this knowledge.” This posi-tion was reached because there is no evi-dence that blood products transmitvCJD, and no diagnostic test or preven-tative treatment. Also, it was felt that thenews would cause “unjustified worry”and “create permanent blight on theirlives, e.g. life or health insurance.” Atmost, about 300 people in the hemophil-

ia community were directly affected, hesaid. None of the factor concentrate wasused abroad, but the immunoglobulinand albumin were.

In general, directives from theDepartment of Health are managerialand should be followed, Dr. Giangrandestated. The British hemophilia care com-munity decided to force the issue. Theyknew that it was not an option not toinform. The cat was out of the bag andthe only questions remaining were how,when, and what patients should be told.Treaters anticipated a wave of pressurewhen the story broke in the media. Dr.Giangrande said he would have pre-ferred to inform patients in person attheir six-month review, but since waitingmeant risking that patients would findout from headlines in the media, thiswas not possible. The two options con-sidered were a full and frank disclosureup front, or an offer to inform.

After some debate over informing allpatients and asking them if they wantedconfirmation, it was decided to informonly those patients who had received thebatches. In the end, each hemophiliatreatment centre (HTC) made its owndecision on how exactly to inform.Letters were prepared which emphasizedthe lack of evidence of transmission ofvCJD and the fact that BPL plasma-derived concentrates are now made fromimported plasma. An effort was made toensure that letters did not arrive onFriday so people would not be callingtheir HTCs over the weekend when noone would be there.

Dr. Giangrande highlighted what he feltwas positive about the response to theincident, including rapid disseminationof news to the hemophilia treaters byBPL and the National Blood Authority.Specific information about implicatedbatch numbers was quickly tracked

Session 5:Communicating Risk - The Example of vCJD



There are other users of blood productswho were not informed of their exposureto risk, a participant said. Some peopleoutside the hemophilia community wereinformed but thousands were not.Patients who have a national society areeasier to contact.

A participant told of a patient notifica-tion system instituted in his country fouryears ago, which allows people to regis-ter to be notified. It is voluntary and isintended to protect privacy. It was notedthat databases for such purposes needconstant refinement so that they arealways ready for use.

It was noted that in quality control ques-tionnaires, patients are asked what theyknow about their own status. Denial is acommon part of the human condition.Full disclosure and reiteration are neces-sary. Patients have a right to directknowledge in real time, but patients alsohave a right to choose not to beinformed.

One member of the audience assertedthat a voluntary system works but it isnot the full solution in and of itself.

A participant from Canada praised theresponse of British treaters and patientgroups to the crisis. He said he hopedCanadians would respond in the sameway in a similar situation. A standard-ized bar-coding system would help intracking recipients of bad batches, hesuggested.

Nurses are a vital link in the communi-cation chain, another participant assert-ed. The nurse must have the informationbefore the patient. Nurses with trainingas counsellors are on staff at Britishcomprehensive care centres.

An audience member said the decisionto inform is quite easy if one were to putoneself in the patient’s position. It isimportant that the patient and familyunderstand the risk. Clearly, it wouldalso be right for all recipients of suspectblood products to be informed.

Mr. Taylor said the greatest distress wasamong parents, particularly those whohad recently switched their children torecombinant products. There was alsothe fear of discrimination and actualincidents of discrimination. One childwas called “mad cow” in school.

Mr. Taylor said that future incidents suchas this case are inevitable. Speaking as apublic relations consultant who special-izes in crisis communication, he said, itis important to remember, “You will beasked what did you know, when did youknow it, and what did you do? So tellthe truth, tell as much as you can, andtell it as quickly as you can.”

Discussion

Participants then asked for elaborationfrom Dr. Giangrande and Mr. Taylor ondetails about the incident. Most centrescommunicated with all their clients butsome offered the choice to not know ifsomeone had received a bad batch. Mr.Taylor said that patients would be askedat their six-month review if they want tobe informed in the future.

The news did not leak to the media untilthe end of January, after the letters wentout. There was an effort to coordinatethe letter from the UKHS with lettersfrom treatment centres. This was notalways successful. It took time to trackdown the information about who to con-tact, and it was a race to do a responsi-ble job before the media got wind of thestory.

A participant asked why people withhemophilia were denied surgery notingthat eating meat is a quantifiable riskwhile evidence of a CJD risk from bloodproducts is still unclear. “Are those whoeat meat exonerated? Why are peoplewith hemophilia singled out?” Anotherparticipant agreed but noted that peoplewith hemophilia are generally not deniedsurgery. It was noted that even with theuse of disposable equipment surgicalprocedures are not without risk.

ally responded well, he said. He paidtribute to BPL for its ethical decision toinform the hemophilia communityquickly.

Patient groups were concerned about theU.K. Department of Health policy ofnon-disclosure. Emotions were highbecause of the sensationalist media inter-est in BSE and vCJD on the heels of afour-year public inquiry. There was ahigh probability of a leak to the media.

Patient groups were interested in main-taining the trust of the hemophilia com-munity. Complicity in a cover-up wasnot an option. They also wanted tocounter the inevitable alarm that wouldbe generated by the media. Patientgroups supported hemophilia centres asthe primary source of advice to peoplewith hemophilia but wanted to providean additional trusted source.

The U.K. Haemophilia Society (UKHS)sent a letter to all members timed tocoincide with the treatment centres’ let-ters. There were problems because someletters did arrive late in the week, andthe help-line is not staffed on weekends.The UKHS felt that they had a duty toinform all people with hemophilia of theincident. They were concerned that therewas no uniform or standard communica-tion by the hemophilia centres. Not allhemophilia centres could be trusted tocommunicate the message to patients.Anecdotally, Mr. Taylor said that thesmaller centres, which tend to lack long-term corporate memory regarding HIVand hepatitis C, were less communica-tive than the larger centres.

The UKHS database needed some workto make sure that letters weren’t sent outto children. This should have been a“fail-safe” backup to communicationfrom the hemophilia centres, but inmany cases it was not.

Regarding the responses of people withhemophilia to the incident, Mr. Taylorsaid that older people were more philo-sophic. Those who were already angryabout blood safety crises just got angrier.



One participant said spreading informa-tion on vCJD, as the WFH TSE TaskForce does, is seen by some as spreadingpanic, however, he does not accept theargument that ignorance is bliss. Anotheragreed, noting that the Department ofHealth philosophy is insulting paternal-ism.

One participant said the entire BPL inci-dent could have been avoided. Beforethe products in question were used, therewas a campaign for all patients to be onrecombinant products. The governmentdenied funding for recombinant factorVIII and so patients were exposed tothese products.

Mr. Taylor and Dr. Giangrande said theywould be happy to share more abouttheir experience as well as the text of theletters that were used.

Participants voted on the following ques-tion:

Given the current state ofknowledge, do you think aperson with hemophilia whohas received a factor concen-trate manufactured with plas-ma from a donor later diag-nosed with vCJD should beinformed of the fact?

Yes 93%No 7%



which would effectively create authorityover the whole process. Dr. Farrugianoted that while there were nationalrequirements in place before 2000, theywere not nearly as comprehensive as thedraft directive.

Some serious issues have arisen over the2000 draft directive. One surrounds therequirement that blood and plasma products be from voluntary and non-remunerated donors, even if the producthas been imported. Dr. Farrugia saidalthough he personally endorses volun-tary, non-remunerated source product,this requirement could have a seriousimpact on therapeutic access and wouldrestrict products significantly. The worldsupply is so dependent on the U.S.plasmapheresis sector – which is notvoluntary and non-remunerated – thatthis regulation could create a snowballeffect culminating in worldwide short-ages, he said.

In response to those concerns, the draftwas amended and now stresses the needfor testing, quality management, and aEurope-wide surveillance system, whilesupporting the ethical position that vol-untary, non-remunerated donations arepreferable.

Europe also uses a plasma master fileconcept. This is a system that documentsthe epidemiology of donors, sources, andtesting procedures. The EMEA uses cen-tralized procedures for products thatinvolve high technology or high risk, Dr.Farrugia explained. Other products gothrough a mutual recognition standardwhereby they are accepted after theassessment of other regulated Europeannations.

An important element of the Europeanregulatory structure is an exemption incases of “exceptional circumstances.”That flexibility is especially important

Review of AssessmentProcesses Worldwide

Albert Farrugia, Australian Commonwealth TherapeuticGoods Administration and WorldFederation of Hemophilia

Dr. Farrugia noted that plasma productsare very heavily regulated and dominat-ed by the FDA in North America and theEMEA in Europe. He described the sec-tor as “disproportionately regulated,”given the actual risks involved, but con-ceded that it was a response to publicpressure based on historical events.

In less-resourced countries, there is atendency to accept the assessments anddecisions of the FDA and EMEA; this isundesirable because it does not take intoconsideration important local issues anddiscourages the development of inde-pendent regulatory authorities, Dr.Farrugia said.

Regulation, however, plays only one partin issues around blood products; marketforces are also very important.

Every regulatory agency has essentiallythe same primary goals: safety, quality,and efficacy of products. With plasmaderivatives, these concerns are addressedthrough facility licensing, the promotionof good manufacturing processesthrough pre-market product assessment,and surveillance of the product’s per-formance after it is marketed.

There are various agencies involved inregulation and the evolution of regula-tion in Europe. They include theEuropean Union through the commonmarket, its general legislative structure,and the promotion and use of the new

currency. The Council of Europe, whichis distinct from and much broader thanthe EU, also plays a role, as do govern-ments and agencies in the individualnations.

Dr. Farrugia reviewed the applicable leg-islation and its evolution within theframework of the oversight of medicalproducts:

• 1965: The EEC instituted the regu-lation of proprietary medicinalproducts. (Directive 65/65/EEC)

• 1975: This regulation was ampli-fied with standards and protocolsfor proprietary medicinal products.(Directive 75/318/EEC)

• 1975: Set up the CPMP and admin-istrative measures for 65/65/EECand 75/318/EEC products (howev-er, all three of these measuresexcluded medicinal productsderived from human blood).(Directive 75/319/EEC)

• 1989: Extended earlier regulationsto blood products (Directive89/381/EEC)

Actual formal oversight of blood andplasma products in the EU came rela-tively late in the day, Dr. Farrugia said.In 1975, the principles set out in thedirectives of 1965 and 1975 wereacknowledged as being applicable, butnot entirely adequate, for medicinalproducts derived from human blood orplasma. A subsequent directive in 1989incorporated new details for oversightacross Europe. However, Dr. Farrugianoted that regulatory oversight of trans-fusion has not been centrally adminis-tered in Europe – it has been limited tolarge-scale production of fractionates,and not donors or other issues.

Near the end of 2000, a new draft direc-tive set standards for quality, safety, pro-cessing, and distribution of products,

Session 6:Global Regulatory Assessment of Products



Dr. Snape asked participants to considerwhether the focus on viral safety wasappropriate or “obsessive.” He comparedrecent data on fatalities from transfu-sion-transmitted infections (TTIs) tofatalities from medically incorrect bloodtransfusion. It revealed that only threepercent of fatalities in 1998/99 werefrom TTIs. While we know that transfu-sion-transmitted infection is a seriousissue, it needs to be put in perspective,he said.

There is a danger that stakeholders inthis process will treat TTI as the onlyissue to be considered, he warned.Plasma products, without exception, aresterile products manufactured aseptical-ly, he observed. There is no terminalsterilization process; consequently safetyis totally dependent on the quality of themanufacturing process to deliver a prod-uct that will not transmit bacterial infec-tion, or cause endotoxic effects or otherproblems. Assurance of the quality andsafety of plasma products involves theassurance of plasma quality, through avalidated process that incorporates viralelimination or viral inactivation.Therefore, there needs to be monitoring,oversight, and testing at all stages in theprocess.

Dr. Snape emphasized that good manu-facturing practice must be ensured at theplasma centre and in the fractionationfacility. Various factors can help mini-mize risks, including the exclusion ofdonors, mandatory serology testing onall plasma, exclusions based on post-donation information, and nucleic acidamplification testing (NAT). The processof safety assurance continues at the frac-tionation lab, with pool testing usingviral marker tests and NAT. Samples aresent to national regulatory authorities fortesting, and traceability back to thedonor is maintained.

The process must be robust. Good man-ufacturing practices are developed toensure that poor practice does not lead tothe release of bad products, he said.

Assessment of ProductsNot Licensed by the FDAand the EMEA

Terry Snape, Pharmaceutical Consultant

Dr. Snape spoke of how procedures andregulations impact on products, andwhat has to be done outside of Europeand the U.S. to gain some of the benefitsof regulation.

He agreed with Dr. Farrugia that thebasic goal of regulation is to ensure thesafety, quality, and efficacy of plasmaproducts. Regulators are necessary, hecontended, because “over the yearsmany people have made mistakes thathave harmed the people they were tryingto help.”

Dr. Snape outlined several examples:

• In 1937, in the United States, acontaminated cough syrup killedover 100 people.

• In 1959, in Europe, the “thalido-mide tragedy” resulted in thou-sands of fetal abnormalities.

• In 1966, in Europe, thyroid tabletscontaining salmonella werereleased.

• In 1972, in the United Kingdom,contaminated intravenous fluidscaused six deaths.

In terms of blood products, there havebeen too many examples of incidentsinvolving plasma products. There is areal need to look at the root causes ofthose incidents to learn the lessons nec-essary to make the supply of blood prod-ucts safe, Dr. Snape said. The root caus-es varied. Some incidents were causedby products that did not undergo viralelimination or viral inactivation. Somewere caused by the failure to use goodmanufacturing practices, and someinvolved poorly designed products. Inaddition, there is always the possibilityof new infectious agents.

for hemophilic products which requireflexibility to ensure life-saving supplycontinuity.

By contrast, in the U.S., blood productshave always been regulated under theVirus, Serum and Antitoxin Act of 1902.In the 1970s, control of biologicsswitched from the National Institutes ofHealth to the U.S. Food and DrugAdministration.

Generally, the FDA’s responsibilities aresimilar to those of the EMEA. It pro-vides basic regulatory oversight, productevaluation and research, and housesmassive resources for oversight. TheFDA Center for Biologics Evaluationand Research (CBER) oversees a widerange of products, primarily throughTitle 21 of the Code of FederalRegulations (CFR) and a series of guid-ance documents. These guidance docu-ments are developed with input fromacademia, government, and industry, andthrough public consultation.

Dr. Farrugia conceded that there hasbeen criticism levelled against the use ofvoluntary guidance documents, ratherthan legally binding legislation.However, in practice, he maintained, theFDA is so powerful and legal liability sosubstantial, that it is rather difficult forindustry to ignore them. Moreover, theuse of guidances allows the FDA tomove more quickly than following a leg-islative route in many cases.

The CFR specifically applies to humanalbumin, plasma protein fraction, andimmunoglobulin. Special proceduresapply for certain advanced technologicalproducts, including recombinant andsynthetic therapeutic products. However,licensing of all therapeutic products isstill required.



The WFH RegulatoryGuide

Terry Snape, Pharmaceutical Consultant

Dr. Snape explained that he had beenasked to assist in the development of the“regulatory cookbook,” recommendedby participants at the last WFH GlobalForum. The guide is intended to provideassistance to product prescribers, pur-chasers, and regulators by providinginformation that is current, definitive,and helpful.

While attentive to FDA and EU process,the guide is targeted to less-regulatedenvironments. It will cover factors con-tributing to the quality, safety, and effi-cacy of hemophilia treatment products,and guidance on good practices in invit-ing tenders and evaluating products. Theguide will provide an overview of estab-lished regulatory systems and include aglossary of terms. The guide stresses theimportance of considering plasma sourceand processes, and not depending onproduct post-testing, he said.

Dr. Snape briefly outlined the format thefinal guide will take and presented abrief history of its development process.The guide is slightly behind schedule butwill likely be ready in 2002, he conclud-ed.

Discussion

Simon Taylor asked participants to dis-cuss whether the detail of informationsupplied by the FDA and EMEA isappropriate to other countries, or if itcreates a barrier to countries whereaccess to basic products will save lives.

One participant said he would have likedto hear more about the regulatory envi-ronment in Japan. Dr. Farrugia apolo-gized, saying that he was not well versedin the Japanese system, though it is awell-reputed structure. A participant

Dr. Snape questioned the value of fin-ished product testing by third-party labo-ratories. He acknowledged that peoplehave concerns that something might bemissed or that a product could becomere-infected after manufacture. However,he contended that post-production test-ing is essentially a marketing tool toallay public fears and has little realvalue. It is “a knee-jerk reaction withoutpractical value,” he said. The tests werenot developed for use on finished prod-ucts and typically produce inconclusiveresults, he asserted.

National regulatory authorities areattempting to establish and maintain sys-tems of licensing and control. Thelicence is essentially a contract betweenthe manufacturer and governments.Inspection and enforcement ensure thatthe contract is respected, and requireappropriate quality systems.

Some common features of establishedregulatory provisions include:

• the review of data in the marketingapplication, especially plasma qual-ity commitment through plasmamaster files, process and batch test-ing, and the review of safety, effi-cacy, and pharmacokinetic data;

• the inspection and enforcement ofthe plasma donor base, the manu-facturing process and facility, andthe storage and distribution net-work;

• control batch review and release;• post-marketing surveillance and

follow-up.

In regions where there is no formalizedregulatory system, agencies responsiblefor blood products must act and be seento act, Dr. Snape said. Individuals inthose scenarios will lack experience andresources, he conceded. The playingfield is not level and agencies, particu-larly in developing countries, have diffi-culty paying for expensive monitoringand testing processes. In those countries,there are often several generations ofproduct concurrently available and thebenefits of choosing one over another

are not always very clear. Guidance isessential, he said.

Variability in quality of plasma used forproducts is inevitable. How can the reg-ulator make judgements in the absenceof information? The regulators in thesecases cannot know if the collection andmanufacturing process has been safe andif the product is high quality. Moreover,they need to respond to changing cir-cumstances that are entirely beyond theircontrol since product price and availabil-ity are driven by events in the U.S. andEurope, Dr. Snape noted. He added thatthere is a perception that the most recentproduct is probably the best one, but thatis not necessarily the case.

In many countries, there is great pres-sure to choose products on the basis ofprice alone. However, Dr. Snape stressedthat political expediency does nothing toensure safety, quality, or efficacy. Insome cases, it might be easier to workthrough a broker, but he noted that trans-parency is lost. Many of the laboratoriesinvolved are not properly qualified toconduct the tests; samples are often toosmall for reliability and the tests havenot been designed for finished products.

Although the challenges facing non-FDA and non-EMEA regulators are sub-stantial, Dr. Snape maintained there aresome measures that can be taken. Herecommended developing direct, man-aged relationships with suppliers; select-ing products that have been licensed byestablished regulatory authorities; usingpre-contract questionnaires; and auditingsuppliers. He cautioned against usingpre-shipment data as the primary sourceof information and reiterated the impor-tance of auditing batch expiration infor-mation. Finally, he encouraged peoplein these situations to ask for help whenthey lack the resources to do thingsthemselves.



make informed choices and adapt themechanism to the particular situation ina country.

Several participants agreed that theguide was the most important result ofthe last forum. One participant asked ifthere is a plan in place for its distribu-tion, and stressed the importance of get-ting it out before the information in itbecomes redundant. A representative ofPPTA volunteered that organization’sassistance in the distribution process.

It was suggested that in addition to theguide, it would be helpful to have apanel of experts who can provide practi-cal information and advice.

Another participant recommended tyingthe guide to work being done by theWHO to lend it greater weight and cred-ibility.

Most developing countries have little orno regulating authorities in place, a par-ticipant noted, even for other pharma-ceuticals. The guide could be extremelyvaluable in evaluating products that haveno established track record, he said, andlooked forward to its release.

from Japan said that his country uses thesame types of measures as the FDA andEMEA.

At the last global forum, there was morerepresentation from treaters and patients,a participant said. However, what theythink is irrelevant, he said, since govern-ments still have ultimate regulatoryauthority and each makes decisions itsown way.

Another participant cautioned againstgiving the message never to test finishedproduct. She agreed that there are prob-lems with post-production testing, butsuggested that it is more important toexplain the limitations and urge thedevelopment of more meaningful fin-ished product tests. While she lauded thedevelopment of the regulatory guide, sheurged participants to remember theimportance of education around manyissues.

Dr. Snape was asked how it would bepossible for the guide to be so short,only 25 pages. He replied that the guidedoes not spend a lot of time describingthe complexities of EU and U.S. regula-tions; but focuses instead on what theydo that is suitable in other environments,and what can be substituted to ensuresuitable assurances of quality and safety.

A participant from a developing countryrecalled that the guide started with therealization that developing countries donot have the resources to design regula-tory processes themselves, and that fol-lowing EMEA and FDA guidelineswould result in a total lack of affordableproducts. Therefore, he asserted, theguide was intended to be a set of goodminimum standards. If the guide doesnot meet those requirements, he said,there is not much advantage to publish-ing it.

Another participant suggested that twodifferent documents are needed. Thefirst, he said, should be an evidence-based mechanism that explains theresults of doing without particular meas-ures or processes, so each country can



He explained that forum organizersmade an effort to keep the event a dayand a half long so that people could fit itinto their schedules, particularly those inindustry. No one disagreed with thatthinking.

One participant commented that the vot-ing mechanism was a valuable way tomeasure opinion, and said it was inter-esting to see how opinions changed dur-ing the meeting. She encouraged contin-uing this practice.

Another participant expressed disap-pointment at the low number of partici-pants from European national hemophil-ia organizations.

The first forum involved plenary ses-sions and breakout sessions into smallerworking groups, one participant recalled.Mr. Taylor explained this format was notadopted this time because everybodywanted to hear and participate in all dis-cussions. At the first forum, it was diffi-cult to report back from the workinggroups, he added. As well, the work-shops varied in effectiveness dependingon the level of discussion. There wassome discussion on the merits of the twoformats.

Another participant suggested that sincethe forum is made up of groups with dif-ferent viewpoints, it might be beneficialfor those groups to split off and thencome back to a plenary session for livelydebate.

Should we have workshops atthe next forum?

Yes 58%No 42%

Because some participants had to leaveearly to start their journeys home, Dr.Peter Jones opened the final session bythanking WFH Executive Director LineRobillard and her staff for their terrificjob organizing the forum. He thankedthe audiovisual team for a nearly glitch-free meeting. He thanked Simon Taylorfor his hard work, the speakers for theirbrevity and focus, and the delegates fortheir participation.

Brian O’Mahony explained that thefeedback session is an opportunity totalk about safety and supply issues andfuture steps. He introduced members ofthe WFH Task Force on TSEs and gavethe assurance that if there is a majordevelopment in the area the TSE TaskForce will get the word out. The WFHintends to be more proactive and provideinput when changes to regulatory prac-tices are being considered, he stated.

Mr. O’Mahony noted that this is the sec-ond global forum and asked participantshow it compared with the first. Shouldthere be a third forum and if so, whatformat it should take?

A participant from industry said that thiswas his first forum and he found it veryhelpful and would like to see another.

Participants voted on the following ques-tion:

Should the WFH organizeanother global forum?

Yes 92%No 8%

Montreal was chosen as the site for thefirst two fora because it is cost effective,WFH staff is there, and it has good linesof communications, Mr. O’Mahony

explained. Participants then voted on thefollowing question:

Should Montreal be the site ofthe next forum?

Yes 77%No 23%

A forum member noted that the year2003 is the 40th anniversary of the WFHand asked if there would be a celebrationof sorts, such as a retrospective or fore-cast at an event that year. Mr. O’Mahonyreplied this is being planned.

Keeping the forum topical is important,Mr. Taylor said. He encouraged partici-pants to send along ideas and issues thatshould be discussed.

It was suggested that time be spent onthe issue of developing products thatwould be accessible in countries withoutmuch money. Mr. Taylor said he felt thatthere was quite a focus on developedworld issues this time. Participants thenvoted on the following:

Was the balance betweenspeakers and discussionabout right?

Yes 60%No 40%

Should we have more discus-sion and fewer presenta-tions?

Yes 59%No 41%

Mr. Taylor said he took these results tomean that the balance was not far off.

Session 7:Feedback and Next Steps



scheduled session focusing directly onthe supply of recombinant products.

There was a call for a full discussion ofthe Bayer-related shortage problem,since there are a lot of lessons to belearned from what happened. Dr.Giangrande replied that the decision hadbeen made to add extra symposia onsupply issues for plasma and recombi-nants at the WFH congress.

Various groups are represented at theforum and the proper relationshipbetween these groups is an issue, a par-ticipant said. The relationship variesfrom country to country. Lack of com-munication or too much collaborationcan both be problems. In the U.S., therewas a feeling that individuals and doc-tors had too much of a role. On the otherhand, mistakes can be made due to alack of communication. Bridge buildingbetween groups is essential, and eachrelationship is a balancing act.

Another participant responded that inEurope, patients are still beating on thedoor to get in. “We’d like the problem tobe that of being too close.”

Mr. O’Mahony agreed that nationalhemophilia organizations would benefitfrom examining their structure and theirrole.

He expressed his thanks to everyone formaking the journey, and said the WFHwill organize another forum for nextyear.

The breakdown of participants wasroughly 30 from industry, 20 clinicians,20 hemophilia organization leaders, and10 regulators. This was seen as a goodnumber of participants that allowed fordiscussion among the various stakehold-ers. One of the dynamics that organizerswanted to maintain was a feeling ofequality, a sense that participants are allpeers. They were pleased to have moreregulators than at the last forum.

A participant expressed support forkeeping the forum about the same sizebecause the nature of the discussionswould change with a larger group.

It was good to hear other points of view,another said. “We are all used to talkingto our own groups. Here, we hear viewsthat we aren’t usually exposed to.” In thefirst forum, the group was broadly splitbetween developed and developingcountries on most issues.

There was a suggestion that more casestudies be presented next time. Peopleagreed that hearing “war stories” andpractical examples was one clear benefitof the forum.

Mr. Taylor thanked participants for theirthought-provoking input; the WFH hasvaluable perspectives and findings totake back, Mr. Taylor said. He asked ifparticipants felt that too much or notenough time had been spent on vCJD.

A participant noted the heavy criticismon the issue of how and when batches offinished product can safely be released.It would be interesting to hear from anexpert; he made a proposal to inviteexperts on batch release to provide anoverview. He asked if the European reg-ulatory system would be reviewed at afuture forum, and suggested invitingsomeone from the EMEA secretariat.

Another participant said that it wouldhave helped those who were affected bythe shortage caused by Bayer problemsto hear from the FDA. He also askedwhat will be revisited at Seville. Dr.Giangrande replied that there is one



List of Participants

Nabil Ackad, Novo Nordisk Canada Inc., CanadaFereydoun Ala, National Blood Service, U.K.Tom Alloway, Canadian Hemophilia Society, CanadaPantep Angchaisuksiri, Hemophilia Society of Thailand, ThailandInger Antonsson, Biovitrum AB, SwedenNorhanim Asidin, Haemophilia Society of Malaysia, MalaysiaMary Bauman, Bayer, U.S.A.Alain Baumann, Baxter Bioscience, U.S.A.Wolfgang Biering, Octapharma Pharmazeutika, AustriaWalter Brulez, Biotest Pharma GmbH, GermanyJ. M. Bult, Plasma Protein Therapeutics Association, U.S.A.Manel Canivell, Grupo Grifols S.A., SpainSharon Caris, Haemophilia Foundation of Australia, AustraliaLarisa Cervenakova, The American Red Cross Holland Laboratory, U.S.A.Joy Charley, Belize Hemophilia Society, BelizeGordon Clarke, European Haemophilia Consortium, Northern IrelandSally O. Crudder, Centers for Disease Control and Prevention, U.S.A.Luis Cruz, Aventis Behring LLC, U.S.A.Francine Décary, Héma Québec, CanadaMario Donoso Scroppo, Ministry of Health, ChileJohn Edwards, Wyeth/Genetics Institute, U.S.A.Magdy El Ekiaby, Egyptian Society of Hemophilia, EgyptBruce Evatt, Centers for Disease Control and Prevention & World Federation of Hemophilia, U.S.A.Theo Evers, European Plasma Fractionation Association, the NetherlandsBruce Ewenstein, National Hemophilia Foundation, U.S.A.Armand Famiglietti, Alpha Therapeutic, U.S.A.Steve Farrell, Aventis Behring LLC, U.S.A.Albert Farrugia, Therapeutic Goods Administration and World Federation of Hemophilia, AustraliaDenis Flanaghan, Alpha Therapeutic Corporation, U.S.A.Neil Frick, National Hemophilia Foundation, U.S.A.Peter Ganz, Health Canada, Health Products and Food Branch, CanadaCesar Garrido, Associacion Venezolana para Hemofilia, VenezuelaPaul Giangrande, Oxford Haemophilia Centre & World Federation of Hemophilia, U.K.Marc Greenwood, Bio Products Laboratory, U.K.Stefano Guazzini, Kedrion, ItalyManfred Haase, Paul Ehrlich Institut and the European Agency for the Evaluation of Medicinal Products (EMEA), GermanyMathias Haun, Canadian Blood Services, CanadaCheryl Hayden, National Hemophilia Foundation, U.S.A.W. Keith Hoots, University of Texas Houston Health Science Center, U.S.A.Ching-Li Hu, Shanghai Second Medical University, ChinaHeather Hume, Canadian Blood Services, CanadaPeter Jones, World Federation of Hemophilia, U.K.Carol Kasper, Los Angeles Orthopaedic Hospital, U.S.A.Howard Kelly, Baxter, U.S.A.Timothy Keutzer, Wyeth/Genetics Institute, U.S.A.Stephen Kinsman, Magnus Consultants, CanadaJames Kreppner, Canadian Hemophilia Society, CanadaDaniel Lapointe, Canadian Hemophilia Society, CanadaKoon Hung Luke, Children's Hospital of Eastern Ontario, CanadaJane Martin, Bio Products Laboratory, U.K.



List of Participants continued...

Laurel Mc Donnell, NuFactor and FFF Enterprises, U.S.A.Rene McRogers, Bayer, U.S.A.Judi Miller, Octapharma Produtos Farmaceuticios, PortugalElizabeth Myles, World Federation of Hemophilia, CanadaAnthony Nagle, Bayer, U.S.A.Masako Nakamura, Wyeth/Genetics Institute, U.S.A.Maria Foshi, Nivia Unidade de Hemofilia - Hospital Brigadeiro, BrazilBrian O'Mahony, World Federation of Hemophilia, IrelandAna Padilla, World Health Organization, SwitzerlandDavid Page, Canadian Hemophilia Society & World Federation of Hemophilia, CanadaAndy Pickett, IPSEN Limited, U.K.Glenn Pierce, National Hemophilia Foundation, U.S.A.Dominique Pifat, BayerMan-Chiu Poon, Southern Alberta Hemophilia Clinic, CanadaPeter Pustoslemsek, Biotest Pharma GmbH, GermanyJ. Wesley Rees, Canadian Blood Services, CanadaBruce Ritchie, Association of Hemophilia Clinic Directors, CanadaLine Robillard, World Federation of Hemophilia, CanadaWolfgang Schramm, Ludwig-Maximilian University Hemophilia Centre, GermanySam Schulman, Karolinska Hospital & World Federation of Hemophilia, SwedenDorothy Scott, Food and Drug Administration, U.S.A.Claudio Siqueira, Biotest Pharma GmbH, GermanyMark Skinner, National Hemophilia Foundation, U.S.A.Terry Snape, Pharmaceutical Consultant, U.K.Alok Srivastava, Christian Medical College Hospital, IndiaJean St-Louis, Maisonneuve & Ste-Justine Hopitals, CanadaBob Summers, American Red Cross, U.S.A.Hideaki Suzuki, Ministry of Health, JapanSimon Taylor, The Haemophilia Society, U.K.Aliakbar Tchupan, Iranian Hemophilia Society, IranGeoffrey Thomas, Baxter Corporation, CanadaH. Marijkeala van den Berg, Van Creveld Clinic - National Hemophilia Center, GermanyAshok Verma, Hemophilia Federation (India) & WFH, IndiaPeter Vichi, IPSEN Inc., U.S.A.Jean-Marie Vlassembrouck, Baxter Bioscience, BelgiumFrantisek Vondryska, Czech Haemophilia Society, Czech RepublicChaim Waissman, ALEH - Israeli Hemophilia Organization, IsraelCharles Waller, Plasma Protein Therapeutics Association Europe, BelgiumXuefeng Wang, Shanghai Haematology Research Center, ChinaJosé Willemse, Netherlands Haemophilia Society, The NetherlandsJun Xu, Shanghai RAAS Blood Products Co. Ltd., ChinaKin Yeung, American Red Cross, U.S.A.Yuri Zhulyov, Russian Hemophilia Society, Russia

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