July 21, 2009 Transcript for the Meeting of the

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					             U.S. FOOD AND DRUG ADMINISTRATION




             BLOOD PRODUCTS ADVISORY COMMITTEE

                       July 21, 2009




          Hilton Washington DC North/Gaithersburg
                      620 Perry Parkway
                Gaithersburg, Maryland 20877




   “This transcript has not been edited or corrected, but
    appears as received from the commercial transcribing
service. Accordingly the Food and Drug Administration makes
            no representation as to its accuracy”




                      Proceedings by:
                  CASET Associates, Ltd.
                 Fairfax, Virginia 22030
                        703-266-8402
                        TABLE OF CONTENTS

                                                             Page

Opening Remarks, Statement of Conflicts of Interest            1

Recognition of Retiring Members                                2

Committee Updates:

Summary of the April 30-May 1, 2009 Meeting of the DHHS        3
Advisory Committee on Blood Safety and Availability
Richard Henry

Summary of the June 12, 2009 Meeting of the FDA                7
Transmissible Spongiform Encephalopathies
Advisory Committee – David Asher

2009 A/H1N1 Influenza Update
  Joseph Bresee                                               38
  Louis Katz                                                  48

Topic III: Informational Session: Hemovigilance

Pilot Hemovigilance Module of the National Health Care        59
Safety Network – William Bower

FDA's Sentinel Initiative and CBER's Analytic Epidemiology    69
Branch – Robert Wise
                                                                    1


               P R O C E E D I N G S          (9:00 a.m.)
           Agenda Item:   Opening Remarks, Statement of

Conflicts of Interest

           DR. SIEGAL:    Good morning.   I rarely have any

opening remarks of note, but today since it is my last

official meeting on this committee and my last meeting as

Chair, I just want to thank the FDA and especially Jay

Epstein and Jesse Goodman, but also Bill Freas and Dawn Jane

and Pearlie Muckleby for the wonderful opportunity I have had

to be a part of this committee and this process, and what a

tremendous honor it was to have done so.      So I want to thank

you all.

           On that note, I'll turn the meeting over to Bill.

           DR. FREAS:    Good morning.    I have a brief conflict

of interest statement announcement that pertains to today

only that I would like to read into the record.

           This brief announcement is an addition to the

conflict of interest statement read at the beginning of the

meeting on July 20 and will be part of the public record for

the Blood Products Advisory Committee meeting on July 21,

2009.   The committee will hear updates and informational

presentations on the April 30 and May 1 meeting of the DHS

Advisory Committee on Blood Safety and Availability.        The

June 12, 2009 meeting of the FDA Transmissible Spongiform

Encephalopathy Advisory Committee and an overview of the
                                                                  2


epidemiology and virology of the 2009 A/H1N1 influenza virus

and its impact on the U.S. blood system.     The committee will

also hear informational presentations on recent hemovigilance

efforts, including the pilot hemovigilance module in the

National Health Care Safety Network.

            These updates and presentations are not for

discussion by the committee members, and therefore the

committee members were not screened for financial conflicts

of interest relating to these presentations and informational

updates.    The conflict of interest statements will be

available for review at the registration table.

            Dr. Siegal, I'll turn it back over to you.
            Agenda Item:   Recognition of Retiring Members

            DR. SIEGAL:    The next item on the agenda is the

recognition of retiring members, I suppose.

            DR. FREAS:    Dr. Midthun, would you come and make

the presentations?   Dr. Midthun is our Acting Center

Director.

            DR. MIDTHUN:   Good morning.   We have many members

rotating off our Advisory Committee in September.     This will

probably be the last meeting where many will be in

attendance.   I know what a large amount of work this is to be

part of this committee.     People really spend many, many hours

and days working for us and contributing their expert advice,

and we very much appreciate it.     This was just a small token
                                                                  3


of our appreciation, but nonetheless it is very important to

us.

          I would like to start by presenting plaques to some

of our departing members.   If Dr. Ballow would please come up

so we can present him with his plaque.

          If Dr. Cryer would please come up next.

          If Dr. Kulkarni would please come up.

          Then last but certainly not least, Dr. Siegal, if

you would please come on up.   Dr. Siegal has been the Chair

of our Advisory Committee, and that really presents an added

burden, and we really wish to thank him for all his work.
          Agenda Item:   Committee Updates

          DR. SIEGAL:    Now it is time to get serious.   Let's

start with the committee updates.   The first update will be

provided by Richard Henry, Advisory Committee on Blood Safety

and Availability, summary of the April 30 to May 1, 2009

meeting of the DHHS Advisory Committee on Blood Safety and

Availability.
          Agenda Item:   Summary of the April 30-May 1, 2009

Meeting of the DHHS Advisory Committee on Blood Safety and

Availability

          DR. HENRY:    Good morning.   Thanks for having me.   I

am Rich Henry from HHS Secretary's office.    I will be

providing a brief summary of our May meeting of the Advisory

Committee on Blood Safety and Availability.
                                                                4


          Before the committee met, we set out some goals.

We wanted the committee to comment on the elements that would

characterize a more robust and transparent decision making

process for transfusion safety policy.   We also wanted the

committee to comment on whether use of formal tools of policy

analysis such as risk assessment and cost effectiveness or

cost utility modeling would be of value to enhance the

current decision making process, and how they might be

integrated into the current system.

          We asked specific questions of the committee.     What

are the advantages and disadvantages of comparative

effectiveness models?   What next steps if any does the

committee recommend to enhance the quality and transparency

of federal decision making for transfusion and

transplantation safety policy?

          The committee came back afterwards and sent several

messages to the Secretary.    Decisions regarding transfusion

and transplantation safety are often complex and require

consideration of multiple features, including scientific,

medical, economic, social and political aspects of the issue

in question.

          Medical and scientific considerations should be

paramount in guiding blood policy decisions on transfusion

and transplantation safety.   However, the state of knowledge

is often incomplete or imperfect.
                                                                5


          Two more statements to the Secretary.   Ultimately

safety and not economic considerations should be the primary

feature considered.   However, decisions should not be made in

an economic void.   Safety decisions should be made in an

ethical transparent manner with adequate input from all

involved stakeholders, including end users, the public and

expert resources from diverse backgrounds relevant to the

question at hand.

          After the statements to the Secretary, the Advisory

Committee made five specific recommendations.   The first

one's theme is stabilization of the role of HHS in the

decision process. The recommendation was, recognizing the

importance of stability in staff and funding for transfusion

safety within HHS, the committee recommends establishment of

a line item or a budget item in the Secretary's budget for

support of these activities.   Currently there is none.

          The second theme is access to critical public

health information.   Recognizing that a robust and sustained

biovigilance reporting network for monitoring transfusion and

transplantation safety is essential, the committee recommends

that the Department of Health and Human Services identify and

provide short term bridge funding to continue the necessary

pilot and recruitment phases of the National Biovigilance

Network with consideration of mandatory requirements in

participation and reporting.
                                                                6


          Further, to convene a group of stakeholders to

define the optimal long term funding model for national

biovigilance, including a blood, tissues and organs program

whose implementation the Secretary will insure.

          The third theme was prioritization of issues.

Whereas optimizing the safety of transfusion and

transplantation is a universally shared priority, policy

making without overt consideration of reimbursement and other

systemic implications may have adverse impacts on the

allocation of limited health resources and on patient health.

          To address this issue, the committee recommends

ongoing assessment of transfusion risk and prioritization of

threats and opportunities.

          The fourth theme was the alignment of funding.      The

implementation of blood safety initiatives requires funding

that currently is not linked with policy decisions.    This

disparity creates distortions to decision making, adverse

tradeoffs and possible delays of implementation of safety

measures within the blood system.

          The committee then recommends, when policy

decisions are reached, there must be linkage of funding to

insure system wide implementation of desired safety

enhancements.

          Transparency.   The committee recommends the

rationale for blood safety enhancements must be communicated
                                                                    7


to all stakeholders, including end users, the public and

treating physicians.      Where needed, adequate support should

be provided to meet educational needs of these stakeholders.

            The committee also recommends convening a workshop,

including requisite legal, ethical, economic and consumer

representative to explore public understanding and tolerance

of transfusion related risk and its relationship to

mechanisms of compensation for harm.

            Our next advisory committee will be on October 1

and 2.   By then we should have our new Advisory Committee

members seated.   There are approximately five seats that we

are trying to fill at the moment.       It will be held at the

university, the same place as last time, just north of here.

We do not have an agenda or a theme for the meeting yet, but

it will take place on October 1-2.

            Thank you.

            DR. SIEGAL:    Thank you.   Next we will hear from

David Asher from OBRR, FDA, a summary of the June 12, 2009

meeting of the Transmissible Spongiform Encephalopathies

Advisory Committee, TSEAC.
            Agenda Item:    Summary of the June 12, 2009 Meeting

of the FDA Transmissible Spongiform Encephalopathies Advisory

Committee

            DR. ASHER:    Thank you, Dr. Siegal.   On the 17th of

February the United Kingdom's Health Protection Agency
                                                               8


announced that evidence of infection with the agent causing

variant Creutzfeldt-Jakob disease, as evidenced by the

detection of abnormal prion protein in the spleen, had been

found postmortem in a person who had died with hemophilia.

The patient was over 70 years old and died of a condition

unrelated to variant CJD with no symptoms of that or any

other neurological condition prior to death.   The abnormal

protein was identified during a very extensive postmortem,

including more than 20 sections taken from the spleen.

          The conclusion was that what had until then been a

theoretical risk associated with a human plasma derived

coagulation factor must now be considered an actual risk, at

least to certain individuals.

          The Center for Biologics Evaluation and Research is

committed to re-evaluate the risk of spongiform

encephalopathies to the blood supply and supply of plasma

derivatives periodically when important new information

becomes available.   This finding appeared to us to constitute

such an event.   We have not had a meeting of the Spongiform

Encephalopathies Advisory Committee since December of 2006,

but we hurried to convene one on the 12th of June.   Two of

the members of today's committee were present.    What I am

going to present to you is largely my own impression of what

went on at that committee, and if they or the FDA staff have

something to add, I encourage them to do that.
                                                               9


           The overall trend for variant Creutzfeldt-Jakob

disease has been favorable for the last few years.   The

bovine spongiform encephalopathy accepted as the source of

food-borne variant Creutzfeldt-Jakob disease has been in

decline in Europe, although some uncertainties about bovine

spongiform encephalopathies remain, particularly some

countries that are believed to have been at risk for it have

not reported any cases, so we still consider it an infection

of worldwide significance.

           The trends for variant Creutzfeldt-Jakob disease

have also been encouraging.   Declining cases in the United

Kingdom, at least among persons with the prion protein

encoding gene, codon 129, which has been associated with all

clinical cases until recently, there has been a marked

decline.   I'll show you some of that information in a minute.

           However, last year a typical clinical case of

variant Creutzfeldt-Jakob disease was observed in a person

who was not homozygous for methionine at that locus.

Although the family declined to provide tissue either during

life or at autopsy, clinicians in the United Kingdom appeared

to consider that to be a bona fide variant Creutzfeldt-Jakob

disease, which creates increasing concern that there may be a

second wave of the disease among people of genotypes

previously spared.   There is some other information that

suggests that.
                                                               10


            Another concern has been the marked discrepancy in

estimates of the prevalence in the United Kingdom.   I will

show you some of the information that was presented at the

meeting and why that is important.

            There have been four transfusion transmitted

infections of variant Creutzfeldt-Jakob disease associated

with non-leuko-reduced red blood cell concentrates in the

United Kingdom, but there have been no new report of

transfusion transmitted vCJD since the winter of 2007, and

now this, the presumptive transfusion by a plasma derivative.

That is the reason for the meeting that we had on the 12th

of June.

            The morning was devoted to a decisional issue,

which was to critique the review of a modified FDA risk

assessment looking at the risk for plasma derived factor 8 in

the United States.   There were also a number of informational

issues.    We had reports of the BSC situation in the United

States, Canada and the European Union, plus three research

topics related to TSEs and blood safety, one a promising

monkey model infecting monkeys with BSE and vCJD agent and

finding infectivity in blood, important because it provides a

possible blood reference material that it appears we are not

going to get from human infection.   Efforts to develop

antemortem tests to identify infected people during the

incubation period of TSEs, the prospects at the moment seem
                                                               11


guarded, and problems in correlating abnormal prion proteins

with infectivity in blood and tissues, which has implications

for the future of antemortem testing.       I won't go over any

of those this morning. They are available in the transcript,

and there is some supporting material that is available

through the Web.

           Robert Will, founder of the United Kingdom CJD

Surveillance Unit, reviewed the vCJD situation in the United

Kingdom.   In the Transfusion Medicine Epidemiological Review

Alan Williams reviewed FDA's geographic deferral policy to

reduce the risk of transfusion transmitted variant and plasma

derivative transmitted variant Creutzfeldt-Jakob disease.

Dot Scott, the properties of TSE agents in blood and

approaches to estimating their clearance by plasma

processing.   Albrecht Groener, representing the Plasma

Protein Therapeutics Association, presented actual spiking

studies clearing TSE agents from various intermediates of

plasma derivatives.   Then the risk assessment itself and

modifications to it for plasma derivatives were presented by

Steve Anderson from our CBER Office of Biostatistics and

Epidemiology.

           In your package I have listed the agenda for

informational presentations, but time doesn't permit me to go

through those.   But I do want you to see the questions that

were posed to the TSE Advisory Committee.    The committee was
                                                              12


asked whether it agreed with updated and new inputs to the

FDA risk assessment model for U.S. licensed plasma derived

factor 8.   The updated inputs were a change in the estimated

prevalence of vCJD in the United Kingdom for one set of

scenarios; a change in the estimated time in which infections

had been acquired.    That was essentially a bookkeeping change

correcting an error from the original assessment from 2006.

Then the time during an incubation period when infectivity

might be present in blood.   We felt it was prudent to become

more conservative, and we changed the estimated time from 50

percent of the total incubation period to 75 percent, that

is, onset of agent in blood starting 25 percent of the way

into the infection.   Of course, we really don't know when

infectivity appears in blood.

            Then three new inputs.   The effect of the genotype

at codon 129 of the prion protein encoding gene on genetic

susceptibility to infection, now assumed to be universal, and

the proportions of persons in the United States with various

genotypes, because at least the incubation period and

possibly the attack rates will almost certainly be different.

Our assumption is that the genotype proportions in the U.S.

can be assumed to be more or less similar to those in the

United Kingdom, the distribution of incubation periods for

persons of different genotypes and the age of persons with

asymptomatic variant CJD infections.
                                                                 13


             The original second question was modified, because

after the information packet had been circulated, a risk

assessment appeared from the U.K. Health Protection Agency

suggesting that although the infection in their patient was

very unlikely to have resulted from food exposure, red cell

transfusions or endoscopy, but considering the probable high

prevalence or possible high prevalence of preclinical variant

CJD in U.K. plasma donors, the infection was at least as

likely to have resulted from treatments with non-vCJD

implicated factor 8, as from one batch of factor 8 to which a

known patient had contributed, which had originally been

thought to be the most likely source of the patient's

infection.

             So the question was reworded to read, despite the

finding of minimal additional risk in FDA's modified risk

assessment, should the recent report from the U.K. Health

Protection Agency attributing a case to treatment with U.K.

sourced factor 8 alter our interpretation of the risk for

U.S. licensed preparations of factor 8, and based on

available information should we recommend additional risk

reducing steps for plasma derivatives, recommend revised

warning labels, or recommend modifications to our public

communications.

             Bob Will summarized the 211 cases of variant CJD

observed so far worldwide.    That does not include
                                                              14


asymptomatic infections, 168 of them in the U.K., 43 outside

the U.K., and eight of them outside the U.K. in persons who

might have been infected in the U.K.   That would include

three of the four cases in North America, two cases in the

United States who were longtime U.K. residents.   We have had

one case in a recent arrival from Saudi Arabia, thought by

the CDC probably to have been infected through meat imported

into Saudi Arabia from the United Kingdom.

          BSE peaked in the United Kingdom in about 1991 and

variant CJD deaths in about 2000, the first transfusion

transmitted case December 2003, and the transfusion

transmitted case reported in February of this year.

          There has been an interesting comparison possible

of variant CJD with a look-back study conducted by the

American Red Cross over many years for other forms of CJD.

For variant CJD only 26 recipients of labile components have

survived for more than five years without coming down with

variant CJD, whereas the report of Cary Dorsey and Shim Yen

Zu, Roger Dodd and others suggest that similar recipients of

CJD implicated red blood cells and labile components in this

country, that of 144 persons to have lived five years, none

of them has come down with CJD.   So the risk is clearly an

order of magnitude at least less for sporadic CJD, non-

variant CJD.

          Incubation periods for food-borne CJD, minimum
                                                               15


possibly as short as four and a half years, usual 12 years.

Transfusion transmitted cases, incubation periods which can

be determined precisely, have ranged from six years and four

months to eight and a half years.   The one plasma derivative

associated case, if the implicated plasma derivative was

responsible, the incubation period was 11 years, and if it

was one of the other plasma derivatives, it could have been

considerably longer.

           But we can conclude that during the last three and

a half years of incubation period of variant CJD, some

clinically healthy donors who later developed variant CJD

were already infectious.   We don't know how much longer their

blood might be infectious, how much infectivity is present in

their blood.   We don't know if donors with other genotypes in

the prion protein gene are also infectious during the

clinical illness.   They have to be assumed to be, we believe,

how long they might be infectious and how much infectivity is

present.

           In 2006, Steve Anderson and colleagues developed a

risk model for looking at the theoretical risk of

transmissions attributable to plasma derivatives.   One of the

important things they did was to conduct a sensitivity

analysis in which all of the elements of risk are held

constant except for one.   They are varied stepwise one at a

time, and they look at the output to see which elements of
                                                                 16


risk are the most important.

           By far, the most important effect on risk came from

reductions in infectivity offered by the manufacturing

process.   More about that in a minute.   Also important was

the amount of factor 8 used by a person each year.    In third

place, the prevalence of variant CJD in the donor population.

Other features that can't be controlled are the efficiency

of infection by the intravenous route, because most of what

we know comes from animal studies using the intracerebral

route.   We know in most models, infection by the intravenous

route is less effective, and the quantity of infectivity in

blood, which we only know for animals.

           Let's look at prevalence.    A survey was conducted

looking at appendix and tonsil tissue in the United Kingdom

and published in 2002.   This is based on the observation that

at autopsy, abnormal PRP is found consistently in tonsils,

lymph nodes, appendix and spleen of persons dying with

variant Creutzfeldt-Jakob disease.     In the appendix,

fortuitously three patients have had appendectomies years

before they came down with variant CJD, and abnormal protein

was detectable at eight months and at two years, but not at

ten years before onset of illness, which was the basis for

this survey.

           When Hilton and colleagues looked at over 12 and a

half thousand appendices from persons without overt vCJD in
                                                                17


the United Kingdom, they found three positives.    Two of them

could have their genes sequenced, and they were both

homozygous for valine at that locus.

             A subsequent survey has used tonsillar tissue but a

less sensitive and all negative, with over 60,000 tonsils,

but considering the first survey, that could have been

expected.    The prion protein detection test used was less

sensitive.    So we are left with a possible prevalence of one

case out of 4,000-some in the United Kingdom, which

translates into over 160 cases per million.

             Another survey was based on modeling using the

number of cases of variant CJD and a number of assumptions to

generate a mathematical prediction of the number of

infections.    That was much less troubling.   The original

prediction was 1.8 cases per million population per year, but

it ignored the possibility that the two genotypes that had

not been observed in patients might also be infected.    When

they are included, the predicted prevalence comes up to

something more than four, four and a half cases per million

per year, much less than that predicted by the tissue survey.

             Now, reduction of infectivity by the production

process.    Albrecht Groener presented a very helpful summary

of spiking studies that had been assayed either for residual

infectivity, and by injection of animals, so-called

bioassays, which showed anywhere from a six to an eight log,
                                                                18


ten, decrease in infectivity, total decrease, or four to over

nine using immunochemical assays for abnormal prion protein.

          The conclusion of PPTA was that manufacturing

processes do remove prions, TSE agents, reducing factors of

at least four logs demonstrated for all U.S. licensed

products, but in addition PPTA members do not use either U.K.

or other European plasma to manufacture U.S. licensed plasma

derivatives.    Our U.S. recommended donor deferral policies

are in place.

          They concluded that the recent report regarding the

patient with hemophilia has no bearing on the safety profile

of products manufactured by their members.   The implicated

product 8Y that was put into the record by Dr. Groener was

sourced from U.K. plasma, and an analysis of that process by

the respected risk assessment and management consultant firm

Det Norske Veritas published in 2003 concluded that that

product was produced by a method with a clearance capacity

that was low, probably less than two logs.

          The decisional portion of the meeting concluded

with a risk assessment and its modifications presented by

Steve Anderson, who leads the risk assessment section of our

Office of Biostatistics and Epidemiology, with three of his

colleagues.    This was a modification of an assessment first

presented in 2006.   I have taken 16 slides from Steve's

presentation.   I don't have to show them all.   If Bill will
                                                              19


wave his hands whenever you have had enough of those, I can

fast forward to the end of my own presentation.

          For those of you who are not familiar with the

basic principles of these risk models, what they attempt to

do is to figure out all the things that have to happen for an

adverse event associated with a product to take place.

          So for example, for a TSE infection from a plasma

derivative, first the donor would have had to be exposed to

the BSE agent, gotten infected by the exposure.   Infectivity

would have to appear in the blood, and as well as being

present in blood it would have to be present in plasma.

Would have to enter the manufacturing process and then

survive the various steps, and these vary from company to

company, the various steps used to purify the plasma

derivative.

          Finally, from that the chance that a given dose of

the product was infected would have to be estimated, and then

based on how much of the product a patient used, you could

figure out what the possible risk was to that patient.

          In the case of variant Creutzfeldt-Jakob disease,

it is very important to estimate what the chances are that a

given plasma donor is incubating infection.   If you stop and

think about it, although we have had small numbers of BSE

cases detected in this country, so we are not absolutely free

of BSE, but it is a couple of orders of magnitude less than
                                                             20


what has been seen in the United Kingdom.   So we reckon that

most of our infected donors in all the patients with variant

Creutzfeldt-Jakob disease in this country recognized to date

will have been infected in another country, the United

Kingdom being the greatest source of exposure and the

greatest source of donors in this country who have been

exposed.

           So a risk model was set up with four modules.

Module two represents the possible prevalence of infection in

our donors, and that largely results from the prevalence

demonstrated in the United Kingdom, which is why those

discrepant estimates of the prevalence turn out to be so

important for doing the final risk assessment.

The next module would be the reduction in infectivity by

processing, and finally the utilization by a typical patient.

           To improve the information in each of those

modules, the risk assessing group proposed the three updated

inputs and the three new inputs that we have already listed.

           You can't estimate the risk for every single

patient, so what they attempted to do was to estimate the

risk for two groups of patients who are at the highest

exposure, having the highest potential exposure to factor 8.

Those would be those with severe hemophilia A and those with

severe von Willebrand disease.   What they attempted to

generate was the potential risk for one year of treatment,
                                                               21


that year being 2002, but they think that the results can be

extrapolated to other years.

           They used an analytical approach that set up actual

probabilities for each of the steps needed to produce an

infected product, usually presented as statistical

distributions.   I'll show you that in just a second.   They

used a probablistic computer   based model in which the

likelihood of each step is multiplied, and then a Monte Carlo

method in which the possible exposure values are selected at

random by the computer from the various risk elements.

           So for example, the example of a distribution.

This shows schematically how Monte Carlo analysis was used to

estimate the number of IV infectious doses that might be

present in a milliliter of donor plasma.

           We know that for hamsters with scrapie that most of

them have at least at the end of infection anywhere from

seven to ten lethal doses of scrapie agent per milliliter.     A

few of them have as little as two, and an occasional one has

as many as 27.   So what one does is to set up a triangular

distribution in which most of the numbers in the box from

which you are going to be pulling values are going to be near

ten.   A few of them will be as low as two, and a few of them

will be as high as 30.

           Now, obviously we don't know what the infectivity

is in human blood, but this is the only actual data available
                                                               22


to us at the moment.   I might have been more comfortable if

we added a safety factor and said that in vCJD it could go as

high as 1,000, but there is no actual data to suggest that

for any TSE.

          As for the percentage of infectious doses that

would enter the plasma, there is only one piece of

information generated by Bob Rohr, Lisa Gregory and

colleagues.    That showed approximately 60 percent of the

infectivity was in the plasma.   So instead of doing a

distribution there, they took a point estimate.   So all the

samples are going to show 58 percent of the infectivity going

into the plasma.   It is clear that in most models, it takes a

lot more infectivity, perhaps ten times more, to infect by

the intravenous route as by the intracerebral route.     But

some studies show that IV infectivity is almost equivalent to

intracerebral infectivity, and we don't know how to sort the

data so they took what is called a flat distribution.    So

those possibilities are presented as equally common in the

box containing those numbers.

          When you multiply those together you get not a

point estimate, but another distribution of the possible

intravenous infectivity in plasma, and that goes into the

model to generate the next step.

          I'm sorry I spent so much time with that, but it is

I think important in looking at these models to understand
                                                               23


what it is that the risk modelers, among whom I don't count

myself, are actually doing it.

          At any rate, they increased the estimated

prevalence of vCJD for the lower prevalence model.    They

decided to look at two different prevalence’s.   Since you

can't just stick two such discrepant estimated prevalence’s

into the same distribution, they decided to do two.   In one

of them they increased the possible prevalence from 1.8 to

four and a half million per million population, the other one

they left the same, adjusting just slightly for age and time

during incubation period when they might be infectious.      The

goal of that is to estimate the U.S. prevalence, which would

mean the prevalence among our donors.

          This summarizes what I just said.   In order to

estimate prevalence, we have to consider the effectiveness of

our U.S. donor deferral policy, summarized at the bottom of

this slide.   We assume from a study of donors regarding

history of IV risk that we eliminated about 92 percent of the

vCJD risk, the remaining risk being due both to people who

might have gotten infected during a short stay in the United

Kingdom or people who had made a mistake in giving histories.

          Here are the age distributions for the probable

incubation periods for the two kinds of genotypes.    This got

plugged into the model.   The goal is to estimate from these

numbers the percentage of vials that would contain a dose of
                                                                24


vCJD agent and the quantity of agent in each vial.

          There are problems with those, in that each plasm

product has a different purification step with different

potential clearance.    A lot of the data we have is not

specific to a product.   It is generic.   It is not available

for all purification steps in the studies, the spikes and the

agents used all vary.    But we believe that, as asserted by

PPTA, that probably all our U.S. licensed factor 8 is

manufactured by processes that provide at least a four log

clearance of spiked model infectivity and probably a good

deal more than that.

          So the risk assessors stratified the clearance to

two levels, one a lower level of four to six logs and then a

higher level of seven to nine logs, and from that they

calculated a number of the infectious doses per vial, the

quantity of agent in a vial, and the annual use of patients

to generate an annual potential dose of infectivity per

patient, and hence the risk.   They generated final estimates

as we have mentioned for severe hemophilia A and von

Willebrand, taking into account that people on prophylaxis

use more product than people who are treated just for bleeds

in surgery, and that people with factor 8 inhibitors or

immune tolerance also use more, in some of those data they

generated from the CDC survey.

          To make a long story short, there was -- only
                                                                25


looking at the worst-case scenario, which would be assuming

the higher prevalence of over 100 cases per million in the

U.K., a four to six log reduction.   In somebody with an

inhibitor and immune tolerance, the risk went up from one in

15,000 seen in the lower right to one in 12,000, which

considering all the uncertainties in this model is really a

negligible increase.

            The risk, assuming a lower prevalence of vCJD, but

going from 1.8 to 4.5, did increase to a modest but

significant extent.    Looking at the various scenarios based

on the higher risk, the risk went up anywhere from five times

to 18 times.   But as I will conclude in just a second, that

does not affect our final estimate of the real risk to

patients.

            Similar result were obtained looking at von

Willebrand's disease.   There is what I think is a typo in

your hand out that we will attempt to check with the

assessors and correct on the Web.

            At any rate, to conclude, the updates to the FDA

2009 model, accounting for susceptibility to the entire

population have not caused important changes between the risk

estimates for December 2006 and June of 2009.   The results

for the model indicate that estimates of vCJD risk had

increased using the lower prevalence by approximately five

fold to 18 fold.   However, using the higher prevalence, the
                                                                  26


risk estimates were similar to those in 2006, which means

that we have not substantially changed our interpretation of

the risk, because our 2006 estimate was based on the higher

prevalence, not the lower prevalence.

             Accordingly, now as in 2006, we are assuming that

the current risk from the use of U.S. licensed plasma derived

factor 8 may not be zero, it is not zero, but it is most

likely extremely small.

             I would add that this is a work in progress.   The

risk model is being shopped out to various professional risk

assessors.    Suggestions have been made concerning

improvements to the number of iterations, particularly when

risk is very small.    These models tend to be unstable.    The

way that that is addressed is by increasing greatly the

number of iterations that are examined.

             Finally, what did the committee tell us?   Question

one, did they agree with the update.    There was no

disagreement.    They made some minor suggestions, the risk

assessors did, to improve the model.

             Despite finding minimal additional risk, should the

recent report attributing case to treatment with U.K. sourced

plasma derived factor 8 alter our interpretation of the risk,

and the vote was unanimous, 15-no.    That is, they did not

recommend any changes to current policies.

             Should we recommend additional risk reducing steps
                                                                    27


for the manufacture of plasma derivatives?     Discussion

suggested that there didn't seem to be significant risk.

However, we should encourage those processes that clear more

spiked TSE agents as opposed to those that are closer to four

logs.

            Should we revise our warning labels for plasma

derivatives?   Yes, because variant CJD can no longer be

considered just a theoretical risk, and that should be

disclosed on the label.

            Should we modify our public communications about

the risk?   Of course, we can no longer say that no cases

attributable to a plasma derivative have been observed.        So

we should include a reference to the case reported in the

United Kingdom.

            With that, I have finished what I wanted to tell

you about our meeting on the 12th of June.     If there is time,

I'll be happy to answer questions.     Otherwise, during the

break.

            Thank you.

            DR. BALLOW:   With plasma derivatives, was there a

difference in risk with the nature of the plasma derivative?

Like, one patient had factor 8, so is the risk higher

potentially in the model with higher factor 8 than say IVIg,

because it is derived differently?

            DR. ASHER:    That wasn't addressed in this risk
                                                                28


assessment.    However, a pilot study suggests that factor 8

has the highest risk among the commonly used plasma

derivatives.   The risk is much less for -- and this again was

not generated by this assessment, but by spiking studies --

the risk is considerably less for IG IV and less than that

for albumin.

          DR. BALLOW:    So are you going to relabel these

plasma products?   Is that what I understand?

          DR. ASHER:    Am I going to?

          DR. BALLOW:    Well, is the FDA --

          DR. ASHER:    You know the way the FDA works.   These

things are going to be entered into discussions in the

agency.

          DR. BALLOW:    I think that would be an important

point, because I can just see my patients now going

absolutely crazy trying to make a decision.

          DR. ASHER:    Well, there hasn't been a case.   It is

true that the United Kingdom has warned recipients of at

least large amounts of IVIg that they may be at increased

risk for variant CJD.   But taking into account the source of

the plasma used to produce IG IV in this country and the more

robust methods used to produce it compared with factor 8,

remember, cryoprecipitate has almost no reduction in spike

TSE infectivity using a variety of models, has almost no

reduction at all, whereas that is not true for IG IV.     And
                                                                  29


there has been no case of CJD of any kind attributed to

exposure with IG IV.

            But is the risk zero?    You know if the vCJD agent

is in the donor, it will get into the blood, it will get into

the plasma used in the finished product, used to prepare the

finished product.   So the risk can't be zero if it is in the

raw material.   On the other hand, the demonstrated risk, and

I suspect the risk that would be predicted by a probablistic

risk assessment would be considerably smaller than that for

factor 8.

            DR. BALLOW:    I agree, you can never say never in

medicine.   The risk is never zero.    But I hope when there is

consideration for relabeling these plasma products, that

there is additional information that is added to the labeling

as you just described, to give some assurance to patients

that the risk is very, very low.

            DR. ASHER:    Well, it is a risk communication issue,

I agree completely.      I cannot tell you what the agency will

do, except that it will be given a lot of consideration, both

the real risk and the communication issue.

            DR. HOLLINGER:    David, how did they determine that

-- this is a 70-year-old hemophiliac, so presumably he was

not a severe hemophiliac.     Maybe he was, but I doubt it.   How

did they determine that this was not just an associated --

that it had no relationship to the plasma product that he
                                                               30


received, and that it just wasn't a confounding factor here.

           DR. ASHER:   There is a possibility, since everybody

in the United Kingdom, at least everybody who had beef had a

potential exposure, the number of cows at the peak of the

epidemic, infected cows, was very great in the United

Kingdom.

           However, there is a very striking age distribution

of patients.   This would only be the second person or third

person over the age of 70, and maybe only one clinical case,

almost all the cases are considerably younger, their late

teens, 20s and 30s, which is one of the differences in the

behavior of this infection.

           So looking at that, and looking at the overall rate

of exposure in the United Kingdom, of course the attack rate

is still relatively low for an agent with such wide exposure.

The probability of an infection coming from a food exposure

or from his transfusions with a number of units of red blood

cells from donors who did not come down with variant CJD or

previously endoscopy, that he had seemed to be much less than

the likelihood that he got it from a plasma derivative.

           One of the derivatives that he was treated with,

one of those derivatives came from a pool to which a known

infected donor came down later with variant CJD, had donated.

So taking that all together, doing an analysis of the

probabilities, the likelihood that he got it from food
                                                                 31


exposure is very small.

           This question will be answered unfortunately just

as it was for transfusion transmitted variant CJD, where the

same kind of argument was posed after the first patient came

down.   That is, if this bona fide, I think we can

unfortunately expect to see other patients.

           DR. HOLLINGER:    But as you know, when you have

somebody who has had a transfusion, everybody looks for

transmission.   The question is, are they equally looking for

the same kinds of things in people who have not received

transfusion, who are 70, or other things as well with the

same degree of enthusiasm.    As you said, they had to make 20

evaluations or at least 20 cuts looking at the tissue

extensively to find it.     So I just wonder if they are doing

the same thing.

           DR. ASHER:    At least at the time this case was

observed, the answer is no, for several reasons.     One, it may

not be as low as ours, but the general autopsy rate in the

United Kingdom for people dying of other things, the autopsy

rate is nowhere near as high as it is for people who are

under surveillance.     This person had received treatment with

a known implicated lot, which means he was under surveillance

by the U.K.   There are some 4,000 other people similarly

situated, not to mention the other patients with hemophilia

who did not receive such an implicated lot.
                                                                 32


           But the general population is not being followed

with such enthusiasm.     And certainly 23 sections of spleen

are not being stained by immunohistochemistry from the

average autopsy, which is one of the reasons why we don't

know with any certainty what the prevalence is in the United

Kingdom.

           DR. EPSTEIN:    I just wanted to come back to Dr.

Ballow's question about product labeling, to clarify the

situation and   what we might do.

           The current labeling for blood products identifies

a theoretical risk for a transfusion of CJD.    That would be

classic CJD.    That label was put in place a decade ago when

we were worried about CJD.

           What we have learned since is that if there is a

risk at all, it is more likely from vCJD, and we can no

longer say that it is theoretical.    So there is a need for a

technical correction to the label.

           However, our assessment of the magnitude of the

risk has not changed.     That is what makes any communication

about this tricky, because if we change labeling and draw

attention to risk, people will think there must be more risk.

The assessment of risk as you just heard has really not

changed, but we are uncomfortable leaving the labeling as it

is, because it is not telling the whole story, as it were.

           DR. KULKARNI:    I have two questions.   The first one
                                                               33


is, the vCJD was found out on postmortem.   Years ago at the

CDC when I was there, we tried to get all the hemophilia

treatment center segment, or get an autopsy on patients with

hemophilia who had died.

          Do you think the time has come to resurrect that

between CDC and FDA to make sure that all these patients --

the reason it never succeeded was because of the cost of

autopsies at various institutions, even though I think there

was a central place for these to be done.   That is question

number one.

          Question number two.   Recently I have been made

aware that there are patients on Coumadin for sustained

trauma who also receive PCCs, prothrombin complex

concentrate.   Even though the exposure is for a short time,

nonetheless it is an exposure.   So is there any plan to put

that in your model as to minimal exposure versus long time

cumulative exposures?

          DR. ASHER:    The CDC has an ongoing study of

hemophilia patients which now comprises 30,000 patients who

have died to miscellaneous causes.   I know that none of them

has had clinical evidence of Creutzfeldt-Jakob disease.

          As you know, one of the problems one has with

definitive diagnosis of some of these conditions in the

United States is the generally very poor autopsy rate for a

variety of social and economic reasons, that I'm sure you are
                                                               34


all aware of.

           The CDC does support to a certain extent through

the National Prion Disease Pathology Reference Center

performing autopsies on patients with suspected Creutzfeldt-

Jakob disease.   I can't tell you what their success rate is

in getting those autopsies done.

           As for doing ongoing surveillance of people exposed

to various products, particularly people who don't belong to

organizations that would cooperate with the CDC, not that

they are uncooperative, just that the organizations don't

exist, given the current staffing at the CDC, which amounts

to three and a half people for the whole national

surveillance system, I think it is relatively unlikely that

they be able to get that set up.

           What they do now, in addition to investigating

clusters and cases under the age of 55, feeling that they

would greatly enriched for variant Creutzfeldt-Jakob disease,

is to do a survey of annual death certificates, looking for

codes that might represent Creutzfeldt-Jakob disease, which

has been pretty good when they did more intensive targeted

surveys of neurologists, neurosurgeons, neuropathologists, et

cetera.   The death certificate survey is pretty good at

picking up diagnosed cases of CJD, but there is nothing that

would pick up a suspected infection in a person who had not

shown clinical evidence of CJD.    It is hard enough in people
                                                                 35


who have clinical illnesses that might be CJD.

            DR. TRUNKEY:    I think Dr. Hollinger's question was

very pertinent.   There was a recent article, I believe it was

in Nature, where some neuropathologists were intrigued by the

amyloid in kuru and the amyloid in dementia.     So they did

some studies and they showed indeed that the amyloid in

dementia was attached to a prion.     But I don't think all of

those were blood transmissions.

            DR. ASHER:    This is a current and very important

issue.    There are a number of amyloid forming diseases, but

only the spongiform encephalopathies have been convincingly

demonstrated to be experimentally transmitted.     That includes

Alzheimer's disease.      The amyloid proteins in general are

sticky.   They stick to themselves, they aggregate.    They

stick to other proteins, they stick to organelles.

            So although the phenomenon that you describe may be

important in the pathogenesis of this disease and in other

diseases, I don't want people coming away to think that there

is a great likelihood that some of these other amyloid

forming diseases represent transmissible infections that

endanger the blood supply, in the way that Creutzfeldt-Jakob

disease clearly does.

            DR. COLVIN:    Considering the spleen studies and the

tonsil studies, is there any convincing data about what the

incidence of disease might be after exposure to the prions,
                                                                 36


the vCJD prion that we are talking about?

            DR. ASHER:    Well, experimental animals, if you want

long enough, if the animal is infected, the animal becomes

ill.    Some of the incubation periods are so long that the

animals die of old age related illnesses.

            DR. COLVIN:   But that may be with much higher

exposure than what we might see in a case of --

            DR. ASHER:    No, I am talking about animals --

            DR. COLVIN:   I understand, but what I am saying is

that they may not be the proper model.     In that case you may

be overloading the system and they all may get it.     But at

lower doses it may not be the same.

            DR. ASHER:    How many infected people reach the end

of their lives without having clinical disease?     We don't

know.   As you point out, it would probably depend on the

infecting dose and the age at which someone is infected.       We

know that the incubation periods exceed 40 years and perhaps

50 years for kuru.   There has been a well documented case of

iatrogenic Creutzfeldt-Jakob disease from a single very short

five-day exposure in childhood to growth hormone with an

incubation period of 38 and a half years.     So we know these

incubation periods can run longer.     But if you have an

infection that has not become symptomatic and you are hit by

a bus, you will never have the disease diagnosed.

            DR. COLVIN:   But what I am thinking is, looking at
                                                                  37


the epidemiology, that doesn't seem to fit for vCJD.     The

peak in the cow population with eight years before the peak

in the human population would suggest that the incubation

period is not -- it may be longer, but it is around that.

           So it almost seems like there should be a way to

get an incidence of disease following exposure, based on how

many people we could find prions in in the U.K. versus how

many people actually get the disease.    But it seems like it

is hard to figure out what that number is, what the N is.

           My other question is, do we know the genotype of

the man with hemophilia in the U.K. who died?

           DR. ASHER:    They haven't published it.   They know

it, we don't.

           DR. COLVIN:   They haven't published that?    Finally,

in the U.S., moving back to the U.S. for a second, was there

any discussion about looking at any kind of surveillance of

the bovine herds in the U.S. at all, even if it is just

random?   It seems like at the moment, we are not testing at

all.

           DR. ASHER:    Oh, no, that is not so.   There are

limitations to the Department of Agriculture testing system.

This is not the time or the place to go into that, but there

was a period of enhanced surveillance that picked up three

cases in the United States.    Ongoing surveillance is

continuing.
                                                                  38


           Is there enough?    The Department of Agriculture

makes the point that we exceed the requirements of the World

Organization for Animal Health. I would be more comfortable

if we were doing more, because I can't believe that

considering that we had open borders, free trade with Canada

in live animals, meat products and rendered proteins until

May of 2003 and they have had 16 cases in a smaller cattle

herd, I can't believe that we have had only three cases.        But

I have no data to substantiate my concern.

           But there is ongoing surveillance in this country.

They screen by an ELISA test, and any repeat reactive by

ELISA they examined a section of the brain stem by

immunohistochemistry.     So there is a surveillance program.

Is it perfect?    No.
           Agenda Item:    2009 A/H1N1 Influenza Update

           DR. SIEGAL:    Excuse me, but I think we have to stop

discussion on this very interesting topic and proceed,

because we are now 20 minutes late.    So let's go on.    Thank

you, Dr. Asher.

           We now have an update on influenza A/H1N1 by Joe

Bresee, Chief of the Epidemiology and Prevention Branch,

Influenza Division, CDC, and Louis Katz of the Mississippi

Valley Regional Blood Center.

           DR. BRESEE:    Thank you so much.   My name is Joe

Bresee.   I am from the Influenza Division at CDC.    I am
                                                                39


mindful of the time.   What I am going to try to do is take my

15-minute talk and make it into a five-minute talk, to give

Dr. Louis Katz enough time.   We are split into two.   I meant

to give a talk on the update on H1, and then Dr. Katz is

meant to do the heavy lifting and give a talk on the meaning

of that for blood supply and blood safety.   So I am mindful

that that is probably the meat of this talk, and I will cut

mine and hope to make it a coherent story while I cut down.

          I'll make the slides available to you.    You don't

have a handout, but I'll make the slides available to you,

whoever wants it, by however you want it.    So don't fret if I

pass over slides very quickly.

          I am going to start here.    This is a slide I used

to show in a lot of my talks.    It goes to the fact that a lot

of our efforts have been towards avian flu and H5

preparedness and less so on swine preparedness.

          But just to show that we are not complete boneheads

at CDC, over the last five or six years we have actually paid

quite a bit of attention to swine influenza as well.      Two

things drove that.    First is the development of something

called the novel flu A case definition.   The CSTE, Council of

State and Territorial Epidemiologists, made it a nationally

notifiable disease.    So if a lab in the United States

identified an influenza A virus but couldn't type it as a

seasonal virus, they were obligated to notify CDC and send
                                                                40


the sample to CDC, so that we could characterize it.    It was

developed as an early warning or increased certainty that if

a pandemic developed in the United States or was introduced

in the United States from somewhere else, we would pick it up

more quickly.

           The second thing we did was the second bullet

there.   We equipped state labs, all state labs and public

health labs, with the capability of doing real time RT PCR

for influenza and influenza A, insuring again that if there

were influenza in the community, especially clusters, that

state health departments would pick it up fairly quickly, and

we wouldn't rely on the existing surveillance to pick it up.

           So those two efforts that started in 2005-2006 bore

fruit initially.   We picked up 12 cases among humans of swine

influenza virus infections between 2005 and 2009, about three

per year for the past three years, compared to about one per

three years for the ten years prior to that.

           What this bore fruit in as well clearly is that in

late March 2009, two kids in Southern California both

developed febrile respiratory illnesses.   They didn't have

any common exposures, didn't have any exposures to each

other, had no pig contact, had a fairly mild illness.     One

had a fever of 103, 104, but both recovered uneventfully.

           It was interesting, because both went to the

doctor, both got tested, which is very strange in the first
                                                              41


place, and both happened to be living in sites that CDC was

doing enhanced surveillance for flu.   That is the only reason

they got tested.   That sample was flu positive, was sent to a

reference lab, was A positive but negative for seasonal types

and negative for H5.   It was sent to CDC as planned.   We

looked at it and found it was a swine H1 virus.   That is not

too crazy, since we had seen significant viruses, but swine

viruses from Southern California was odd, because the pig

populations are so minor.   When we found out they didn't have

any pig exposures, it became more interesting.      Clearly

when we looked at the viruses more closely, the genes of the

viruses, they had a unique combination of genes from a

variety of sources, such that we hadn't seen either in humans

or in pigs in the U.S. or elsewhere.

          To make a long story very short, after the first

couple of cases, there were a couple of cases identified in

teenagers in Texas, then a couple in Ohio, then other states.

So from mid-April or so through now, there has been a rapid

increase in the numbers of states reporting positives, and

the number of positive tests reported.

          Last Friday, CDC reported 40,000 confirmed cases,

of which about 11 percent were hospitalized and 262 deaths.

All states and territories have reported at least one

confirmed case at this point.

          After we identified the first two cases in Southern
                                                                 42


California in mid-April, it wasn't a few more days before

Mexico identified their first cases.   They had outbreaks of

respiratory disease prior to that, but the first testing was

positive on April 23 in Canada and the U.S.

          Canada two days later had their first case.      The

first case outside of America was noted in Spain a couple of

days later, and finally with additional cases and spread in

both North America and Europe.    WHO raised the pandemic alert

to phase five, and went to phase six, which is a full

pandemic, on June 11.    So in three months from the first

identification of a couple of kids in Southern California,

almost every country in the world has been affected by the

pandemic so far.

          This is a map of WHO.    You will notice, dark colors

are where more cases occur, light colors or white is where no

cases have occurred, or light yellow in your screen.          It is

130, 135 countries that have reported cases so far.    The

places that haven't, Sub Saharan Africa, Central Asia that

you see there, are places for the most part that have poor

detection methods and likely won't detected cases very easily

without support.

          What do we know?    We know this, first.   This is

hospitalized patients.   You see on the left side of the

screen, most of the patients have respiratory symptoms, which

is not terribly surprising, consistent with flu.     On the
                                                               43


right side of the screen though, you see that a quarter of

the patients hospitalized presented with either vomiting or

diarrhea or vomiting and diarrhea.   This is interesting.   We

see this sometimes with kids and flu, not so much with

adults.   Gastrointestinal symptoms have been present in 25

percent in both kids and adults with this virus.

            The next three slides show the age distribution,

what we know now, and has some interesting features.   This is

an age distribution by rate in odd age groups, I admit, but

they are our surveillance age groups, so we are stuck with

them.    If you look at the graph, you see that there is a left

shift.    The highest rates of confirmed cases have occurred in

the young children and young adults, less so in older adults

and even less so in elderly, atypical with flu.    Typically we

have higher rates of illness in school age kids, but not to

this magnitude.   This is the age distribution that has been

seen almost anywhere or everywhere that they have looked.

            This is the same sort of age distribution, same age

groups, but now looking at hospitalized cases.    You see again

the shift to the left.   You see a little higher incidence of

hospitalizations among the elderly, but nothing like what we

see in seasonal flu, which I will show you in two seconds.

            This finally is deaths, again shifted a little bit

to the right.   Most of the deaths occur in young adults and

relatively few deaths in people over 65.
                                                               44


           If you look at the deaths, a couple of interesting

things.   The median age is higher in all cases, with mostly

adults, but 67 percent of the deaths and about the same

proportion of hospitalizations have a known underlying

disease that confers a known higher risk for severe flu.    So

these deaths are occurring less so in young previously

healthy adults, more so in adults with known risk factors for

severe influenza complications.

           I just for comparison show the age group of normal

seasonal flu from a study that Bill Thompson in our group did

a few years back.   It shows more the classic J-shaped curve,

where high rates in young kids, especially kids under two

years old, but the highest rates in people over 65.   These

bars are for hospitalizations.    The red line I just put on

there is for deaths, which shows even a more dramatic effect

of high rates in the elderly population, with 94 percent of

all deaths occur generally among people over 65.   So the age

distribution for this bug is very different than we would

normally see for flu.

           I mentioned that people with severe disease have

underlying risk factors.   These are what they are.   You won't

be able to see it from the back.   Just note that the light

blue is the prevalence of risk factors in H1 confirmed

hospitalizations.   The dark blue is the risk factors in the

population background. It just shows what you would expect,
                                                                 45


that people with chronic lung diseases like asthma or COPD,

people with diabetes, immunocompromising conditions,

pregnancy.    Known risk factors for seasonal influenza

complications also appear to be risk factors for complicated

courses of H1 disease.

             The last epidemiologic feature I want to highlight

is also a classic flu epidemiologic feature.      That is the

locality of infections geographically.      What we see with

seasonal flu is, you get spotty disease here and there

temporally in different places.       So far in the truncated

spring wave we have seen just that, with some states like

Texas and Wisconsin and Illinois with relatively intense

transmission of the virus, with some states less affected.

             If you look at this, this is the same data

presented slightly differently now for hospitalizations.        On

the far left you see the age distribution of hospitalizations

I just showed in the bigger graph.      But notice that some

states -- Illinois, Minnesota, New Jersey, New York, Utah,

New York City -- have exceedingly higher rates of

hospitalizations compared to the U.S. average, which of

course means that some states have much lower than the U.S.

average.   So in the spring wave we see what we do in an early

influenza season in the United States, some places more

affected than others.

             What is happening now?    This is a curve of sentinel
                                                               46


providers, which are a group of doctors that report to CDC

each week during the flu season and all year round now, the

total number of patients they see that week and the

proportion of those patients that have influenza-like

illness.

            You see the initial winter flu season.   If you look

in the middle of the graph, the red curve represents the

seasonal flu and green represents the previous two seasons'

curves.    You see the nice peak in seasonal influenza in March

and February, followed by our usual decline, and then a spike

with the emergence of novel or pandemic H1 disease, and now a

slightly -- if you look at the far right of the graph -- a

diminishing proportion in these clinics, hopefully meaning

that we are in for a slight lull before the fall increase.

You can look at that by region, and it is going down in

almost every region.

            These are our lab data.   I just want you for

instant pattern recognition to see two things.    First, the

emergence of H1 caused a big bump in lab detections that you

see on the right in the orange, but on the far right you see

the black line, which is the proportion that test positive

for flu going down in the last three weeks.    It looks like in

the last few weeks we are starting to see a decline in

overall circulation of this virus that we expected to see

some time ago, but may be finally seeing.    But still pockets
                                                              47


of disease that are fairly intense.

          Finally, my last virus slide is to remind you of

the fact that this virus continues to be sensitive to the

neuraminidase inhibitors, Oseltamivir and Zanamivir,

continues to be resistant to Amantadine, and those patterns

haven't changed appreciably.

          Summary.   Once this virus emerged in the human

population in North America, it spread very quickly, not to

all five states, but to all 50 states, globally it spread

just as quickly, and now is worldwide.   Some areas clearly

more affected than others.   We don't know what that means for

their risk in the fall.

          We expect continued summertime circulation of this

virus, especially in areas where people cluster, like camps.

We have seen that.   Elderly, seemingly relatively spared so

far, and there are probably immunologic reasons for that.

The virus, while we have seen a relatively mild pandemic so

far like seasonal flu, clearly capable of causing deaths and

hospitalizations, mostly in high risk populations, and the

sensitivity remains the same.

          What is next?    We expect it to persist.   We expect

a fall increase and a fall wave.   We don't know if this virus

will be the predominant virus or a seasonal virus will be

predominant this year.    Nancy Cox, my boss, always tells me,

if you have seen one flu year you have seen one flu year.     So
                                                                 48


I don't think we can predict that yet.     We know we will have

flu this year; we don't know what it will be.      We are looking

at the Southern Hemisphere to give us guidance on what will

happen, and we have learned some lessons from that, which I

am happy to share.      Vaccine development is on the way, and

surveillance is continuing.

            I'll turn it over.

            DR. SIEGAL:    Thank you very much.   Now Louis Katz,

someone familiar to us.

            DR. KATZ:    Thank you for the invitation.   Some

might say a bad penny, Fred.

            I am the Chair of the AABB's Interorganizational

Task Force on Pandemic Influenza and the Blood Supply.      We

were tasked three years ago to produce some documents for the

blood community that would allow them to get started on

pandemic planning and to update them as necessary as new

developments occurred.

            We have produced a background paper, an issues

paper and a checklist for blood organizations to use in

planning.   We are getting ready this winter to revise them

based on what we saw happening predominantly with H1N1, and

encouraging blood centers to do tabletop exercises and

whatnot, when we got the ultimate tabletop exercise starting

in late April.

            What I want to do today is primarily describe to
                                                                49


you the state of planning in the blood community.    I think it

is reasonably reassuring.

             First of all, would you stop calling it swine flu?

I am from Iowa, substantially more pigs than people, and

when the price of hogs does this, we can't get potholes

repaired on the lane to my farm.    So I would like people to

refer to it by the proper name, pandemic H1N1/2009.

             This is probably the important slide, the status of

planning.    This looks at 47 ABC centers that responded to a

survey in the 36 American Red Cross blood regions.    What you

can see is that 36 of the ABC centers and all of the American

Red Cross regions in fact had plans in place before H1N1.       So

that left 11 of the independent centers without plans before

H1N1, nothing like an event to focus the mind, ten now are

planning and one is not, and    I am not going to tell you

which one, so don't ask.

             The question on our survey was, did you activate

your plan.    The numbers are a little odd here, but the

American Red Cross activated in their field units, divisions,

regions and labs.    It is more of a unitary organization

obviously than the 74 or 75 independent blood centers that

make up America's blood centers network.    So they did

activate their plan.    Fifty-five percent of the ABC centers

did, 32 did not.    The nothing to activate is that group of

centers, some of which had no plan, some of which started to
                                                               50


develop a plan on the fly and whatnot.   So most of the blood

supply was operating under their pandemic plan by the middle

of May, in fact.

          The extent of activation I have shown you here.      We

asked about communication plans, supply chain assessment,

hand hygiene programs, command and control, assessment of

inventories and use of personal protective equivalent, staff

antiviral provision, the implementation of PPE plans, staff

screening at entry points and antiviral use.   These are

percents that show you the extent of activation.

          I don't think there is anything terribly surprising

here. The use of PPE was not robust.   I think that since we

asked people to be well on the day of donation, we asked our

staff to stay home when they are sick, that should not be

surprising.   Very little strong consideration of antiviral

use, although some places have in fact investigated

purchasing stockpiles of Oseltamivir for this indication.

Pretty straightforward stuff.       The ARC as you can see

activated command and control, their communication plan, did

their supply chain assessment and hygiene.   They actually

issued PPE not for their donor room staffs, but for some

clinical individuals that go into hospitals to do things like

therapeutic aphoresis.

          Impact on collections was in fact not much.      Of the

centers that responded, 75 percent said there was none.     Then
                                                               51


you can see a smattering of blood drives that were lost

across the country.

           My center represents one percent of the blood

supply.   We run on an average day between ten and 15 mobiles.

So if you multiply it out, you can see that the number of

lost drives is quite small.   A substantial number of these

were very early on in the activity, in Texas primarily, where

there was a fair amount of interest early in May.   Those lost

collections were recovered very quickly.

           This is the percent of respondents to the survey

with unchanged inventories.   What we are seeing here is,

everybody's inventories remained pretty stable.   In fact,

those with changed inventories, some had more inventory and

some had less.   It has until the last three weeks been an

extraordinarily robust blood supply for a number of months,

and no real impact of our dry run during May and June on any

of the important components that we supply.

           I have emphasized repeatedly to the membership of

AABB and the people that are using our materials that I think

one of the most important things to do very early on is to be

in contact with public health agencies in order to be sure

that we are on the radar of public health when the discussion

of social distancing, cancelling events and that sort of

thing starts.    We want to be able to get messaging from

public health that says, except for blood drives.   If you are
                                                                 52


well, you can go to the blood center.    They are going to

design their drives and design their donation sites to

protect you maximally, and a well-oiled health care system

requires blood on the shelves at all times.

          Maybe not as much as I would like, but half or more

of the centers had talked to somebody at the state, local or

county level.    When we drilled down on what the contacts were

about, it was basically about being sure that the public

understands when people start talking about social

distancing, that there is an exception built in for continued

blood donation.

          Communication initiatives.     I think you will see, I

have a couple of slides of lessons learned after action,

everybody has identified consistently that appropriate

communication was a critical issue.

          These are the sorts of things that were done.

Overwhelmingly, contact with staff to let them know what we

think the impact of H1N1 is and should be, reminding them to

wash their hands, reminding them not to come to work when

they are sick, those sorts of things.    Much less

communication to other stakeholders.     I think over on the

right, not a whole lot of communication with hospitals, which

may be worrisome and may be a lesson learned as we start to

see things take off once again in the fall.

          PPE.    Not a lot of issues.   A lot of us have been
                                                                53


very concerned that donors pushing on staff or staff pushing

on donors to use N95 masks or this or that or the other thing

would distract us from more important tasks, like making sure

sick people don't come to drives, sick employees don't come

to drives, and people do hand hygiene.   Really very minimal.

I know that in some of the independent centers in Texas, the

staff wanted masks to protect themselves from well donors.

As I said, I'm sure that provision of respirators or surgical

masks to clinical personnel going to hospitals to do

therapeutic procedures is probably more widespread than it

looks here, but not really a lot.   I think this shows a

rational response.

            We asked about, would you give donor flu shots if

you had the vaccine.   My center has been running a pilot

project for two years now, providing influenza immunization

to committed donors to see how many we could get to take them

and what the effect would be on donation behavior during the

winter.    It has been a very successful program. The donors

love it.

            More interestingly, if we can get pandemic vaccine

from HHS and CDC through the state health departments, would

blood centers be willing to immunize their critical donors.

So that would be platelet phoresis donors, maybe O negative

and O positive red blood cell donors, not as robust a

positive response as I would have hoped.   Most centers
                                                               54


already provide to their staff, 90 percent, as you can see at

the bottom.   But if we could get pandemic vaccine, 43 percent

that would be willing to administer it to critical donors.

That depends on getting donors designated as a high priority

group.   We are working through Jerry Homberg in HHS to try

and get them added to the tier one of potential vaccine

recipients.   A lot of liability concern in provision of

vaccine, so I think that is really what is driving a somewhat

negative response.

           Do your hospitals have transfusion triage plans for

blood transfusions in a pandemic.   This is my personal

nightmare, that I am going to be sitting in my regional blood

center, situated in the middle of a region that goes 350

miles north to south and 300 miles east to west, telling

hospitals who gets the red cell and who doesn't get the red

cell, when I am not at the bedside assessing the need of the

patient.   I really don't want to be in that position.    I want

my hospitals to have triage plans that will drive blood usage

down commensurate with whatever impact on supply there is

from lack of donors or lack of staff in the blood center.

           At this point, I am not so happy to say that it

looks like there is a very substantial plurality of hospitals

that have not done any planning.    The ARC believes most of

their hospitals have plans.   I would like to see those plans

in writing.   When I asked my 55 hospitals for their plans, I
                                                                55


got none.   I got none.

            So this is a major concern that I think we are

going to be pushing on.   In fact, I am now working on

adapting a shortage plan that was written by Canadian Blood

Services in Quebec to the blood system to the United States

to use as a template to provide through AABB to the hospitals

that might get them moving along on how they are going to

ration blood in the event of a severe pandemic.

            H1N1 doesn't look so bad so far, and I don't think

it is going to be a risk this fall.    But we are getting a

nice dry run here, and I think it is important to think ahead

on this one.

            No supply chain or transportation disruptions

recognized by anybody with the events of this spring.       Very,

very few donors calling either the independent centers or the

American Red Cross with post donation information, which has

implications for our ability to study some things that FDA is

interested in like viremia in asymptomatic donors who

subsequently develop confirmed infection.    We are not

developing a robust inventory of those plasmas.

            I think at last check, Sue Stramer, who is going to

hold these for study, had about ten units.    These aren't all

necessarily from individuals with confirmed infection with

the pandemic strain.   Very little staff illness.

            Lessons learned.   The task force is a pretty
                                                                 56


diverse group of people from public health and the blood

community and the regulators and whatnot.   I think we all

agree that emphasizing command and control very early on is

critical.   So it is a little disturbing that more of the

centers in the independent system did not activate their

command and control system.   You can always turn it off, and

it is only a meeting a week or a meeting every morning or a

meeting every other day to be sure everybody is touching the

right bases.

            Planning is more important than the plan.   Most of

the plans that were written were written for something that

looked more like 1918.   This wasn't, and so things that were

written in the plan and triggers that were written in the

plan prove not to be necessary.   But the point is that if you

had done the planning it was very easy to back off.     If you

had done nothing, you wind up like at least one center that

we are aware of in the Southwest United States that was

caught short of platelets because they had not made contact

with public health early on and didn't have a plan for

bringing in their donors early.   They spent about a weekend

short before public health messaging by their county health

department beefed up the supply quite nicely.

            The messaging needs to be simple.   Keep it simple,

stupid.   This is very, very important.   I think everybody

that is talking about this blood community and public health
                                                              57


from top to bottom has realized that extraordinarily simple

messaging is very important to allay angst.

          There was a fair amount of confusing messaging

coming from a variety of public health agencies, particularly

leading up to the pandemic declaration by WHO.   I think that

was an issue.   WHO phases were totally geographical incidence

sorts of triggers.    CDC has a pandemic severity rating, so at

one point WHO giving one set of messages, and the CDC says,

that is all fine, WHO says that, but it is not changing what

we are doing.   The reason it wasn't changing what they are

doing is because they were in part triggering activities

based on perceived severity where WHO wasn't.    It was

confusing in some venues.

          There were varying donor deferrals around the

world, mainly having to do with what donors could you defer

without actually deferring any material number of donors.     So

when Australia deferred donors who had travelled to Mexico,

it didn't cost them much, whereas if you are in South Texas

or California and you wanted to do that at the end of April

and May, it would have had a material severe effect on the

blood supply.

          This is a key point.    State plans for deployment in

SNS are individual.   My main center is on the Mississippi

River in Iowa with access to the Strategic National

Stockpile, through the state of Iowa, and our county health
                                                                 58


department, whereas half of our region is in Illinois and

part of it is in Missouri and part of it is in Minnesota.

All the plans for distribution are state level, so they are

all different.    The centers that cross state lines will have

to pay attention to varying availability of items from the

Strategic National Stockpile under that circumstance.

             We need to clarify PPE provisions, need to decide

what to do.    To that end, the Society of Hospital

Epidemiology of America has recently released a position

paper advocating in most settings to use surgical masks, not

N95's, which should make our lives easier.

             We need to coordinate supply chain information so

there aren't 140 blood regions all calling the same day

asking about bag supply or calling Abbott and asking about

test supply.    We are working on that through an e-mail system

into the group purchasing functions of the major blood

organizations to allow the companies to report to essentially

one place.

             That is all I have.

             DR. SIEGAL:   Thank you, Louis.   We are now running

about 25 minutes late.     I would like to know whether there is

anyone in the audience who is planning on speaking at the

open public hearing, because it will affect our planning.      If

there is no one interested in speaking at the open public

hearing, then why don't we do our 15-minute break now and
                                                                  59


reassemble at five of.      That will give us enough time to get

through the remainder of the program, if people keep on time.

             Thank you very much.   We are in break.

             (Brief recess.)
             Agenda Item:   Topic III: Informational Session:

Hemovigilance

             DR. SIEGAL:    Topic III is another informational

session on hemovigilance.      The first speaker will be William

Bower from CDC, talking about the pilot hemovigilance model

of the National Health Care Safety Network.      Dr. Bower, are

you there?
             Agenda Item:   Pilot Hemovigilance Module of the

National Health Care Safety Network

             CAPT. BOWER:   Yes, right here, thank you.   Thank

you, everyone.    As was stated, I am Captain William Bower

from the Office of Blood, Organ and Other Tissue Safety in

the Division of Health Care Quality Promotions, CDC.

             I am going to talk a little bit about our pilot for

hemovigilance, but first a little background on

hemovigilance.    In 2005 the Patient Safety and Quality

Improvement Act was enacted.      Its goal was to improve patient

safety by encouraging voluntary and confidential reporting of

events that adversely affect patients.

             Following that, in 2006 Health and Human Services

Advisory Committee on Blood Safety and Availability
                                                               60


recommended to the Secretary that a national system for

surveillance of recipient outcomes of blood and blood

products was needed.   Also in 2006, AABB formed an

interorganizational task force on biovigilance to develop a

comprehensive and integrated national patient safety program

to collect, analyze and report on outcomes of collection and

transfusion of blood combinations and derivatives.

            CDC has also had a long term goal to improve

surveillance for adverse events associated with biological

products.   Given that, the task force recommended CDC and

AABB form a public-private partnership to develop

hemovigilance surveillance using the National Health Care

Safety Network, or NHSN.

            I just wanted to say that the hemovigilance is just

part of a larger planned U.S. biovigilance network

collaborative.   Number one, the blood recipients which I am

going to talk about here is just one component, but there is

also a blood donor, which would be the safety of blood

donors, which is being worked on by HHS and AABB as well.

There is also a tissue and organ transplantation surveillance

system for diseases transmitted through tissue and organ.

That is being worked on by UNOS, or United Network for Organ

Sharing, and CDC.   There has been a prototype devised for

that.   Then for cellular therapies, the fourth component of

the biovigilance network, is to be developed.
                                                              61


            As I stated, this hemovigilance is going to be

added on to the current National Health Care Safety Network,

which I will talk a little bit about.   It is an Internet-

based surveillance system that monitors patient and health

care personnel safety.   It integrates surveillance systems

previously managed separately in the Division of Health Care

Quality and Promotion, which were the national nosocomial

infections surveillance system, Dallas' Surveillance Network

and national surveillance system for health care workers,

which some of you all may be familiar with or have used in

the past.

            The purpose of NHSN was to collect data from a

sample of U.S. health care facilities to permit valid

estimations of the magnitude of adverse events among patients

and health care personnel, including health care associated

infections and blood and body fluid exposures for health care

personnel, and to be able to analyze and report collected

data to permit recognition of trends.

            Additional purposes of NHSN were to provide

facilities with data that can be used for inter-facility

comparison and local quality improvement activities, to

assist facilities in developing surveillance and analyze

methods that permit timely recognition of patient and health

care personnel safety problems, and prompt intervention with

appropriate measures, and to conduct collaborative research
                                                                62


studies with members.

           NHSN would allow us to determine if there is a

problem.   This would be done through NHSN by comparing of

local rates to benchmarks.   Then if there appeared to be a

problem, then groups could get together at the local level or

at higher levels to determine what the problem was.     Then

they could figure out some intervention that could be

determined to effect a change.   Then NHSN could help to

determine if the changes worked by monitoring progression

towards improvement based on a change in the rates that we

might have seen here.

           As I said before, the biovigilance component is

going to be placed within the NHSN structure.   You see the

components.   They are already in existence, the patient

safety component, health care personnel safety component, and

a research and development component.   You can see that the

biovigilance component will sit here.   Currently the

biovigilance module is the only portion of this component,

and we are thinking about trying to add some of those other

components into the biovigilance component.

           The purpose of the hemovigilance component were

very similar to the purposes that I previously described for

NHSN, but they are specific to blood and blood products.       It

can provide the number of adverse reactions and errors and

accidents associated with blood transfusions that can be used
                                                                63


in aggregate data for comparative purposes.    Another

component would be that it could enhance at the individual

reporting level to encourage hospitals to report to FDA.

             The methodology for the hemovigilance component.

It will have both active and passive surveillance.    The

active component, that there be people in the transfusion

services that are going to be trained on the hemovigilance

module.   They are going to know the case definitions, and

they will actively look for cases.    But there would also be a

passive component, because there will be people in the

hospital that aren't trained in the surveillance system, but

they are going to be aware that if there is a reaction

potentially related to blood products, that they should

report it.

             It is going to be patient based, in that when a

reaction occurs there will be a review of the patient's

chart, and the health care providers will be contacted about

the reaction.    It is a perspective rather than retrospective

that is going to occur while the patients are in the

hospital, and their charts will be reviewed.    Comprehensive,

in that it will include all transfusions that occur in the

hospital and not just a subset of a certain group of patients

or a certain unit in the hospital.         Its intent is to

provide incident rates for adverse reactions or incident

errors.   Initially these would be crude rates that will be
                                                               64


compared from one hospital to another, but as we get more

information, as more data comes in we can do more risk

analysis and incidence rates.

           There is a protocol or user's manual for

hemovigilance.   It provides rules for the hemovigilance

surveillance so that participating facilities collect

information the same way.   It includes case definitions,

other definitions, code lists that will be used in the

hemovigilance module.   This content was based on input from

AABB and CDC working group members, approved by the working

group, CDC and other agencies at HHS.   When a facility agrees

to participate, they agree to follow the protocol when they

sign on.

           Again, the protocol will provide the rules for the

surveillance and the reference material.   There are case

definition criteria for adverse reactions for blood

transfusions that are based on the International Society of

Blood Transfusion definitions, and they will provide

definitions for definitive, probable and possible cases, a

severity grade, and relation of the transfusion to the event.

It is reporting definitions also.   The codes are derived

from MERS TM (?) and the test systems that were used at

Columbia University and in the Canadian system respectively.

           The forms that are going to be used in the

hemovigilance module are listed here.   There is an annual
                                                               65


surveillance survey which gives us information about the

facilities that are participating, a monthly reporting plan

for the hemovigilance component.   The monthly reporting plan

is always the same.   The reporting plan differs for other

components in the NHSN, but as I said, for hemovigilance it

will be the same.

          There is a monthly reporting denominators

basically, the number of units and what type are transfused

each month, and then forms for adverse reactions and

incidents, which I will go over in a little more detail.

          You can see there is the top part of the form for

adverse reactions.    Each month each participating facility

will enter each transfusion associated adverse reaction,

which is defined as an undesirable response or effect in a

patient temporarily associated with the administration of

blood or blood products.   This is based on the case

definition criteria that I described before that is part of

the protocol.   It will also list the severity grade that goes

from grade one of no severity, where there is limited

clinical harm, all the way to grade four which would be

death, and the relationship of the transfusion to the event.

Also, information on components and unit details.

          Here is a list of the adverse reactions that we

have definitions for that are provided in the protocol.

There are 12 that we have, from allergic reactions all the
                                                                66


way through infections.   There is a category for others that

they can specify in the text field if it doesn't meet any of

these.   Then there is a final category for a reaction where

there was unknown pathophysiology involved with the reaction.

           Here is the incidence form.    Each month the

facilities will report each incident associated with blood

products, which is defined as an accident or error that could

lead to an adverse outcome affecting the safety, efficiency

or quality of blood products, or the safety of the blood

product recipient.

           All incidents will be included from product check-

in to product administration, and they will be collected on

the date in time and how and where the report was discovered,

the occurrence, the date and time when it occurred, the

incident results, the product action, and also it will be

linked to any adverse reaction that may have occurred based

on this incident by the patient ID.

           Here is an example.   As I said it is from product

check-in to delivery.    There are several steps that an

incident can occur in.    This is just an example where the

blood drawn for typing and cross match.    Here is all the

potential incidents that can occur with the code that goes

with each one of those incidents.

           Another important component of the data collection

is the reporting requirements.   As part of this there should
                                                                67


be immediate reporting of complications that may be related

to blood donor or to the manufacture of the blood component

to the collection facility, and also reports of suspected

transfusions related to fatalities directly to the FDA.

          Now I just wanted to go over a little bit of the

pilot so far.   We have nine pilot sites.   They range in size

anywhere from approximately 100 beds to greater than 1,000.

They are pediatric as well as adult facilities, and

university as well as community based hospitals.

          Enrollment began May 7, planned for the pilot for

six months.   Then after we have looked at the pilot data and

made any changes that may need to be, there will be

enrollment from all facilities that wish to participate

starting in January 2010.    There are efforts underway to

develop methods for electronic submission of data.    We have

contacted vendors to discuss this. As I said, this will allow

for transfer of data to FDA so that the participating

facilities won't have to double enter data.

          Here, as of June 24, you can see that we have nine

sites enrolled.   Seven have completed the enrollment process

and five have completed their annual survey, and five have

also completed their monthly reporting plans.    Only two have

entered their monthly denominators for the number of blood

products that they have transfused each month.   Four have

entered adverse reactions.
                                                                68


           Three of them went back all the way to January

2009.   After the pilot process is over and we start enrolling

facilities, the calendar year that they enroll in, they will

be allowed to go back to the beginning of the year to enter

data if they wish.   You can see here that as part of the

pilot, three chose to go and enter data starting from January

1, and two decided to just enter data from the time that they

enrolled in May 2009.     As of June 24, as I said, there has

been a total of 224 adverse events entered into the system,

and that is adverse reactions and incidents.     I don't know

the exact number of adverse reactions and incidents, but it

is about a tenfold difference, with the incidents being

tenfold higher than the number of adverse reactions.

           If you want more information on the hemovigilance

module, the website is there that you can go and get more

information.   If you have any questions or comments, the e-

mail address there you can send a query to.

           Thank you.

           DR. SIEGAL:    Thank you very much.   We will now

proceed to the last discussion.    This will be FDA's Sentinel

Initiative and CBER's Analytic Epidemiology Branch, Robert P.

Wise, M.D. of FDA.


           Agenda Item:    FDA's Sentinel Initiative and CBER's

Analytic Epidemiology Branch
                                                              69


          DR. WISE:   Good morning.   I am happy to be here

this morning to discuss the sentinel initiative and a similar

set of activities in our new Analytic Epidemiology Branch at

CBER. What I would like to discuss is some background on

medical product safety surveillance in general, and then

specifically the Sentinel Initiative and the Analytic

Epidemiology Branch's similar work.

          This entire group in the audience is probably fully

familiar, but just to set the stage, the evaluation of safety

throughout a medical product's life cycle, whether it is a

drug or a biological or medical device or something else,

really begins with preclinical work in animals, and then in

phase I studies for looking at safety, but of course only in

small numbers of patients.   In phase II we have an

opportunity to discover somewhat less frequent adverse

events, but still only things that are relatively common.

Then in phase III trials, for some products we may have only

some dozen or a few dozen patients exposed to a new product.

In other kinds of phase III trials we could have hundreds or

thousands of patients exposed.   The level of information that

we can learn about the safety of a new product in a phase III

trial depends a great deal on the size of that population.

          Even for a vaccine product, however, with as many

as tens of thousands of exposed patients in a phase III

trial, we aren't usually going to have the power to find, to
                                                                70


reliably detect the least frequent and rare suspected or

actual side effects.   In other words, diseases or symptoms or

signs or syndromes that may emerge in these treated or

exposed patients which are subsequent to the exposure and

potentially are side effects.    At this stage, of course, if

there are very few observations of such events, it may remain

inconclusive as to whether they are actually due to the

exposure during that clinical trial.

           Then approval occurs for many products.   After

approval, orders of magnitude more patients typically become

exposed to these new products.   It is therefore during the

spontaneous reporting, the passive safety surveillance from

the anecdotal case reports that patients and physicians and

sometimes parents or neighbors or pharmacists or others

submit to the FDA or to the AERS and VAERS program for

vaccine products.   It is true that in passive safety

surveillance we often do learn again about tentative or

definite side effects that may be due to these products, but

occurring at much lower rates than were possible to detect

before approval.

           So that is the overall picture.   Safety is our

theme.   When we identify a concern, a definite or possible

suspected side effect, then we typically try to think about

how we can manage that risk, even though the risk may be as

yet an uncertain risk.
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           The most common consequence of recognition of a new

risk is probably addition of a few words or a term to the

package insert.   In some situations, other kinds of risk

management interventions, particularly in the communication

domain, come into play.

           The Food and Drug Administration's Amendment Act of

September 2007 brought new authorities and roles,

responsibilities and activities, to the FDA in the safety

surveillance theme.   The FDAAA requires postmarketing studies

and clinical trials to assess a serious risk or a signal of a

serious risk.   That is not quite accurately stated.   It gives

the FDA the authority to require a postmarketing study and so

on.   It gives us the authority, the power now to require

sponsors to make safety labeling changes, where in the past

this kind of revision of a package insert was a negotiation.

           It gives the FDA the power, now the authority, to

require sponsors to develop and comply with risk evaluation

and mitigation strategies, REMs.   We are now able to develop

validated methods to establish a postmarketing risk

identification and analysis system to link and analyze safety

data from multiple sources, with goals of including an

aggregate -- this is from the FDAAA language -- at least 25

million individuals by July a year from now, and at least

four times that many two years later.

           The Sentinel Initiative and to a lesser extent the
                                                              72


Analytic Epidemiology Branch that I will be discussing today,

really illustrates the operationalization of this kind of

activity, to get access to information from large numbers of

patients in HMO or medical claims or other health information

systems, in order to allow us to systematically evaluate

hypothesized risks.   We look first at the Sentinel

Initiative.

          I think there is a graphic I may have taken out,

but in general the spontaneous reports often present the

hypothesis.   We have got a small number of reports of a

particular type of possible side effect reported anecdotally

after licensure, or there may be inconclusive information

from before licensure, and using these large data sets we can

sometimes go out and systematically evaluate the hypothesis

of a relationship between that product and that disease,

syndrome or whatever.

          An overview of the Sentinel project.   Approximately

a year ago the Sentinel Initiative began to coalesce and take

real substance, so I am very happy to describe it now.     It is

the development of an active electronic safety monitoring

system to strengthen our ability to monitor the safety after

licensure for these medical products.   It is going to

augment, not replace, our passive safety surveillance and

other systems.   It will enable the FDA to get access to data

from these HMO or other computerized health systems through
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partnership relationships with insurance companies, health

maintenance organizations or other owners of electronic

health data.

          The data will remain within the owner's control.

The data will not be delivered, the primary data about these

patients will not be delivered to the FDA.   The data holders

will be able to run queries that we request or potentially

other parties may request, and the data holders can decline

to run a query.

          What the data holders will deliver to the Sentinel

project or to the requester at FDA or elsewhere would only be

the results for our review, the result tables, the derivative

tabulations.   All of this work would follow strict privacy

and security safeguards.

          How does the Sentinel Initiative complement what we

are already doing?   Well, safety issues can be identified and

evaluated in near real time.   The H1N1 vaccine products that

will be rolled out this fall are going to be illustrating

that sort of approach, but it is not blood related.   The

Sentinel is going to expand capacity for evaluating safety

issues, by giving improved access to data on subgroups of

population and other kinds of special populations.    We are

going to have improved precision of risk estimates due to the

expanded number of populations available for study.   In

general, active surveillance we believe is going to help us
                                                               74


to identify an increased risk of a common side effect such as

a heart attack or a fracture that health care providers might

not otherwise suspect to be due to a medical product.

           If you think about it, the submission of an adverse

event report to VAERS, the MedWatch system or other

spontaneous passive safety systems, that submission currently

depends on the clinical suspicion or recognition of

unexpectedness on the part of the physician or of the patient

or parent, or whichever party it may be.   Using systematic

data sets like HMOs, we can go into the proactive signal

recognition mode, as we use for example in acute safety

studies in phase IV immediately after licensure of a new

product.   We can dredge the data intentionally to look for

diagnoses that are occurring more frequently, for example,

within one month after exposure to a new product, than during

the three months period previous to that exposure in that

patient.

           There are a variety of designs available for this

kind of analysis -- case control, cohort mode, patient self

controlled -- there are a variety of techniques, but the

bottom line is that you are to look systematically and

potentially detect increases in risk that might not have

triggered clinical suspicion because the adverse event itself

is common and therefore not unexpected.

           Work in progress within the Sentinel Initiative
                                                                 75


includes an initial report that was issued in May a year ago.

There is a long term project concept, and we are just moving

in evolutionary stages.    We are currently trying to work out

the nitty-gritty, the how and what of what the Sentinel is

going to be.    Using a broad public forum and collaborations,

the FDA is delineating possible governance structures and

functions.    We are developing mechanisms for sharing ongoing

related activities, scientific and methodologic projects, and

we are identifying the steps that are necessary or going to

be necessary to insure the strict privacy and security

safeguards.

             The infrastructure is based in the Commissioner's

office, the Office of Critical Path Programs.    A senior

management team has representatives from each center plus the

Office of the Commissioner for Informatics, Privacy and

Planning.    The senior management team insures the involvement

of the appropriate representatives and subject matter experts

or SME's, an acronym we love to hate at FDA.    Between the SMT

and the SME's we provide project briefings and updates to the

FDA centers and offices and occasionally an advisory

committee.    We assist in prioritizing requirements and system

functions, and we insure that the Initiative is carried out

responsibly and in a timely fashion.

             The Sentinel Methods Working Group has agency

epidemiologists from the Office of Critical Path Programs and
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for the medical products centers.   It provides expertise to

assist in developing scientific and technical aspects.     It

contributes experience from activities in the centers to

inform the Sentinel Initiative and CBER's analytical

epidemiology material that I will be describing in a moment

as a strong example of that kind of activity from CBER, that

is helping the larger Sentinel Initiative folks understand

what is feasible and what we have learned from previous

experience.   The members can function as agency

representatives to Sentinel related activities conducted by

outside organizations.

          Between March and October last year there were

multiple stakeholder meetings.   Some of you may have

participated.   In December there was a public workshop.   In

May of this year we had a joint Sentinel rounds to provide an

overview of the Sentinel for the FDA community, and we had

presentations of contract deliverables by four of the initial

eight contractors.

          In June 2009 there was an internal FDA Sentinel

Summit to begin discussions on how FDA will identify and

prioritize the medical product adverse event pairs that could

potentially be studied in pilot projects and eventually more

systematically and efficiently within the Sentinel

Initiative.

          Each medical product center has internal processes
                                                                77


already for evaluating postmarketing safety issues that are

going to have to interface with the Sentinel system for

inputs and outputs, for queries and for results.

            There is a Federal Partners Working Group that

shares information and discusses issues related to

complementary efforts being carried out by the various

agencies within the federal government.   I won't read all of

these participant acronyms, but ask me if you are not

familiar with any of them.   You can see the broad range, from

the Consumer Product Safety Commission, completely non-

medical public health agency, I guess it is the Department of

Commerce, isn't it?   And of course FDA, NIH and others.

            Collaborations with CMS, the Centers for Medicare

and Medicaid Services, are in progress, the Department of

Defense and the Veterans Health Administration.    Several

ongoing projects within the medical product centers are

evaluating potential mortality adverse event signals and

developing active surveillance and statistical methodologies.

            The SafeRx program you may hear about in other

contexts.   This is a collaboration with CMS to develop new or

real time active surveillance methods using Medicare data.

            A variety of contracts have been let for looking at

possible database models, identifying methods to recognize

safety signals, examining the timeliness of medical uptake of

new products, figuring out governance and operational
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structural alternatives, evaluating potential data sources

for the Sentinel.   This is a project that CBER has

particularly led to find potential data sources for tissue

and blood -- I'm sorry, it is the second number five on

there; the pragmatic data contact is the one that we have

been primarily involved in.   The Booz Allen is the more

general for drugs and devices in general.    Number seven is

also device specific.

          That second number five with the pragmatic is the

one where we are looking to learn more about what kinds of

data may be available in fewer than ten potential vendors of

or sources for data on blood and tissue safety questions.

Then there is a contract on the engagement of patients and

consumers to make sure that privacy is maintained.

          There is an updated website that you can look at.

I'm sorry for the long name at the bottom, but if you just

think FDA's Sentinel Initiative and put that into Google, it

will probably pop right up.   If you just put FDA Sentinel

into Google, it is probably sufficient.

          We are increasing communication.    There is a video

that explains the Sentinel Initiative.    We have some

collaboration and interfacing with the Observational Medical

Outcomes Partnership, which is a somewhat analogous effort to

experiment and develop appraisals of the value of feasibility

and utility of observational data for identification and
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evaluation of safety risks and benefits of prescription

drugs.   The OMOP is primarily drug oriented, not

biologically, and yet a lot of the information and methods

that are developed there should have direct application for

us.

           The eHealth Initiative is another partner.    It is

testing and analyzing the value and utility of using

electronic health information to detect and evaluate drug

safety signals with a variety of data, again including

clinical information as well as claims or claims plus

laboratory data.

           The eHealth Initiative collaboration is exploring

opportunities to use clinical information in these electronic

databases in two large health information exchanges to

identify and assess known drug adverse event associations

such as Warfarin and bleeding or statins and liver toxicity.

           The next steps planned are going to be contracts

again.   One will be called the Mini Sentinel.   An RFI for the

Mini Sentinel has been posted.   The synopsis was posted, and

the solicitation just went out about a month ago.

           The Mini Sentinel will develop an actual

distributed data model, a pilot project to assess three

health care data environments with a variety of attributes

for conducting these analyses.   It will involve the

development of a planning board, a safety science committee
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for operational purposes, an infrastructure for communication

and queries, will identify and prioritize potential medical

product event pairs for evaluation, and will engage

appropriate legal counsel to identify and address data

privacy and security issues.

             It will include evaluation of epidemiologic and

statistical techniques to find signals and to refine our

understanding of them and then finally to test hypotheses,

and will synthesize lessons learned, looking at what the

obstacles may be, how we can prioritize those obstacles and

overcome them, and what kinds of costs and time are needed to

remove each of these obstacles.

             I would like to turn now to the CBER Analytic

Epidemiology Branch.    This is an organization that does not

exist.   Legally, creation of a new branch requires some steps

that are beyond my pay grade, but we are working as though it

did exist.    It is sort of an acting Epi Analytic Branch at

this stage.    Formally you might not see it on the Web, on a

diagram of the FDA's structure because it is not yet

completely official.

             The challenges that the AEB is tackling reflect the

diversity of biological products that require a variety of

surveillance and safety assurance strategies.    AEB recognizes

like the Sentinel an open-ended and real time safety

surveillance need to detect unexpected or potential risks at
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the earliest possible phase.   And of course the FDAAA and

funding technologies offer a lot of promise, we believe, for

development of more robust capabilities to recognize signals

earlier and evaluate them systematically and more

efficiently.

          The group that is now assembled as the Analytic

Epidemiology Branch has been working with CMS data,

particularly Medicare data, for some years.    CMS data have

about 45 million people enrolled.   The great majority are

elderly folks, but there are also about seven million other

people with end stage renal disease or disabilities that

qualify them for Medicare assistance.

          Individual health utilization data are available

for 85 to 90 percent of the population covered by Medicare,

which is enrolled in fee for service Medicare.   A

prescription drug benefit began in 2006 which in turn is

going to make a new body of data available to us that we are

hoping to work with very shortly.

          I mentioned the SafeRx collaboration previously.

          This graph illustrates the potential power of the

enormous numbers in the CMS data.   What we are looking at

here are cellulitis and urinary tract infection diagnoses

among hospitalizations less than a month after or within the

first month after pneumococcal vaccinations.

          The urinary tract infections are the control group.
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You can see that that they are pretty constant across this

period with minor fluctuations, but cellulitis diagnoses in

hospitalized patients jumps abruptly after the pneumococcal

vaccination.   Those might not be real patients with true

bacterial cellulitis.   They might simply be exuberant local

hypersensitivity reactions, but the physician or somebody

thought, we need to rule out cellulitis or prescribe an

antibiotic in case it is cellulitis.   Our point here is

simply that we have an opportunity with this very large data

set, although it is cumbersome to work with, to recognize a

potential anomaly, a potential pattern that may indicate a

safety risk for a new product.

          Transfusion related acute lung injury in elderly

Medicare claims data, elderly patients, inpatient only, 2007

is a project that we have launched.    Our reason was that

there are no previously published population-based TRALI

studies focusing on the elderly and our AEB staff have

previously used CMS data to describe blood product

utilization in this age group from the same data, and so we

felt that this study would be feasible.

          We are simply trying to assess the occurrence, the

incidence rate, of this diagnosis in recent CMS data.    The

methods are using ICD-9 diagnosis and procedure codes.     It is

an exploratory analysis of TRALI rates among the inpatients

who have a recorded transfusion.
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          We anticipate the ability to break the data down by

type of product received and to compare the TRALI diagnosis

rates to others, in terms of variables like the demographic

characteristics of the transfusion recipients, what clinical

diagnoses and procedures these patients had, hopefully

identify predisposing factors related to the transfusion or

related to the recipient or the donor.   We would like to

identify possible preventive modalities or options or

potential preventive strategies, and describe the extent of

severity and mortality from TRALI.

          We think it will be necessary to get to the actual

medical records to be able to reliably distinguish between a

diagnosis that is rule-out in the mind of the person who put

it down, and a real occurrence of TRALI.   Purposes for

looking at the medical records include the validation of the

diagnosis and further assessment of potential risk factors,

pulling out additional information about the transfusion and

about the donor, and about recipient diagnoses, and so on.

          In 2008 AEB issued an RFP, a Request for Proposal,

whose primary goal was to get us access to data systems

analogous to the Sentinel effort, in order to be able to

respond to urgent public safety concerns about the use of

vaccines, blood or tissue products.   We wanted to conduct

collaborative mission oriented pharmacoepidemiologic research

to test hypotheses on these kinds of products and their
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safety and effectiveness, including those coming out of the

spontaneous reporting to AERS and VAERS.   We want to develop

improved methods for rapid detection of adverse events from

biological products in large U.S. population-based data

sources.

           One example, this first task order under this

contract, is looking at idiopathic thrombocytopenic purpura

after vaccination.   We are working with the Harvard Pilgrim

Group and the HMO Research Network based on the Northeast,

where the weather is sometimes better in the summer, but this

year I think we have got better weather.

           There is a known association between measles,

mumps, rubella vaccination and ITP.   It is not clear yet

whether that association pertains to other vaccine products

as well.   We do have spontaneous reports of ITP after other

vaccinations, including live virus varicella vaccine and

others, but also reports in some numbers after vaccinations

that do not include live virus products.

           The objective in this study is to assess the

incidence and risk factors for ITP after routinely

administered vaccines and to enlarge and refine the research

network infrastructure for future studies to allow for more

efficient and timely monitoring of suspected side effects,

including near real time monitoring, that we will be

attempting for the H1N1 products.
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           Other kinds of AEB collaborations are looking at

herpes zoster vaccine safety in the Medicare population, MMR

and anaphylaxis in the Defense Department setting, rapid

cycle evaluations in CDC's Vaccine Safety Datalink, H1N1

vaccine safety evaluation in the military.    The European

Medicines Evaluation Agency and Canadian regulatory

authorities and Health Canada are working with us to

coordinate pharmacovigilance activities and information

exchanges, and we expect along with CDC to collaborate with

WHO and others to foster the technical capacity for H1N1

vaccine adverse event investigations.

           That is as far as I am going to go today, but I'll

be happy to take any questions before I disappear, if that is

appropriate, Chair.

           DR. SIEGAL:    I was just going to invite Mark Ballow

to ask his question.     Thank you very much, Dr. Wise.

           DR. BALLOW:    That was very impressive.   It looks

like this initiative dovetails very nicely with the

Administration's goal to incorporate electronic health

records into physician offices.    Have you been working with

the EHR companies to develop modules that might help your

efforts?

           DR. WISE:   I probably shouldn't answer that

question, because my 23-year-old son has just taken a job

with one of the important software manufacturers, Epic
                                                                86


Systems, outside of Madison, Wisconsin.    But seriously, he

doesn't have anything to do with this work so far.

           We are not working directly right now with the

electronic medical record vendors.    We are working actively

with standards development organizations.    Particularly -- I

was talking with Bill earlier -- the HL7 organization, one of

its standards is called ICSR, individual case safety report.

An ICSR can be a submission to AERs, a suspected side

effect.   So we are trying at FDA as part of the eGov

initiative to use and work through and help develop standards

of various sorts that can help us do our mission more

effectively.   The ICSR format is one of those.

           The vendors can then recognize that there is a

stable pattern, a stable file format or message format or

whatever that has been formulated and identified, and then

they can build linkages from their internal data architecture

to that output file and facilitate more efficient

communication.

           That sort of answers the question?

           DR. BALLOW:   Yes.   I was just going to say, because

physicians of their time commitments, sometimes things fall

through the cracks as far as reporting these adverse events,

particularly in practice who you report it to.    You have to

go through a government agency, I guess, the CDC and FDA, who

may watch other mechanisms.
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            But it just occurs that the electronic health

record would be a mechanism whereby, if physicians are

already incorporating that into their everyday practice, that

might be one mechanism to more easily -- for the physician to

have access to this kind of Sentinel program.

            DR. BIANCO:   Dr. Wise, we heard your program.   We

heard Dr. Bower's before.    How do both connect?   We didn't

hear you mention hemovigilance, for instance.

            DR. WISE:   I had to pay him a lot of money to ask

that question.   Thanks for a very good question.   We haven't

discussed today the enhancement, the successor to the AERS

program.   I have mentioned AERS, the Adverse Event Reporting

System.    The successor program is going to be called MedWatch

Plus.   It is going to be a unified portal or mechanism, web

based, for people to submit adverse event reports for any

kind of medical product regulated by FDA.    Actually beyond

medical, also foods, for example, veterinary products.

            Now, the MedWatch system according to current plans

is going to be able to receive an adverse event submission

from an individual person.    So what we are envisioning, still

somewhat tentative, details are still being worked out, is

that the AEBB, NHSN, CDC hemovigilance adverse event report

or incident report, after submission to the NHSN, will then

present the reporter with an option:    would you also like to

submit this report to the FDA.    Or there will be some
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equivalent like a check box that the reporter can choose to

click on if he or she wishes.

             The key distinction is that the NHSN reporting is

anonymous.    Once the data are received by CDC, there is

absolutely strict protection of the reporter's identity and

certainly the patient's identity.    The internal CDC folks

will know the characteristics of that hospital and what

hospital it came from, so that they can extrapolate these

data to national patterns by hospital size and geographic

region and so on.    But the identity of the reporter and of

the patient can't be transmitted outside of that internal

NHSN technical office.

             Therefore, voluntary submission also through FDA

would allow the next screen to pop up, which is the MedWatch

Plus portal screen, pre-populated with all of the details

that have already been filled in.    If this information is

coming from an electronic record, now the patient's identity

and age and birth date and place of residence can be pulled

in electronically.    But any missing data can then be filled

in by the reporter and with another click the record comes

over to the FDA.    This allows the FDA to follow up when and

where it is necessary to ask further questions or to

recognize that there is a cluster forming of some sort in a

certain area.    So we think that this partnership is going to

be very productive.
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           Thanks again for asking that question.    I would

have paid you a lot of money if I had thought of it in

advance.

           DR. SIEGAL:   Are there any more questions?      In that

case, thank you very much.

           DR. WISE:    You're very welcome.   Thank you.

           DR. SIEGAL:   Is there any further discussion or any

new issues that the members of the committee wish to raise

before we adjourn?

           DR. FREAS:    I would just like to remind the

committee members that we have a two-day meeting scheduled

for November 16-17, which will be our next BPAC meeting.

           DR. SIEGAL:   Thank you all for attending and

participating.   This meeting is adjourned.

           (Whereupon, the meeting was adjourned at 12:00

p.m.)